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C H A P T E R

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Primary Immunodeficiency Diseases


Francisco A. Bonilla and Luigi D. Notarangelo

CHAPTER OUTLINE
COMBINED IMMUNODEFICIENCIES IMMUNE DYSREGULATION POLYENDOCRINOPATHY
Severe Combined Immunodeficiency ENTEROPATHY X-LINKED SYNDROME
Other Forms of Combined Immunodeficiency with DEFECTS OF IL-2–MEDIATED SIGNALING
Variable Presentation AUTOIMMUNE LYMPHOPROLIFERATIVE
MANAGEMENT OF COMBINED IMMUNODEFICIENCY SYNDROME
Diagnostic Approach ITCH DEFICIENCY
Hematopoietic Stem Cell Transplantation IMMUNODEFICIENCIES WITH IMPAIRED CELL-
Gene Therapy MEDIATED CYTOTOXICITY
IMMUNODEFICIENCY SYNDROMES FAMILIAL HEMOPHAGOCYTIC
LYMPHOHISTIOCYTOSIS
Wiskott-Aldrich Syndrome
X-LINKED LYMPHOPROLIFERATIVE DISEASE
WAS Protein-interacting Protein Deficiency
IL-2 INDUCIBLE TYROSINE KINASE DEFICIENCY
DiGeorge Syndrome
CD27 DEFICIENCY
FOXN1 Deficiency
CD16 DEFICIENCY
Ataxia-Telangiectasia
IMMUNODEFICIENCIES WITH SELECTIVE
OTHER IMMUNODEFICIENCIES ASSOCIATED WITH PREDISPOSITION TO PATHOGENS
DEFECTIVE MECHANISMS OF DNA REPAIR
Mendelian Susceptibility to Mycobacterial
IMMUNODEFICIENCIES WITH CHROMOSOMAL Diseases
INSTABILITY
Epidermodysplasia Verruciformis
PIGMENTARY DILUTION DISORDERS
Herpes Simplex Encephalitis
MUTATIONS OF THE NUCLEAR FACTOR κ-B
PATHWAY Susceptibility to Trypanosomiasis
DEFECTS OF TOLL-LIKE RECEPTOR SIGNALING HUMORAL IMMUNODEFICIENCY
THE SYNDROME OF WARTS, The Agammaglobulinemias
HYPOGAMMAGLOBULINEMIA, INFECTIONS, AND Other Predominantly Antibody Deficiency
MYELOKATHEXIS Syndromes
HYPERIMMUNOGLOBULIN E SYNDROME CAUSED Management of Humoral Immunodeficiency
BY STAT3 MUTATIONS COMPLEMENT DEFICIENCIES
AUTOSOMAL RECESSIVE HYPER- Deficiency of Classical Complement Pathway
IMMUNOGLOBULIN E SYNDROME CAUSED BY Components
TYK2 MUTATIONS Deficiency of Alternative Complement Pathway
CHRONIC MUCOCUTANEOUS CANDIDIASIS Components
IMMUNODEFICIENCIES WITH SKELETAL Deficiency of Lectin Pathway Complement
ABNORMALITIES Components
IMMUNODEFICIENCIES ASSOCIATED WITH Deficiency of Terminal Complement Components
DISORDERS OF FOLATE AND COBALAMIN Deficiency of Complement Regulatory Factors
METABOLISM Diagnosis and Management of Complement
GATA2 DEFICIENCY Disorders
IMMUNODEFICIENCIES WITH IMMUNE
DYSREGULATION
AUTOIMMUNE POLYENDOCRINOPATHY-
CANDIDIASIS-ECTODERMAL DYSTROPHY
SYNDROME

886

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24  Primary Immunodeficiency Diseases 887

Immune compromise arises either as a heritable genetic TABLE 24-1  Internet Sites with Information
defect (primary immune deficiency diseases, PIDDs) or as Relevant to Primary Immunodeficiency Diseases
a consequence of another pathologic process such as
infection, malignancy, malnourishment, or iatrogenic URL (http://+) Name/Description
immunosuppression (secondary immune deficiencies).
bioinf.uta.fi/idr/Immunology ImmunoDeficiency Resource,
Immune dysfunction in patients with PIDDs is most often .shtml University of Tampere,
manifested as recurrent and chronic infections; however, Finland
malignancy and autoimmunity are common and may be
www.aaaai.org American Academy of Allergy,
prominent in some disorders. In many cases, symptoms Asthma, and Immunology
and signs of immunodeficiency develop soon after birth
or early in childhood. However, in some forms of PIDD www.esid.org European Society for
Immunodeficiencies
clinical onset may be delayed into late childhood, adoles-
cence, or adulthood. Even though many patients with www.immunodeficiencysearch Searchable database, clinical
severe immunodeficiency suffer dramatic morbidity and .com algorithms, laboratory
resources
mortality in infancy and early childhood, the majority of
patients with immunodeficiency have milder forms that www.info4pi.org Primary Immunodeficiency
Resource Center (sponsored
permit survival into adulthood, but often with reduced by the Jeffrey Modell
longevity because of infection, autoimmune disease, Foundation)
malignancy, or constitutional debility. Health-related
www.ipidnet.org Immune Phenotyping in
quality of life is significantly impaired in individuals with Primary Immunodeficiency
PIDDs.1,2
PIDDs may be classified with respect to the specific www.ipopi.org International Patient
Organization for Primary
immune effector mechanisms disrupted.3,4 In broadest Immunodeficiencies
terms, one may distinguish: (a) disorders that affect both
cellular and humoral components of specific immunity www.jmfworld.org Jeffrey Modell Foundation
(connects directly to Primary
(combined immunodeficiencies); (b) defects of antibody Immunodeficiency Resource
production (antibody deficiency syndromes): (c) disorders Center)
of innate immunity (phagocytic cell defects, disorders of
www.primaryimmune.org Immune Deficiency Foundation
Toll-like receptor (TLR) signaling, complement deficien-
cies). Moreover, some forms of PIDD are characterized www.usidnet.org US Immunodeficiency Network
by prominent immune dysregulation. Finally, in some (USIDNET)
cases impairment of immune function is part of a broader
spectrum of symptoms (syndromic immunodeficiency).
Discussed here are a broad range of PIDDs arising from
aberrant development and function of T and B cells, are normally nonpathogenic, such as Pneumocystis jir-
disorders with immune dysregulation, immunodeficiency oveci. Even attenuated vaccine organisms such as oral
syndromes, and complement deficiencies. Phagocytic dis- polio vaccine virus, rotavirus vaccine, varicella vaccine,
orders are the subject of Chapter 22. Table 24-1 lists and bacille Calmette-Guérin (BCG) can cause severe or
several Internet sites with information relevant to primary fatal infection. Transfusion of blood products containing
immunodeficiencies. viable lymphocytes may lead to fatal graft-versus-host
disease. Autoimmunity and other manifestations of
COMBINED IMMUNODEFICIENCIES immune dysregulation (e.g., skin rash) are frequently
observed, especially in patients with residual development
Severe Combined Immunodeficiency of T lymphocytes (“leaky” SCID). Patients with SCID are
The term severe combined immunodeficiency (SCID) des- also at increased risk of malignancies, including lympho-
ignates a genetically heterogeneous group of PIDDs char- proliferative disorders caused by Epstein-Barr virus (EBV)
acterized by impaired development and function of T and other tumors.
lymphocytes. In some cases, development of B or natural Typical symptoms of SCID are recurrent severe infec-
killer (NK) lymphocytes (or both) is also affected (Fig. tions, chronic diarrhea, and failure to thrive.4,5 Symptoms
24-1).3,5 However, because T cells play a critical role also are often seen in the first weeks of life but may be delayed
in most B-cell responses, serious T-cell dysfunction pre- by several months. Antibodies derived from the mother
cludes effective humoral immunity even in patients in by transfer across the placenta may provide some early
whom the genetic defect does not affect B-cell develop- protection. Physical examination may reveal foci of infec-
ment. Complete absence of specific cellular and humoral tion (e.g., thrush) and the absence of discernible lym-
immunity in patients with SCID leads to an extreme infec- phoid tissue. Hypogammaglobulinemia is often present
tious diathesis early in life. Mucocutaneous candidiasis but is not universal. Specific antibody responses are
is a common finding. Infections with common viral almost always severely impaired.
pathogens (e.g., varicella, herpes simplex, measles, adeno- SCID is most often classified according to the periph-
viruses, respiratory syncytial virus, influenza, and parain- eral blood lymphocyte phenotype—that is, absence or
fluenza) are often fatal. Patients are also susceptible to presence of the major lymphocyte types. T cells are absent
opportunistic infections with commensal organisms that (or very low) and nonfunctional in all classic forms of

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888 SECTION VII  IMMUNE SYSTEM

Gamma-Delta T cell
TCRγδ, CD3
Thymus

Helper T cell
TCRαβ, CD3, CD4

Myeloid Double- Double- Single-


Erythroid negative positive positive
Megakaryocytoid T cell, T cell, TCRαβ T cell, TCRαβ Cytotoxic T cell
lineages Pre-TCR, CD3 CD3, CD4, CD8 CD3, CD4, or CD8 TCRαβ, CD3, CD8

NK cell
CD16, CD56
Bone marrow Spleen

Mature B cell
CD19, CD20, IgM, IgD

Pluripotent Common Pre-B Immature Transitional


stem cell Lymphoid cell B cell B cell Memory B cell
Progenitor CD19, CD20
IgG, IgA, or IgE
Lymph node
germinal
center
Immunoglobulin Plasma cell
Figure 24-1  Diagram of lymphocyte development. Pluripotent stem cells give rise to all cellular blood elements. The common lymphoid progenitor
gives rise to the three principal lineages of lymphocytes: T cells, B cells, and natural killer (NK) cells. Most peripheral T cells express the αβ form
of the T-cell antigen receptor (TCR) and develop through distinct stages in the thymus. Mature helper T cells express the CD3 antigen coreceptor
complex along with the major histocompatibility complex (MHC) class II receptor CD4, whereas cytotoxic cells express the MHC class I receptor
CD8. A minority (1% to 5%) of peripheral T cells express the γδ form of the TCR along with CD3, but without CD4 or CD8; less is known about
their development. B cells develop initially in the bone marrow and pass through several stages before exiting to complete development in the spleen.
Mature B cells express distinct markers (CD19 and CD20) along with surface immunoglobulin M (IgM) and IgD. B cells are activated in germinal
centers to undergo class switching and become either memory B cells expressing IgG, IgA, or IgE or Ig-secreting plasma cells. Most IgG-producing
plasma cells reside in the bone marrow. NK cells are a distinct lineage of cytotoxic cells; little is known regarding their development from lymphoid
precursors.

SCID, a phenotype designated “T−.” The presence or ADA deficiency accounts for approximately 10% to 15%
absence of B cells is indicated by adding “B+” or “B−,” of all patients with SCID, or approximately a third of
respectively. The same pattern applies for NK cells. Table SCID cases with autosomal recessive inheritance. PNP
24-2 lists the various lymphocyte phenotypes of SCID deficiency is quite rare, with approximately 70 cases
and the molecular defects associated with them. In as reported.11 Although PNP deficiency is mainly expressed
many as 40% of patients with SCID, maternal T cells as a somewhat selective defect in cellular immunity, it is
may have engrafted in the fetus during gestation, and this
situation may occasionally confuse the diagnostic
picture.6,7 Maternally derived T cells tend to be anergic, TABLE 24-2  Lymphocyte Phenotype
but they may also be associated with clinical manifesta- Classification of Severe Combined
tions similar to those of graft-versus-host disease, such Immunodeficiency and Associated Gene Defects
as eczematous rash, eosinophilia, and splenomegaly.6,7
In rare circumstances, maternal engraftment may lead Lymphocyte Phenotype Genes
to even more unusual clinical findings, such as IgA T−B−NK− ADA, AK2, NP*
monoclonal gammopathy, autoimmune cytopenias, and − − +
allograft rejection.7,8 T B NK DCLRE1C, LIG4, NHEJ1, PRKDC,
RAG1, RAG2
T− B− NK− Severe Combined Immunodeficiency T−B+NK− IL2RG, JAK3
Adenosine Deaminase and Purine Nucleoside Phosphory- −
T B NK+ +
CD3D, CD3E, CD3G,† CD3Z,
lase Deficiencies.  Figure 24-2 shows the salvage pathway IL7R, PTPRC
of purine nucleotide synthesis. Deficiencies of the enzymes *B-cell development is variably affected in nucleoside phosphorylase
adenosine deaminase (ADA) and purine nucleoside phos- (NP) deficiency.
phorylase (PNP) are associated with immunodeficiency.9,10 †
CD3G mutations are rarely associated with a severe T-cell deficiency.

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24  Primary Immunodeficiency Diseases 889

dAdenosine/Adenosine dGuanosine/Guanosine

(Adenosine
deaminase)

(Purine
dInosine/Inosine nucleoside
phosphorylase)
(Purine
nucleoside
phosphorylase)

↑dATP Hypoxanthine Guanine ↑dGTP

Toxicity Xanthine Toxicity

Uric acid

Figure 24-2 Salvage pathway of purine nucleotide biosynthesis. d, Deoxy; dATP, deoxyadenosine triphosphatase; dGTP, deoxyguanosine triphos-
phatase.

discussed here because of similarities in their biochemical [q22;q13]) resulting in the COL1A1-platelet-derived
pathophysiology with ADA deficiency. The absence of growth factor β (PDGFB) fusion gene.22 Between 10%
ADA or PNP leads to intracellular accumulation of deoxy­ and 15% of patients with ADA deficiency may have a
adenosine and deoxyguanosine, respectively. These mol- delayed or late-onset form that may be manifested in late
ecules are not themselves toxic to lymphocytes. However, infancy or early childhood. These patients initially may
when they are converted to their 5′-triphosphates (dATP have variable numbers of circulating lymphocytes and
and dGTP), they inhibit ribonucleotide reductase and some humoral immunity that quickly wanes. The severity
prevent de novo synthesis of deoxynucleotides. Without of the phenotype appears to correlate to some degree with
building blocks for the replication and repair of DNA, the amount of residual ADA activity.23 Autoimmunity is
the cells cease to divide. Lymphocytes die to a much particularly common in patients with residual ADA enzy-
greater extent than other cell types do. In both ADA and matic activity.24
PNP deficiency, T-cell precursors in the thymus appear to Patients with PNP deficiency are very susceptible to
be especially sensitive to death by apoptosis (programmed viral and fungal infections. They have decreased numbers
cell death).12 B cells are more often depleted in ADA of circulating T cells, often initially with normal numbers
deficiency than in PNP deficiency. In the latter the B-cell of B cells and normal serum immunoglobulin (Ig) levels.
phenotype is more variable. With time, humoral immunity usually deteriorates.
Approximately 85% of individuals with ADA defi- Approximately 50% of children with PNP deficiency
ciency will display a SCID phenotype with markedly have neurologic complications such as spasticity, diplegia,
reduced numbers of both T and B cells and low serum paresis, and other motor disorders, as well as cognitive
antibody levels. NK cells are only rarely found in patients impairment.25 Autoimmune manifestations, especially
with ADA deficiency. Additional clinical manifestations cytopenias, are also very common.26
may include radiographic alterations of the ribs, vertebral After clinical suspicion is aroused, diagnosis of ADA
bodies, and iliac crests9 as well as sensorineural deaf- or PNP deficiency is not difficult. Both ADA and PNP
ness,13 liver dysfunction,14 lung disease resembling alveo- activity is readily measurable in red blood cell or leuko-
lar proteinosis,15 and cognitive impairment and other cyte lysates. In symptomatic patients, activity is usually
neurologic abnormalities.16,17 Immune dysregulation is 1% or less of that in normal subjects. These methods may
common in patients with ADA deficiency18; it may mani- be applied also for prenatal diagnosis on cultured amni-
fest with allergy (eczema, asthma) and autoimmunity otic or chorionic villus cells or on fetal blood sampling.
(cytopenias, hypothyroidism, diabetes) and is associated PNP is required for the production of hypoxanthine, a
with loss of regulatory T-cell function.19 Rarely, ADA precursor of uric acid (see Fig. 24-2). Thus individuals
deficiency may present with generalized erythroderma with PNP deficiency will have reduced serum and urine
and infiltration of skin by activated autologous T cells, urate levels.
resembling Omenn syndrome (OS).20 Bone marrow hypo- Several therapeutic options are available to patients
cellularity is frequently observed in ADA deficiency; with ADA deficiency, including hematopoietic stem cell
myelodysplasia also has been reported.21 Finally, patients transplantation (HSCT), enzyme replacement therapy
with ADA deficiency are at increased risk for multicentric (ERT) and gene therapy. Excellent results (survival >85%)
dermatofibrosarcoma protuberans, a very rare tumor have been reported after HSCT from matched sibling
with a characteristic chromosomal translocation (t[17;22] donors, but results of HSCT from haploidentical or

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890 SECTION VII  IMMUNE SYSTEM

unrelated donors are much less satisfactory (43% and NK cell differentiation is usually preserved. Therefore,
66% survival, respectively).27 Moreover, patients with these patients most often exhibit a phenotype other than
ADA deficiency surviving after HSCT remain at high risk T- B- NK- SCID; however, we describe this disorder here
of neurologic complications.28 ERT with weekly intra- because it also affects purine metabolism, similar to
muscular injections of polyethylene glycol–conjugated ADA and PNP deficiencies. OS with oligoclonal expan-
bovine ADA (PEG-ADA) is usually well tolerated and is sion of T cells has been described in a patient with AK2
effective to normalize levels of toxic phosphorylated hypomorphic (partially functional) mutations.36 Patients
(deoxy)adenosine derivatives and to improve immune are at increased risk of myelodysplasia.37 Sensorineural
function.29 However, immune reconstitution is often deafness reflects a role of AK2 in the stria vascularis
incomplete.30 Encouraging results have been obtained of the inner ear.34 Treatment is based on HSCT, but
with gene therapy, associated with nonmyeloablative results are less satisfactory than in other forms of SCID,
cytoreduction.31,32 This represents a very important option and use of myeloablative conditioning is required for
for patients who lack a human leukocyte antigen (HLA)- engraftment.38
identical related donor. HSCT is the only curative thera-
peutic option for patients with PNP deficiency. T−B−NK+ Severe Combined Immunodeficiency
Defects of Recombinase-Activating Genes (RAG) 1 and
Reticular Dysgenesis Caused by Adenylate Kinase 2 Defi- 2.  RAG1 and RAG2 encode for DNA-binding proteins
ciency.  Reticular dysgenesis caused by adenylate kinase that bind to specific recognition sequences flanking coding
2 (AK2) deficiency is a very rare autosomal recessive gene elements of the Ig and T cell receptor (TCR) loci.
form of SCID, associated with agranulocytosis (with a RAG1 and RAG2 initiate the VDJ recombination process
block at the promyelocyte stage of differentiation in the by inducing DNA double-strand breaks at these loci.
bone marrow) and sensorineural deafness.33 AK2 regu- Proteins of the nonhomologous end-joining (NHEJ)
lates levels of ADP in mitochondria. Deficiency of this complex ultimately join coding Ig and TCR elements,
enzyme is associated with abnormalities of energy metab- allowing expression of Ig and TCR molecules (Fig.
olism in granulocytes and lymphocytes (especially T 24-3).39 In patients with RAG defects, B- and T-cell dif-
cells), resulting in apoptosis.34,35 The number of circulat- ferentiation is arrested at an early stage of development.
ing B and NK lymphocytes can be variably affected, and Therefore patients with functionally null mutations of the

RSS

V D J C

RAG1/2

DSB

V D J C

NHEJ Artemis, Cernunnos, Ligase IV

V D J C
+

Figure 24-3  Gene defects affecting lymphocyte antigen receptor gene rearrangement and causing T−B−NK+ severe combined immunodeficiency.
The genes that encode immunoglobulin and T-cell antigen receptors are assembled from subunit segments that are separated in the germline and
undergo assembly or somatic rearrangement during lymphocyte development. In the figure, a TCR or Ig heavy-chain locus is shown. The heavy
chains are composed of four distinct segments: V, variable; D, diversity; J, joining; and C, constant. Some of the segments are flanked by recombi-
nation signal sequences (RSS). RAG1 and RAG2 initiate the process that leads to double-strand breaks (DSB) in DNA. The DNA between coding
segments is looped out and forms circles, with the coding sequences joining to one another. In the case of T cells, the larger DNA circle is referred
to as a T-cell receptor excision circle. All these DNA joins are made by a group of molecules that together subserve the function of nonhomologous
end joining (NHEJ).

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24  Primary Immunodeficiency Diseases 891

RAG1 and RAG2 genes have very low numbers of T and an associated feature of general radiation sensitivity not
B lymphocytes, but NK cell differentiation is preserved.40 seen with RAG1 or RAG2 mutations and is caused by
Some patients with hypomorphic RAG1 or RAG2 muta- mutations in the gene DCLRE1C (DNA cross-link repair
tions may sustain differentiation of a limited number of enzyme 1C), whose protein product is called Artemis.53
T and (less frequently) B lymphocytes, a condition that Artemis has a critical role in the function of NHEJ, or
is also referred to as “leaky” or “atypical” SCID.41,42 In the repair of double-stranded DNA breaks (see Fig. 24-3).
these patients, T lymphocytes often undergo homeostatic During VDJ recombination, it opens the hairpins sealing
proliferation in the periphery and acquire an activated the coding ends at V, D, and J elements that have been
(CD45RO+) phenotype. Oligoclonal expansion of T lym- targeted by the RAG proteins.39 Absence or impaired
phocytes that infiltrate target tissues causing damage is function of Artemis blocks T and B lymphocyte develop-
observed in patients with OS.43 Patients with OS present ment at an early stage, similar to RAG1 and RAG2
with clinical features suggestive of acute graft-versus-host mutations. Artemis is ubiquitously expressed, and loss of
disease. Symptoms include recurrent severe infections, its function in nonhemopoietic tissues may account for
failure to thrive, chronic severe diarrhea, and erythro- nonimmunologic problems (oral and genital ulcers, dental
derma with exfoliation and exudation. Examination may abnormalities, and malabsorption) and for the increased
reveal hepatosplenomegaly and lymphadenopathy. Labo- cellular radiation sensitivity that these patients exhibit.
ratory studies show anemia, hypogammaglobulinemia OS has been observed in some patients with Artemis
with an elevated IgE level, a decrease in the number of defects.54 A partial form of the disease, with residual
peripheral B cells, and presence of activated (CD45RO+) expression and function of the protein, is characterized
circulating T lymphocytes with a restricted (oligoclonal) by reduced number of circulating T and B lymphocytes
T cell repertoire. In vitro proliferation of T lymphocytes and increased risk of lymphoma.55
to antigens and to anti-CD3 is abrogated, whereas pro-
liferation to phytohemagglutinin (PHA) may be variably DNA Ligase IV Deficiency.  DNA ligase IV (LIG4) is also
affected.44 Although hypomorphic RAG1 and RAG2 required for NHEJ. Mutations in the LIG4 gene are
mutations are the most common form of OS, the same associated with microcephaly, cognitive impairment,
phenotype may be observed in patients with hypomorphic bone marrow failure, and cellular immunodeficiency that
mutations in other SCID-causing genes. Some evidence may manifest as T−B−NK+ SCID, “leaky” SCID, or OS.
suggests that expansion of oligoclonal, tissue-infiltrating There is profound cellular radiosensitivity. Patients are at
T lymphocytes in patients with OS may reflect defects of increased risk of myelodysplasia and leukemia.56-59
T-cell tolerance. The study of thymic biopsies from
patients with OS has shown abnormalities of medullary Cernunnos Deficiency.  Cernunnos (also known as XLF)
epithelial cells, with impaired expression of AIRE (auto- is another component of the NHEJ pathway39 and is
immune regulator, discussed later),45 a transcription encoded by the NHEJ1 (nonhomologous end-joining 1)
factor that promotes expression of self-antigens, thereby gene. Mutations of this gene cause lymphopenia, radia-
permitting intrathymic deletion of autoreactive T cells or tion sensitivity, growth retardation, microcephaly and
their diversion to FOXP3+ regulatory T (Treg) cells. Con- developmental delay, bone marrow failure, and an
sistent with this, absence of FOXP3+ cells has also been increased risk of myelodysplasia.60 The T-and B-cell
demonstrated in thymic biopsies from patients with OS.45 immunodeficiency of Cernunnos deficiency is less severe
Environmental triggers may modify the disease pheno- than in patients with RAG or LIG4 defects; however,
type in patients with RAG gene defects. In at least one there are quantitative and qualitative alterations of the
case, progression to OS was observed in a patient with a T-cell repertoire, a severe reduction in the number of
RAG2 mutation after infection with parainfluenza virus invariant NK T cells and mucosa-associated invariant T
type 3.46 Cytomegalovirus (CMV) infection has been lymphocytes,61 and abnormalities of class-switch recom-
associated with in vivo expansion of TCRγδ+ T cells and bination in B lymphocytes (see section on class-switch
autoimmune manifestations.47,48 Finally, somatic muta- defects).62
tions may become superimposed on null or “amorphic”
mutations and yield mosaicism with revertant or hypo- DNA Protein Kinase Catalytic Subunit (DNA-PKcs) Defi-
morphic populations of lymphocytes and resultant OS.49 ciency.  A homozygous missense mutation in the PRKDC
Hypomorphic RAG mutations that result in produc- (protein kinase, DNA-activated, catalytic polypeptide)
tion of mutated proteins with more robust (although gene, encoding for DNA-PKcs was identified in a patient
subnormal) recombination activity have been identified in with T− B−NK+ SCID and cellular radiosensitivity, but
patients with delayed presentation characterized by gran- without microcephaly or mental retardation.63
ulomatous lesions and autoimmunity.50,51 Occasionally,
autoimmunity in patients with RAG defects is associated T−B+NK− Severe Combined Immunodeficiency
with preserved number of circulating B cells and normal X-Linked Severe Combined Immunodeficiency, Muta-
or increased Ig serum levels. One patient with compound tions of the Cytokine Receptor Common γ Chain.  In
heterozygous missense RAG1 mutations presented with Western countries, approximately 40% of all patients
idiopathic CD4 lymphopenia.52 with SCID are males with an X-linked form of the disease,
(XSCID), caused by mutations of the IL2RG (interleukin-
Mutations of DCLRE1C (Artemis).  A form of autosomal 2 receptor γ) gene, that encodes for the common γ chain
recessive SCID with the classic T−B−NK+ phenotype has (γc), shared by cytokine receptors for interleukin-2 (IL-2),

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892 SECTION VII  IMMUNE SYSTEM

T-/NK cell B cell


development, differentiation, T cell NK cell Stimulate
activation lg class switch development Hemopoiesis development CD8 T, B, NK

IL-2 IL-4 IL-7 IL-9 IL-15 IL-21

α β γc α γc α γc α γc α β γc α γc
Figure 24-4 Cytokine receptors and signaling
via γc and Jak3. The γc chain participates in
Jak1 Jak1 Jak1 Jak1 Jak1 Jak1 signaling by way of all these cytokine receptors;
it associates with the Jak3 kinase in every case.
Jak3 Jak3 Jak3 Jak3 Jak3 Jak3 The α chains of each receptor are distinct;
receptors for IL-2 and IL-15 also share a β
chain. The α or β chains or both associate with
STAT3 STAT6 STAT5 STAT1 STAT3 STAT1
Jak1. After cytokine binding, Jak kinases
recruit STAT (signal transducer and activator
STAT5 STAT3 STAT5 STAT3 of transcription) proteins. These molecules
dimerize and then translocate to the nucleus,
STAT5 where they associate with other transcriptional
regulators and alter gene expression.

IL-4, IL-7, IL-9, IL-15, and IL-21 (Fig. 24-4).64,65 Thus a tions of the IL7R gene in humans cause T−B+NK+
defect in a single molecule interrupts several cytokine SCID.75 One case of OS caused by a homozygous mis-
pathways, thereby severely disrupting immune function. sense mutation, permissive for IL-7Rα expression, has
Typically, patients with XSCID lack T and NK lympho- been reported.76
cytes; these defects reflect defective signaling via IL-7R
and IL-15R, respectively. However, some patients with Mutations Affecting Components of the T-Cell Antigen
XSCID may have variable numbers of their own T or NK Receptor Complex
cells and may retain partial immune function, reflecting The TCR/CD3 complex is made up of the TCRα and
some preservation of γc expression and of cytokine- TCRβ (or TCRγ and TCRδ) chains of the receptor
mediated signaling.66 B lymphocytes are typically present, making contact with major histocompatibility antigen-
but they are nonfunctional as a result of impaired IL-21– peptide complexes, as well as components of the CD3
mediated signaling.67 Patients with γc deficiency have signal-transducing complex: CD3γ, CD3δ, CD3ε, and
typical clinical features of SCID. In addition, they are CD3ζ (Fig. 24-5).
unusually susceptible to chronic and severe human papil- Defects in the CD3δ (gene CD3D) lead to a T−B+NK+
lomavirus (HPV) infections, and this phenotype may not SCID phenotype.77,78 Patients have varying degrees of
be corrected after HSCT.68 Delayed presentations have panhypogammaglobulinemia and are susceptible to dis-
been reported in association with hypomorphic muta- seminated viral infections. In some cases, a normal-sized
tions or with somatic mutations in T-cell progenitor cells, thymus was visualized, in marked contrast to almost all
allowing generation of a diversified pool of functional T other forms of SCID, in which the thymus is absent or
lymphocytes that may persist for years.69-71 Gene rever- extremely hypoplastic.77 In one case, CD3δ deficiency was
tant T cells undergoing in vivo expansion may also cause associated with OS.79 A multicenter study of 13 patients
a phenotype resembling OS.72 with CD3δ deficiency treated by HSCT has shown supe-
rior immune reconstitution after transplantation from
JAK3 Deficiency.  A form of T−B+NK+ SCID phenotypi- HLA-matched donors: use of conditioning chemotherapy
cally very similar to XSCID is associated with defects in may be needed to achieve engraftment.79
the tyrosine kinase JAK3.73 The similarity with XSCID is Deficiency of CD3ε (gene CD3E)78 and of CD3ζ (gene
easily understood because JAK3 is a critical signal- CD3Z)80,81 are associated with a similar phenotype and
transducing molecule associated with the γc chain (see Fig. markedly reduced levels of the TCR/CD3 complex on the
24-4). Hypomorphic mutations that allow residual JAK3 surface of circulating T lymphocytes. In one patient with
protein expression and function may associate with CD3ζ deficiency, some of the circulating T cells were
partial preservation of circulating T cells and delayed found to express normal levels of the TCR/CD3 complex
clinical onset, with lymphoproliferation and susceptibil- as the result of somatic mutations on one of the CD3Z
ity to warts and other viral infections.74 alleles, allowing expression of poorly functioning TCR/
CD3 complexes.80
T−B+NK+ Severe Combined Immunodeficiency In contrast, the phenotype of CD3γ (gene CD3G) defi-
Defects of the Interleukin-7 Receptor α Chain.  Signaling ciency is heterogeneous. One of two genotypically affected
through the IL-7 receptor (IL-7R) is required for prolif- siblings presented with clinical features of SCID and
eration of early T-cell progenitors and survival of T lym- autoimmunity associated with severe T-cell lymphopenia,
phocytes. The IL-7R is composed of an α chain (IL-7Rα), whereas the other one had a milder immunologic pheno-
encoded by the IL7R gene, and γc (see Fig. 24-4). Muta- type and remained asymptomatic until 12 years of age,

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24  Primary Immunodeficiency Diseases 893

TCR
CD4
CD3 complex
α(γ) β(δ)

ζ ζ γ ε δ ε

Figure 24-5 Components of the T-cell antigen receptor. The ZAP-70 Fyn


actual receptor making contact with a major histocompatibil-
ity complex (MHC)-peptide complex is a heterodimer of α and
β (or γ and δ) chains. This heterodimer sits in the cell mem-
brane in association with the signal-transducing CD3 complex. Lck
This complex contains two heterodimers, one γε and one δε,
and one ζ2 homodimer. Also shown is the MHC class II core-
ceptor molecule CD4. Tyrosine kinases Lck, Fyn, and ZAP-70
associate with components of the receptor complex via immu-
ITAMs
noreceptor tyrosine-based activating motifs (ITAMs) and
transduce signals after interaction of the receptor with peptide/
MHC.

when he developed autoimmunity and recurrent infec- Proliferative responses to anti-CD3 were profoundly
tions.82,83 This variability of clinical and immunologic impaired.89
phenotype has been confirmed in other patients.84
A homozygous splice-site mutation in the TCRα RhoH Deficiency.  The Ras homology family member H
constant region gene has been identified in two patients (RhoH) is a small GTPase that is phosphorylated in
with a history of recurrent infections and autoimmunity. response to TCR stimulation, allowing recruitment of
Development of T cells expressing TCRγδ was not affected. Lck and ZAP-70 to the TCR-associated signaling
In vitro proliferative responses to mitogens and antigens complex. Mutations of the RHOH gene have been identi-
were decreased, but specific antibody production was fied in two siblings with warts, variably associated with
preserved.85 granulomatous lung disease, psoriasiform skin changes,
and molluscum contagiosum.90 One of the affected indi-
CD45 Deficiency viduals developed Burkitt lymphoma in childhood.
A few patients have been found to have a form of SCID Immunologic abnormalities included reduced number of
resulting from mutations in the gene encoding the protein naïve CD4+ lymphocytes and oligoclonal T cell reper-
tyrosine phosphatase CD45 (gene PTPRC), which plays toire, with accumulation of CD8+ effector memory
an important role in T-cell activation.86-88 These patients CD45RA+ lymphocytes (TEMRA cells) with an
have a SCID phenotype with diminished numbers of “exhausted” (CD45RA+CCR7−) phenotype. The reduced
poorly functional T cells, normal or increased numbers number of lymphocytes expressing skin-homing receptors
of B cells, and variable number of NK cells. (cutaneous lymphocyte antigen, CCR4, CCR6, CCR10,
Other Combined Immunodeficiencies (with T Cells Present)
Table 24-3 lists disorders of combined immunodeficiency
with variable lymphocyte phenotypes. TABLE 24-3  Combined Immunodeficiencies with
T Cells Present and Associated Gene Defects
Relative Deficiency of CD4+ T Cells
Lck Deficiency.  The lymphocyte-specific protein tyrosine Syndrome Gene
kinase (Lck) associates with CD4 and CD8 molecules and Variable T cell lymphopenia CORO1A, MST1
plays a critical role in T-cell signaling by mediating phos-
Relative CD4+ T cell deficiency LCK, MHCIITA, RFX5,
phorylation of immunoreceptor tyrosine activation motifs RFXANK, RFXAP, RHOH
in the intracytoplasmic domains of CD3 subunits and
of the ζ chain–associated protein of 70 kDa (ZAP70). Relative CD8+ T cell deficiency CD8A, TAP1, TAP2, TAPBP,
ZAP70
Homozygosity for a missense LCK mutation was identi-
fied in a child with recurrent respiratory infections, pro- Hyper IgE syndrome type 2 DOCK8
tracted diarrhea, failure to thrive, skin nodules, vasculitis, Veno-occlusive disease with SP110
arthritis, and autoimmune thrombocytopenia. There was immunodeficiency
a severe defect in the number of circulating CD4+ lym- Ion (Ca++ and Mg++) transport MAGT1, ORAI1, STIM1
phocytes, and the density of both CD4 and CD8 mole- defects
cules on the surface of CD3+ cells was markedly reduced.
Other CARD11, IL21R
T lymphocytes showed a restricted TCR repertoire.

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894 SECTION VII  IMMUNE SYSTEM

β7-integrin) may impair defense against cutaneous viral shuttling of cytosolic peptides across the endoplasmic
infections and contribute to development of warts. reticulum to load onto nascent HLA class I molecules for
eventual expression at the cell surface and presentation
Major Histocompatibility Complex Class II Deficiency.  to TCRs (Fig. 24-6). HLA class I molecules are highly
The major histocompatibility complex (MHC) in humans unstable without a peptide in their binding cleft, and
is called the HLA complex. The class I and class II HLA they are not transported to the cell surface. Patients
molecules expressed on cell surfaces are critical for practi- with defective expression of HLA class I molecules suffer
cally all mechanisms of specific immune activation. Class mainly from upper and lower respiratory tract bacterial
I molecules are present on most cells of the body. They infections, bronchiectasis, and granulomatous skin inflam-
present antigenic peptides derived principally from intra- mation. Occasional asymptomatic individuals have also
cellular sources to the antigen receptors of T cells express- been described. The main immunologic abnormality is
ing CD8. HLA class II molecules are generally restricted low peripheral blood CD8+ T cells; antibody responses
to specialized antigen-presenting cells (APCs), including may be normal.
monocytes and macrophages, dendritic cells, and B cells,
but are also expressed by thymic epithelial cells. HLA ZAP-70 Deficiency.  The ZAP-70 tyrosine kinase has a
class II molecules mainly present peptides imported from critical role in TCR-mediated signaling by inducing phos-
outside the cell to antigen receptors of T cells bearing phorylation of the linker of activated T cells and SH2
CD4. Defects in the synthesis, expression, or function of domain-containing leukocyte phosphoprotein of 76 kDa
HLA molecules may be expected to have profound con- (SLP-76) (see Fig. 24-5). Mutations of the ZAP70 gene
sequences on lymphocyte development and on immune in humans are typically associated with severe, early
competence. In particular, defective expression of HLA onset infections. Patients have almost complete absence
class II molecules on the surface of thymic epithelial cells of CD8+ T cells. Although circulating CD4+ cells appear
impairs development of CD4+ lymphocytes by impairing normal, they fail to respond to signals delivered by way
their positive selection. of the TCR.94,95 In a few cases, hypomorphic ZAP70
Most patients with MHC class II deficiency present mutations have been associated with delayed onset of the
early in life with recurrent and severe infections, chronic disease and manifestations of immune dysregulation (skin
diarrhea, and failure to thrive.91 Chronic opportunistic rash, wheezing, eosinophilia).96,97 Treatment is based on
infections of the gastrointestinal tract caused by Crypto- HSCT.
sporidium or CMV organisms may lead to severe liver
disease with sclerosing cholangitis. The number of circu- CD8α Deficiency.  CD8 molecules are expressed on the
lating CD4+ cells is markedly decreased, and delayed cell surface as either a CD8α2 homodimer or a CD8αβ
hypersensitivity responses are impaired. All forms of heterodimer. CD8α (gene CD8A) deficiency is a rare
MHC class II molecules (DP, DQ, and DR) are not autosomal recessive disorder characterized by lack of cir-
expressed. Most patients have profound hypogamma- culating CD8+ lymphocytes and by an increased number
globulinemia; however, some patients have normal serum of CD3+CD4−CD8− cells that express markers of effec-
Ig levels, yet specific antibody responses are not elicited. tor cytotoxic T lymphocytes (CD11b, CD57). The disease
As a rule, these children do not survive without HSCT. is reported here because of some phenotypic similarities
However, bone marrow transplantation in these patients (reduced number of CD8+ cells) with ZAP-70 deficiency;
has not been consistently successful,91 probably reflecting however, clinical manifestations are distinct and more
inability to correct defective expression of MHC class II similar to MHC class I deficiency, with recurrent respira-
molecules on the surface of thymic epithelial cells. tory infections and delayed diagnosis.98
MHC class II deficiency results from defective regula-
tion of gene transcription as a result of mutations in any Other Forms of Combined Immunodeficiency with
of four different genes (CIITA, RFXANK, RFX5, RFXAP) Variable Presentation
encoding for components of HLA class II transcription A number of primary immunodeficiencies may have a
complex.91 Without a complete transcription complex, no variable clinical phenotype; in some cases, patients
HLA class II mRNA is produced, and class II proteins affected with these disorders may present with clinical
cannot be synthesized. The same complex activates tran- and laboratory features suggestive of a combined
scription at all HLA class II gene promoters. RFXANK immunodeficiency.
mutations are the main cause of the disease, which is
more common in Northern Africa and in the Middle Macrophage Stimulating 1 Deficiency
East.92 Macrophage stimulating 1 (MST1), also known as serine
threonine kinase 4 (STK4), is a molecule that controls
Relative Deficiency of CD8+ T Cells apoptosis and survival of naïve T lymphocytes by inducing
Defective Expression of HLA Class I.  Several patients expression of FOXO1, a transcription factor that induces
with defective expression of HLA class I molecules have expression of the IL-7R. MST1 deficiency is associated
been described.93 These patients have mutations in one of with recurrent infections, immune dysregulation, a moder-
two genes encoding either TAP1 or TAP2 (transporter ate degree of neutropenia, and congenital heart disease.
associated with antigen processing 1 or 2) or in the Viral infections are particularly common and include
gene encoding tapasin, a TAP-binding protein molecular warts, molluscum contagiosum, and EBV-driven lympho-
chaperone. The TAP1/TAP2 heterodimer is required for proliferative disease. The number of naïve T cells is

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24  Primary Immunodeficiency Diseases 895

CD8+ T cell

Plasma membrane

Transport of peptide-
MHC complex to
cell surface

Cytoplasmic
proteins
Golgi
Proteasomes

Peptides

Assembly of intact
peptide/MHC class I (TAP 1 deficiency)
complexes
TAP
peptide
α transporter
β 2m
Nascent class I ER
polypeptides

Figure 24-6 Synthesis and assembly of major histocompatibility complex (MHC) class I molecules. ER, Endoplasmic reticulum; β2m, β2-
microglobulin; TAP, transporter associated with antigen processing.

markedly decreased, and there is an expansion of TEMRA lymphomas, leiomyosarcoma). The disease has a severe
cells, associated with a restricted T cell repertoire. T lym- prognosis with high mortality rate; treatment is based on
phocytes show increased apoptosis and reduced prolifera- HSCT.103
tion to mitogens. There is also an increased proportion of Immunologic abnormalities include T-cell lymphopenia
transitional B lymphocytes, with reduced number of with impaired thymopoiesis, a low number of naïve CD8+
memory B cells.99,100 cells, and accumulation of TEMRA lymphocytes. T cell
proliferation to mitogens and antigens is often reduced,
Dedicator of Cytokinesis 8 Deficiency especially within CD8+ lymphocytes. Ig abnormalities in-
Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleo- clude elevated serum IgE and low levels of IgM, and B cell
tide exchange factor that activates Cdc42 and participates responses to TLR agonists are compromised.104 Immuno-
at intracellular signaling in lymphoid and dendritic cells. logic memory is defective in both T- and B-cell compart-
DOCK8 mutations cause an autosomal recessive form of ments. In most cases, the genetic defect is represented by
combined immunodeficiency with hyper-IgE (this is also large intragenic deletions.102
known as hyper-IgE syndrome type 2).101,102 Patients
suffer from chronic viral cutaneous infections (warts, mol- Coronin-1A Deficiency
luscum contagiosum), recurrent skin abscesses and cel- The Coronin-1A protein inhibits F-actin formation in T
lulitis, respiratory tract infections, candidiasis, eczema lymphocytes and thereby modulates cytoskeleton rear-
and other manifestations of severe allergy, autoimmunity rangement and T-cell activation. Coronin-1A deficiency
(cytopenias, central nervous system [CNS] vasculitis), and causes a combined immunodeficiency with recurrent
an increased risk of malignancy (epithelial cell carcinoma, and severe infections, including severe varicella and

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896 SECTION VII  IMMUNE SYSTEM

EBV-driven lymphoproliferation.105,106 Developmental CD4 lymphopenia and impaired T cell proliferation to


delay has also been observed, possibly reflecting a role CD3 stimulation. The MAGT1 gene encodes for a
for Coronin-1A in the CNS.105 There is profound T-cell membrane-associated Mg++ transporter. Female carriers
lymphopenia, with reduced survival of T lymphocytes have a skewed pattern of X chromosome inactivation in
and impaired in vitro proliferation to mitogens and anti- circulating T lymphocytes, suggesting that Mg++ signaling
gens. HSCT can cure the immunologic abnormalities and plays an important role in T lymphocyte development
the increased susceptibility to infections.105 and survival.
Veno-Occlusive Disease with Immunodeficiency Syndrome Caspase Recruitment Domain Family Member 11 Deficiency
Veno-occlusive disease with immunodeficiency (VODI) Caspase recruitment domain family member 11 (CARD11)
syndrome is an autosomal recessive condition character- is a scaffold protein that interacts with B-cell lymphoma
ized by severe infections (often including Pneumocystis 10 and mucosa-associated lymphoid tissue lymphoma
jiroveci and CMV infection) and hepatomegaly with translocation gene 1 proteins, thereby inducing activation
abnormalities of liver function and evidence of veno- of the canonical nuclear factor κB (NF-κB) pathway in
occlusive disease on liver biopsy.107 Cerebrospinal leuko- lymphocytes. Biallelic loss of function mutations of
dystrophy has been reported in several patients.108 CARD11 are associated with a combined immunodefi-
Immunologic abnormalities include T- and B-cell lympho- ciency, marked by increased susceptibility to opportunis-
penia, poor T-cell function, severe hypogammaglobu- tic infections and hypogammaglobulinemia.114 The
linemia, and lack of memory B lymphocytes.108 If number and distribution of T lymphocytes are preserved,
untreated, the disease is often fatal within the first years other than for a reduced number of Treg cells; by con-
of life. Administration of intravenous immunoglobulin trast, there is expansion of transitional B lymphocytes
(IVIG) and antimicrobial prophylaxis may prolong sur- and reduction of mature naïve and memory B lympho-
vival, but the only curative approach is represented by cytes. Moreover, in vitro activation of T and B cells with
HSCT.109 Recurrence of veno-occlusive disease after phorbol myristate acetate is severely impaired, and pro-
HSCT has been reported.108 VODI was initially described liferation of T lymphocytes in response to stimulation by
in patients of Lebanese descent, but the disease has been way of CD3/CD28 is abrogated. On in vitro activation,
reported in other ethnic groups as well. The disease is production of IL-2 by T cells and of interferon IFN-γ by
caused by mutations of SP110 encoding for a nuclear NK cells is decreased.114
body protein that is thought to have a role in regulation
of gene transcription.107 IL-21 Receptor Deficiency
IL-21 regulates proliferation of lymphocytes, differentia-
Immunodeficiencies Caused by Defects of Calcium-Release tion of T helper 17 (Th17) cells, maturation of B cells
Activated Channels into plasmablasts, and induction of NK cell cytotoxicity.
On TCR-mediated signaling, Ca++ is mobilized from IL-21 receptor (IL-21R) defects have been identified in
endoplasmic reticulum (ER) stores. This depletion is four patients from two kindreds whose clinical phenotype
sensed by stromal interacting molecule 1 (STIM1), which included respiratory infections, chronic diarrhea, failure
oligomerizes and binds to the ORAI proteins that form to thrive, and severe liver and biliary tract disease caused
the calcium-release activated channels (CRACs) on by infection with Cryptosporidium organisms.115 The
the cell surface, thereby permitting influx of Ca++, activa- number of T, B, and NK lymphocytes is normal, but the
tion of transcription factors (e.g., nuclear factor of acti- proportion of switched memory B cells is reduced. Serum
vated T cells), cytokine production, T-cell proliferation, IgG levels are low or slightly subnormal, but IgE is ele-
and induction of effector T cell responses. Mutations vated. Antibody responses to T-dependent and
of STIM1 and ORAI1 genes in humans account for T-independent antigens are decreased. On in vitro activa-
autosomal recessive combined immunodeficiencies with tion with CD40 ligand (CD40L) and IL-21, B lympho-
recurrent infections, signs of ectodermal dystrophy, non- cytes from the patients show reduced proliferation and
progressive myopathy (reflecting a role of CRACs in defective class switch recombination. NK cytotoxic activ-
muscle cells).110,111 Autoimmune manifestations (cytope- ity is markedly decreased. T cells proliferate normally in
nias, lymphadenopathy, and splenomegaly) may also be response to stimulation by CD3 and CD28 but fail to
observed, especially in patients with STIM1 deficiency.111 produce IL-17 and IL-22. Proliferation to antigens in
Kaposi sarcoma due to human herpesvirus 8 (HHV-8) vitro is impaired.115
infection has been reported.112 The absolute lymphocyte
count is normal, with preserved distribution of major
lymphocyte subsets. However, in vitro proliferation to MANAGEMENT OF COMBINED
mitogens and antigens is impaired, and cell-mediated IMMUNODEFICIENCY
cytotoxicity and cytokine production are also affected.
Diagnostic Approach
Magnesium Transporter Protein 1 Deficiency Suspicion of SCID or other forms of combined immuno-
Magnesium transporter protein 1 (MAGT1) is an deficiency is prompted by clinical symptoms, family
X-linked disease characterized by severe chronic viral history, or positive results of screening assays. In particu-
infections, chronic diarrhea, and EBV-driven lymphopro- lar, newborn screening for SCID can be performed by
liferative disease.113 Immunologic abnormalities include quantifying levels of TCR excision circles (TRECs; see

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24  Primary Immunodeficiency Diseases 897

Fig. 24-3 legend) in dried blood spots collected at birth.116 one of their haploidentical parents, most often the mother.
TRECs are a by-product of rearrangement of TCR genes In this case, mature T lymphocytes must be removed from
during intrathymic T-cell development. In patients with the graft to prevent graft-versus-host disease. T cell–
SCID, TREC levels are extremely low or absent as a result depleted HSCT from a haploidentical donor for SCID
of lack of significant thymic T-cell output.117 Indeed, since may be performed without or with pretransplant chemo-
newborn screening for SCID has been started in various therapy. Unconditioned T cell–depleted haploidentical
parts of the United States, several cases of SCID have transplantation leads to long-term T-cell engraftment124;
been identified at birth in otherwise healthy-looking new- however, B- and NK-cell engraftment is rarely achieved,
borns.118 However, it is not clear yet whether determina- and lifelong use of IVIG may be needed, especially in
tion of TREC levels at birth may also reliably identify patients who lack B cells (e.g., defects of VDJ recombina-
other forms (and which ones) of combined immunodefi- tion) or those whose genetic defects compromise B-cell
ciency with residual T-cell development. Tandem mass function (γc, JAK3 defects).125 Use of chemotherapy may
spectrometry can also be used for newborn screening of allow stem cell engraftment (and hence also permit recon-
ADA deficiency119 and may also identify subjects with stitution of B- and NK-cell immunity); however, it is also
residual levels of ADA activity, who could otherwise be associated with toxicity. In a large series, overall survival
missed by the TREC-based assay.120 in SCID patients transplanted after the year 2000 was
Quantification of TRECs represents an important, yet 90% when HLA-matched siblings served as donors and
nonspecific, indicator of a possible severe T-cell immuno- 66% after haploidentical HSCT.123 However, when trans-
deficiency, the diagnosis of which must be confirmed by plantation is performed in infants younger than 3.5
appropriate immunophenotypic, functional, and molecu- months of age, survival is greater than 95%, even after
lar tests. Flow cytometry, looking at the distribution and haploidentical donors,126 thus justifying newborn screen-
absolute number of the major T-cell subsets, B and NK ing for SCID based on quantification of TRECs at birth.118
lymphocytes, may provide important information. Deter- HSCT is also the mainstay of treatment for other
mination of naïve (CD45RA+CD62L+) and activated/ forms of combined immunodeficiency with presence of
memory (CD45RO+ CD62L−) T lymphocytes should be residual or normal number of autologous T lymphocytes.
included in the diagnostic panel to correctly identify In such cases, however, pretransplant conditioning must
patients with maternal T-cell engraftment or with leaky be used to achieve engraftment. Overall survival after
SCID and expansion of in vivo activated, activated T HSCT for these conditions is less satisfactory than in
cells. Functional tests include in vitro proliferation to patients with SCID, being approximately 80% from
mitogens (PHA, anti-CD3 monoclonal antibody) and matched siblings and 50% from haploidentical donors.123
antigens (provided that the patient has been exposed to
these through immunization or natural infection). Ulti- Gene Therapy
mately, identification of the specific disease-causing Gene therapy for the treatment of human disease was first
mutation(s) may permit molecular diagnosis of the attempted in patients with ADA deficiency.127,128 A func-
disease. tional copy of the ADA gene in a retroviral vector was
transduced into populations of mature T cells or bone
Hematopoietic Stem Cell Transplantation marrow cells. Transduced cells expressed normal levels
Identification of a patient with SCID should be consid- of ADA and showed normal function in vitro. However,
ered a pediatric emergency.121 Children with this disorder clinical efficacy was difficult to assess in these early
are so prone to infections that extreme measures must be attempts because adjunctive therapy with PEG-ADA was
taken to protect them from microbial invasion. Before mandated on ethical grounds, even after the re-introduction
newborn screening for SCID became a reality, most of transduced cells into patients. More recently, gene
patients were already infected when initially evaluated therapy for ADA deficiency has been performed by trans-
and required aggressive interventions to keep their clini- ducing hematopoietic stem cells without concurrent in
cal course from running inexorably downhill. After full vivo administration of PEG-ADA31,129; use of submye-
immunologic evaluation has been performed (as expedi- loablative doses of busulfan has permitted robust engraft-
tiously as possible), these patients should begin receiving ment and long-term immune reconstitution in the vast
IVIG infusions. Prophylaxis for P. jiroveci pneumonia is majority of the patients.31,32,129 However, the absolute
indicated for all patients. T-cell count remains suboptimal in many patients, pos-
Although alternative therapies may work for some sibly reflecting irreversible thymic damage caused by
patients (e.g., PEG-ADA for ADA deficiency), the defini- toxic adenosine derivatives.
tive treatment for the great majority of patients with The earliest “complete” success of gene therapy is
SCID and other combined immunodeficiencies is HSCT. considered to have occurred with XSCID.130,131 Hemato-
A variety of sources have been used for stem cells, includ- poietic stem cells were transduced ex vivo with a retro-
ing HLA-identical sibling donors, haploidentical related viral vector carrying a functional copy of the γc gene and
donors (usually parents), unrelated donors, and umbilical then infused into patients without any conditioning che-
cord blood.122,123 Transplantation from a matched sibling motherapy. Twenty patients have been treated in this
donor in patients with SCID does not require condition- manner. Most patients have exhibited rapid and persis-
ing and is associated with excellent survival and long- tent reconstitution of T cell–mediated immunity. Recon-
term immune reconstitution. Patients with SCID who stitution of B-cell immunity has been achieved only in
lack a matched sibling donor may receive HSCT from some patients. The therapy appears to be less effective if

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898 SECTION VII  IMMUNE SYSTEM

performed later in life, probably because of deterioration TABLE 24-4  Cellular Immunodeficiency
of the thymic rudiment over time.132 Syndromes and Their Associated Gene Defects.
Unfortunately, 5 of the 20 infants with XSCID treated
by gene therapy have developed leukemia, which was Syndrome Gene
fatal in one. Leukemias were caused by insertional muta-
Wiskott-Aldrich syndrome WAS
genesis. The vector integrated within or near oncogenes
(in particular, LMO2) and the strong enhancers con- DiGeorge syndrome del22q11, TBX1
tained in the viral long terminal repeats (LTRs) caused DNA repair defects:
oncogene transactivation and uncontrolled cell prolifera-  Ataxia-telangiectasia ATM
tion.133,134 Novel clinical trials, based on self-inactivating  Nijmegen breakage syndrome ATLD, NBS1, PMS2
retroviral and lentiviral vectors in which expression of and others
the γc gene is driven by weaker cellular promoters (instead Disorders of chromosome
of the strong viral LTRs), are currently under way in instability:
Europe and in the United States.   Bloom syndrome BLM
  ICF syndrome DNMT3B, ZBTB24
Disorders of pigmentary dilution:
IMMUNODEFICIENCY SYNDROMES  Chédiak-Higashi syndrome LYST
  Griscelli syndrome type 2 RAB27A
The term syndromic immunodeficiencies has been coined   Hermansky-Pudlak syndromes AP3B1, PLDN
to describe the occurrence of abnormal development or types 2 and 9
function of the immune system leading to susceptibility
Defects of the NF-κB pathway IKBKG, IKBA
to infection, autoimmunity, or malignancy in the setting
of a genetically determined disorder with characteristic Defect in Toll-like receptor IRAK4, MYD88
features of altered development or function of other signaling
organ systems or the body as a whole. Here we will WHIM syndrome CXCR4
review several disorders with prominent immune dys- Hyper IgE syndromes STAT3, TYK2
function. These diseases and their associated genes are
listed in Table 24-4. Space does not permit a detailed Chronic mucocutaneous candidiasis CARD9, IL17RA, IL17F,
STAT1
description of the tremendous variety of syndromes that
have been associated with immunodeficiency. Interested Immunodeficiencies with skeletal
readers are referred to an excellent review on this abnormalities:
 Cartilage-hair hypoplasia RMRP
topic.135  Schimke immuno-osseous SMARCAL1
dysplasia
Wiskott-Aldrich Syndrome
Disorders of vitamin metabolism TCN2, MTHFD1
Wiskott-Aldrich syndrome (WAS) is an X-linked disease
characterized by eczema, immunodeficiency, and throm- ICF, Instability facial anomalies; WHIM, warts,
bocytopenia.136 Bloody diarrhea is often seen and may be hypogammaglobulinemia, infec­tions, and myelokathexis.
the initial feature. Eczema may be mild or exuberant;
staphylococcal superinfection is common. Recurrent otitis
media and sinopulmonary infections occur frequently, Platelets are small, do not function normally, and are
and opportunistic infections are also seen. In addition, also cleared more rapidly (although the number of bone
autoimmune hemolytic anemia, vasculitis, inflammatory marrow megakaryocytes is normal or even increased).136
bowel disease, glomerulonephritis, and other autoim- In the appropriate clinical context, measurement of plate-
mune processes have been frequently observed in WAS. let size confirms the diagnosis. In normal individuals
Patients most often die as a result of overwhelming infec- platelet volume is 7.1 to 10.5 fL, with a diameter of 2.3
tion or massive hemorrhage. Those who avoid these com- ± 0.12 µm, whereas platelets from patients with WAS
plications have a greatly increased risk for lymphoma, have volumes ranging from 3.8 to 5.0 fL with diameters
many of which are EBV positive. There is also an increased of 1.82 ± 0.12 µm. The low platelet volume distinguishes
risk of aortic aneurysms.136,137 the thrombocytopenia of WAS from immune thrombocy-
Variability of the clinical phenotype has been reported, topenic purpura (ITP), in which platelets are often large.
and a clinical score has been developed to reflect this However, ITP may develop in as many as 20% of patients
phenotypic heterogeneity.136 A milder form of the disease, with WAS.
characterized by thrombocytopenia with mild eczema and The mainstay of treatment for WAS is HSCT.141
lack of severe infections, is also referred to as isolated Without HSCT, survival beyond adolescence is uncom-
X-linked thrombocytopenia (XLT).138 Although XLT mon. The rates for 5-year survival after HSCT for WAS
patients have better survival rates compared with patients approximates 90% for transplants performed after year
who have classical WAS, nonetheless they have a signifi- 2000. Optimal results (survival >95%) are obtained after
cant risk of complications (e.g., autoimmunity, hemor- HSCT from matched siblings, but significantly improved
rhage). In some cases, the thrombocytopenia may even be outcome has been also achieved after HSCT from unre-
intermittent.139 On the other hand, patients who present lated donors and even mismatched related donors.141
early in life with very profound (<10 × 109/L) and persis- Mixed chimerism is associated with increased risk of
tent thrombocytopenia have very poor outcomes.140 autoimmunity after transplant.141

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24  Primary Immunodeficiency Diseases 899

Pretransplant morbidity and mortality rates may be frequently reported in WAS.151 However, the impact of this
reduced with regular infusions of IVIG and antibiotic phenomenon on clinical phenotype remains unclear.
prophylaxis.136 Blood products, when needed, should be The diagnosis of WAS is facilitated by analysis of
irradiated and tested for CMV. Splenectomy often WASP expression by flow cytometry or Western-blotting;
increases the platelet count, although immune thrombo- however, this approach may miss patients who express a
cytopenia may later supervene. Moreover, splenectomy mutant form of the protein. Ultimately, mutation analysis
markedly increases the risk of overwhelming infections. is required to confirm the diagnosis.136 Female carriers of
Immunosuppressive agents may be needed to treat auto- WAS are generally asymptomatic and have normal plate-
immune complications of the disease.136 let counts but show nonrandom X-chromosome inactiva-
The immune defects in WAS are variable.136,142 Immune tion in lymphocytes and granulocytes.152 Occasionally,
function may be normal in early infancy, but it gradually occurrence of WAS or XLT in females has been reported
wanes. T cell numbers may be decreased, and T cells have as the result of various mechanisms, including extreme
diminished, but not absent, responses to mitogens and lyonization favoring the mutant X chromosome,153,154
antigens in vitro. T cells in WAS will also proliferate in random X-chromosome inactivation,155,156 or WAS gene
response to nonspecific activating stimuli such as phorbol mutation on both X chromosomes.157
esters and calcium ionophores but show a striking absence
of reactivity to immobilized antibodies directed against WAS Protein-interacting Protein Deficiency
the CD3 complex of the TCR. The diversity of the T-cell A single case of a female patient with mutations of the
repertoire appears normal throughout childhood, but it WIPF1 gene, encoding WIP, has been reported. The phe-
may become more restricted with consequent worsening notype included recurrent infections, thrombocytopenia,
immunodeficiency in adulthood.143 defective T-cell proliferation and chemotaxis, and
Serum levels of IgA and IgE are often elevated, whereas impaired NK cell function. No expression of the WIP and
IgM may be low; however, increased serum IgM is associ- WASP proteins was detected in circulating cells.158
ated with an increased risk of autoimmunity and worse
outcome.144 Isohemagglutinins and specific antibody DiGeorge Syndrome
responses to polysaccharide antigens are also diminished. DiGeorge syndrome (DGS) arises as a result of a failure
Although the frequency of class-switched B cells (i.e., of migration of neural crest cells into the third and fourth
those not expressing IgM) appears to be normal, there pharyngeal pouches. Patients display a characteristic
are fewer memory B cells expressing CD27, thus indicat- facies, cardiac defects, parathyroid hormone deficiency,
ing some alteration in B-cell activation in germinal centers and varied immune defects.159,160 The facies consists of
that could underlie or contribute to the humoral immu- hypertelorism; micrognathia; short philtrum; and low-set,
nodeficiency.145 Finally, dendritic cells and monocytes posteriorly rotated ears with small pinnae. Cardiac defects
show impaired formation of podosomes and defective are varied. Type B interrupted aortic arch is the most
directional migration in response to chemotactic signals.142 common and is associated with DGS in 50% of patients
The gene defective in WAS has been identified; its with this defect. Truncus arteriosus and other conotruncal
official name is WAS, and its product is designated the anomalies are also common. Structural anomalies of the
WAS protein (WASP). The same gene is defective in airways have likewise been found in some patients, as well
XLT,146 as well as in X-linked congenital severe neutro- as dysphagia secondary to laryngoesophageal dysmotility.
penia.147 The latter disease is due to activating WAS The bilateral paired parathyroid glands are normally
mutations; its phenotype is very different from WAS adherent to the thymus. Thus these organs are affected
and includes chronic neutropenia with a differentiation together in this disease. The parathyroid deficiency is
block in the bone marrow and an increased risk of often more pronounced than the thymic defect; hypocal-
myelodysplasia.147,148 cemic tetany is one of the more common initial symptoms
WASP interacts with several intracellular partners, of DGS. Even small islands of ectopic thymus tissue may
including the WASP-interacting protein (WIP), Rho permit the development of sufficient T cells for immune
family guanosine triphosphatases, and the Arp2/3 competence. Neuropsychiatric problems and some degree
complex, which leads to reorganization of the actin cyto- of cognitive impairment are seen in many patients and
skeleton in response to activating stimuli in lymphoid and become more prominent during adulthood.161
myeloid cells.142 Partial and complete forms of DGS have been distin-
There is a good, yet imperfect, genotype-phenotype cor- guished on the basis of clinical and immunologic charac-
relation in WAS.149 In particular, XLT is more often associ- teristics.159,160 In the complete form the thymus is absent
ated with residual expression of WASP and with missense or severely hypoplastic.162 These patients have absent or
mutations in exons 1 and 2 of the WAS gene that corre- markedly decreased numbers of T lymphocytes. B cells
spond to a domain of WASP that interacts with WIP. This are present, but specific antibody production is impaired.
interaction stabilizes WASP, thereby explaining reduced Some patients may have erythroderma, similar to that
levels of WASP detected in cells from patients with XLT.150 seen in OS. In this condition, also referred to as atypical
In contrast, the more severe phenotypes are associated complete DGS, oligoclonal, activated (CD45RO+) tissue-
with complete absence of protein or with expression of infiltrating T lymphocytes are detected.162 If untreated,
truncated, nonfunctional forms of WASP. Somatic muta- complete DGS is most often fatal in early childhood;
tions allowing expression of WASP in some cell popula- patients die as a result of hypocalcemia, cardiac compli-
tions (more often, in CD8+ T lymphocytes) have been cations, infection, or a combination of these causes.

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900 SECTION VII  IMMUNE SYSTEM

The occurrence of partial forms of DGS outnumbers 41% and the count of naïve CD4+ cells remained very
that of the complete form by about 100 : 1. T-cell number low.175
and function in most patients are varied and presumably
correlate with the amount of ectopic thymus tissue FOXN1 Deficiency
present. Immune function in patients with complete DGS The transcription factor FOXN1 plays a critical role in
does not improve; patients with partial DGS may have development of the thymus and eccrine glands. FOXN1
less immunodeficiency as they get older. In some cases, mutations in humans cause athymia, profound T-cell lym-
the diagnosis has been made in adults being evaluated phopenia, alopecia totalis, and nail dystrophy, fully
for hypoparathyroidism and hypocalcemia.163 Humoral resembling the “nude” phenotype observed in Foxn1-
immunity is generally intact in patients with partial mutated mice.176 There is complete lack of CD4+ lym-
DGS; however, IgA deficiency and defective antibody phocytes, whereas a low number of oligoclonal CD8+
production have been reported.160 An increase in atopic cells may be present.177 Similar to DGS, reconstitution of
dermatitis and asthma has been reported in individuals T-cell immunity can be achieved with thymic transplanta-
with 22q11 deletion.164 Autoimmunity (especially ITP, tion.178 Alternatively, HSCT from HLA-identical siblings
other cytopenias, juvenile arthritis, and celiac disease) is may provide some immune reconstitution through
observed in 10% of the patients.165 homeostatic proliferation of T lymphocytes contained in
In various series, between 55% and 90% of patients the graft.179
with DGS have 2 to 3 megabase deletions involving chro-
mosome 22q11.2.166,167 Deletions in the same region are Ataxia-Telangiectasia
found in patients with a spectrum of phenotypically over- Ataxia-telangiectasia (AT) is an autosomal recessive dis-
lapping conditions, including velocardiofacial syndrome order with an estimated incidence of 1 in 20,000 U.S.
and conotruncal anomaly face syndrome, and in some Caucasian births (95% confidence interval, 1 in 2500 to
patients with isolated cardiac defects. There is heteroge- 700,000).180 AT is characterized by progressive cerebellar
neity in expression of the DGS phenotype, even in mono- ataxia, oculocutaneous telangiectasia, and immunodefi-
zygotic twins. Approximately 40 genes are present in the ciency.181 Associated features are an increased incidence
deleted regions in DGS, and the contributions of each to of lymphoma and sensitivity to radiation. Impairment in
the phenotype are only beginning to be understood.168 motor development may be noted early in the disease
TBX1 encodes a member of a family (T-box) of transcrip- course and is progressive. Walking may be delayed until
tion factors. Mice that are heterozygous for deletion of 16 to 18 months of age or later. Telangiectases of con-
this gene have a phenotype that is variable but often very junctival and cutaneous vessels do not appear until chil-
similar to that of humans with DGS, including thymic dren are 3 to 5 years of age. The cutaneous lesions are
and parathyroid hypoplasia, cardiac outflow tract abnor- found mainly on the pinnae and in skin creases. Immu-
malities, and abnormal facial structure.169 Two truncating nodeficiency will occur in approximately 70% of patients.
and three missense mutations in TBX1 have been found Manifestation of the immunodeficiency is quite varied,
in a few patients with DGS or velocardiofacial syndrome but it is often seen as recurrent sinopulmonary bacterial
and no detectable 22q11.2 deletion.170-172 Interestingly, infections. Granulomatous lesions are frequently seen
the missense mutations were found to result in gain of and may reflect immune dysregulation.182 Growth retar-
function, suggesting that increased TBX1 activity may dation is a prominent feature in many patients and has
phenocopy TBX1 loss of function or haploinsufficiency.172 been associated with decreases in insulin-like growth
Some patients with DGS have deletions on chromosome factor I and its binding protein.183
10p13-p14.173 The median age at death in patients with AT is approx-
Although recurrent infections can be observed in up to imately 19 to 25 years.184,185 Many patients die as a result
25% to 30% of patients with DGS, severe viral and of progressive pulmonary disease caused by repeated
opportunistic infections are very rare, other than in infection. Possibly, noninfectious and ultimately fatal
patients with complete DGS. Live viral vaccines may be interstitial lung disease may also occur in approximately
administered safely to the great majority of patients.160 By 25% of patients.186 The lifetime risk for malignancies in
contrast, complete DGS has a severe prognosis, but it can AT is 30% to 40%; 85% of the cancers are acute leuke-
be treated successfully by thymus transplantation. Immu- mias or lymphomas.187 Elevated serum levels of
nosuppression is needed to control severe immune dys- α-fetoprotein (AFP) are found in more than 95% of
regulation in patients with complete atypical DGS while patients with AT and have diagnostic value in the appro-
preparing for thymus transplantation.174 In a recent study priate clinical context; however, levels of AFP are physi-
43 of 60 patients (72%) treated with this procedure were ologically higher at birth and for the first two years.188
reported to be alive at a median of 4.7 years after trans- T and B cell lymphopenia is a well-recognized, though
plantation, and they attained an increase in T-cell count variable, feature of AT in adulthood but may also be
with improved function, although absolute naïve CD4+ present at birth and be detected by abnormal TREC levels
and CD8+ counts remained below the 10th percentile in at newborn screening for SCID.189 T cells bearing the
most of them.174 HSCT from matched donors may also TCRγδ constitute up to 50% or more of the total number
provide some immune reconstitution through homeostatic of T cells in patients with AT.190 These cells make up
proliferation of mature T lymphocytes contained in the fewer than 10% of peripheral T cells in normal individu-
graft; however, in a series of 17 patients with complete als. Cutaneous delayed hypersensitivity responses, as well
DGS treated by HSCT, overall survival rate was only as results of in vitro assays of T-cell function, are often

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24  Primary Immunodeficiency Diseases 901

depressed. Varying degrees of humoral immunodeficiency repair pathway. PMS2 deficiency is associated with
are common. IgA deficiency occurs in two thirds of increased occurrence of malignancies, café-au-lait spots,
patients. Decreased levels of IgG2, IgG4, and IgE are also and defective CSR.202 MSH6 deficiency is also associated
common, yet approximately 10% to 30% of the patients with increased risk of cancer and defective maturation of
have increased IgM.191,192 Impaired specific antibody antibody responses, with impairment of CSR and a
responses, particularly to pneumococcal polysaccharide skewed pattern (higher rate of transitions) of somatic
antigens, have also been noted in AT patients.193 hypermutation.203
The gene that is defective in AT is designated ATM (AT
mutated). ATM has critical roles in regulation of the cell IMMUNODEFICIENCIES WITH
cycle: It is involved in the detection of DNA damage and CHROMOSOMAL INSTABILITY
in the initiation of repair.194 There is a marked delay in
induction of the tumor suppressors p53 and BRCA1 after Bloom syndrome is characterized by chromosomal insta-
exposure of AT cells to radiation. Even low-dose radia- bility with increased sister chromatid exchange and ho-
tion leads to significantly greater DNA damage in AT mologous chromosome translocations and is associated
fibroblasts and lymphoblasts than in normal individu- with increased frequency of infections, low levels of IgM,
als.195 ATM mutations are associated with impaired lym- and impaired delayed-type hypersensitivity responses.
phocyte proliferation.196 Lymphocytes of patients with The disease is caused by mutations of the BLM gene,
AT also show a remarkable number of chromosomal encoding for a helicase.204
translocations and inversions. These changes predomi- The immunodeficiency-centromeric instability facial
nantly involve the loci that rearrange to generate mature anomalies syndrome is characterized by hypogam­
Ig (2p12, 22q12, and 14q32) and TCR (7p15, 7q35, and maglobulinemia, facial dysmorphisms, and branching
14q11) genes and reflect defective repair of the double- of chromosomes 1, 9, and 16. The disease may be
stranded breaks produced as part of the physiologic gene caused by mutations in the DNA methyl transferase 3B
rearrangement process during lymphocyte development. (DNMT3B)205 or in the zinc-finger- and-BTB (bric-a-
ATM is also involved in class-switch recombination brac, tramtrack, broad complex)-domain-containing 24
(CSR), and this may explain reduced levels of IgG, IgA, (ZBTB24) genes.206
and IgE seen in patients.197 Mutations of the mini-chromosome maintenance-
No definitive cure is available for AT. Medical man­ deficient 4 (MCM4) gene have been identified in patients
agement aimed at preventing and treating infections with recurrent and severe viral infections (in particular,
(antibiotics, Ig), tumor surveillance, and neurorehabilita- caused by herpes simplex virus 1 [HSV-1], varicella zoster
tion represent the mainstays of treatment.188 Very recently, virus [VZV] and CMV), growth retardation, adrenal
some improvement of neurologic signs has been observed insufficiency, and selective NK cell deficiency with lack of
on administration of betamethasone, possibly reflecting the CD56dim NK subset.207,208 The disease is inherited as
antiinflammatory and antioxidant activity of glucocorti- autosomal recessive trait. MCM4 is a component of a
coids in the CNS.198 multiprotein complex required for both initiation and
Whether pathologic changes result from the heterozy- elongation of eukaryotic DNA replication.209 MCM4
gous carrier state of AT remains a subject of controversy. mutations were shown to cause abnormalities of cell
Carriers heterozygous for ATM mutations have none of cycle, with increased proportion of fibroblasts in G2/M
the classic clinical manifestations of AT; however, the sen- and S phases of cell cycle and an aberrant (>4n) DNA
sitivity of their DNA to radiation is increased, and several content, and genomic instability.207
reports suggest that AT heterozygotes have an increased
rate of a variety of malignancies, such as breast cancer.199 PIGMENTARY DILUTION DISORDERS
OTHER IMMUNODEFICIENCIES ASSOCIATED WITH Pigmentary dilution disorders include diseases in which
DEFECTIVE MECHANISMS OF DNA REPAIR abnormalities in melanosome trafficking within cells
lead to characteristic pale skin and silvery-gray or ashen
The Nijmegen breakage syndrome is a disorder of chro- hair. Several forms of pigmentary dilution disorders are
mosome fragility with autosomal recessive inheritance.200 also characterized by a variable degree of immune defi-
The phenotype is similar to that of AT and consists of ciency, in particular impaired cell-mediated cytotoxicity.
growth retardation, microcephaly, immunodeficiency, In these conditions inability to clear virus-infected cells
sensitivity to radiation, and a high rate of lymphoma. The leads to persistent and exaggerated inflammatory
affected gene is designated NBS1. Nibrin, its protein responses with macrophage activation, release of proin-
product, is another substrate of ATM in the cellular flammatory cytokines, and continuous activation of infil-
response to ionizing radiation. Absence of nibrin function trating CD8+ T cells that secrete high amounts of IFN-γ
leads to disruption of mechanisms of DNA repair, but it and cause tissue damage. Fever, hepatosplenomegaly,
does not appear to result in abnormal function of cell lymphadenopathy, and cytopenia caused by impaired
cycle checkpoints. Another similar syndrome, AT-like dis- hematopoiesis in the bone marrow and hemophagocyto-
order, results from mutations of the gene MRE11A, sis are typical manifestations of immune activation during
which encodes another ATM substrate.201 the so-called accelerated phase of the disease. Impaired
Postmeiotic segregation 2 (PMS2) and MutS homo- cytotoxicity of virus-infected cells reflects defective traf-
logue 6 (MSH6) are components of the DNA mismatch ficking, docking or release of cytolytic granules in NK

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902 SECTION VII  IMMUNE SYSTEM

cells, and cytotoxic T cells. This defect parallels defects vivo.221 However, whether this may affect the disease
of melanosome trafficking. phenotype is not clear.
Chédiak-Higashi syndrome is characterized by partial Patients may suffer opportunistic-type disseminated
albinism, peripheral neuropathy, and increased risk of viral infections and P. jiroveci pneumonia and are also
viral infections. Neutropenia is often present and may highly susceptible to atypical mycobacterial infections.
facilitate bacterial infections. Recognition of “giant” Inflammatory bowel disease is also frequently seen,
lysosomes in leukocytes facilitates the diagnosis.210 The reflecting a role of NF-κB in controlling epithelial integrity
disease is caused by mutation of the lysosomal trafficking and the interaction between the mucosal immune system
regulator (LYST) gene.211 The precise mechanism by and gut microflora.222 Finally, lymphedema and osteope-
which the LYST protein works is not known, although it trosis may also be part of the disease phenotype.220
is thought to regulate trafficking of intracellular vesicles. Most patients are hypogammaglobulinemic and have
HSCT is the only definitive treatment, but it does not impaired vaccine responses (especially to polysaccharide
prevent possible progression of neurologic complications. antigens). Peripheral blood lymphocyte subsets and in
Griscelli syndrome (GS) type 2 also associates partial vitro measures of lymphocyte function may be unremark-
albinism and immunodeficiency with increased suscepti- able or variably diminished; NK cell cytotoxicity may be
bility to infections, fever, and cytopenia. The disease is impaired. Signaling by way of TLRs is also affected.
caused by mutations of the RAB27A gene, which encodes Therapy with gamma globulin and antibiotic prophylaxis
for a protein that permits docking of the cytolytic gran- is essential. Despite these measures, infections may still
ules to the cell membrane.212 In contrast, GS type 1 occur. HSCT may cure the immunologic abnormalities
(caused by mutations of the MYO5A gene, encoding for and resolve increased susceptibility to infections, but
the myosin Va protein) and GS type 3 (due to mutations inflammatory bowel disease may persist, along with
of the gene encoding for the melanin chaperone mela- extra-immune manifestations of the disease.223
nophilin) are characterized by hypopigmentation without A few patients have been found to have a similar phe-
immunodeficiency. notype as a result of a so-called hypermorphic (gain of
Hermansky-Pudlak syndrome type 2 (HPS2) is char- function) mutation of the IκBα chain.224,225 In this situa-
acterized by oculocutaneous albinism, bleeding diathesis, tion the IκBα is resistant to phosphorylation by IKK and
neutropenia, interstitial lung disease, and recurrent infec- cannot be dissociated, degraded, and induced to release
tions.213 Patients are at increased risk of hemophagocyto- NF-κB so that it may translocate to the nucleus to acti-
sis. The disease is caused by mutations of the β subunit vate transcription.
of the adaptor-related protein complex 3 (gene AP3B1)
involved in sorting of proteins to the lysosomes.214 Patients DEFECTS OF TOLL-LIKE RECEPTOR SIGNALING
with HPS9, which is caused by mutations of the pallidin
(PLDN) gene,215 present with hypopigmentation and nys- IRAK-4 and Myd88 are components of a complex mediat-
tagmus; recurrent cutaneous infections also have been ing signaling downstream of all TLRs (except TLR3).226
reported.216 Patients with IRAK4 or MYD88 mutations have severe,
invasive bacterial infections such as meningitis, bacteremia,
MUTATIONS OF THE NUCLEAR FACTOR septic arthritis, deep-tissue abscesses, and osteomyelitis
κ-B PATHWAY with gram-positive organisms (pre­dominantly Staphylococ-
cus aureus and Staphylococcus pneumoniae.227-229 Less
NF-κB is a transcription factor that is critical for the severe skin and respiratory infections also occur frequently.
activation of numerous genes on leukocyte stimulation.217 Most patients begin to exhibit infections in early childhood,
Activity of this factor is regulated by an inhibitor known but these wane significantly in frequency and intensity in
as IκB. Phosphorylation of IκB by IκB kinase (IKK) leads the second decade of life. Most patients have impaired
to IκB degradation and liberates active NF-κB. IKK is antibody responses to pneumococcal polysaccharides, but
composed of three subunits, α, β, and γ; the latter is also other routine tests of immune function are normal. Many
known as the NF-κB essential modulator (NEMO). The patients have high levels of all Ig isotypes, possibly owing
gene encoding NEMO is on the X chromosome. Null to immune stimulation by repeated bacterial infections.
mutations in this gene are incompatible with life for male Signaling is impaired through all TLRs other than TLR3.
subjects and lead to the X-linked dominant disease incon- Management is mainly with antibiotic prophylaxis and IgG
tinentia pigmenti in females. Certain mutations that therapy.
allow partial NEMO function are associated with an
immunologic phenotype that may have some similarities THE SYNDROME OF WARTS,
to hyper-IgM. Along with a combined immunodeficiency, HYPOGAMMAGLOBULINEMIA, INFECTIONS,
these patients may exhibit hypohidrotic ectodermal dys- AND MYELOKATHEXIS
plasia and lymphedema with osteopetrosis.217-220 Distinct
hypomorphic mutations define specific disease character- The syndrome of warts, hypogammaglobulinemia, infec-
istics, thus establishing genotype-phenotype correlation, tions, and myelokathexis (WHIM syndrome) is an auto-
albeit imperfectly.218 Somatic mosaicism in T lympho- somal dominant disorder of leukocyte trafficking caused
cytes has been detected in a significant proportion of by mutations of the chemokine receptor CXCR4.230
males with NEMO deficiency, providing evidence for Patients carry heterozygous mutations in the intracellular
selective advantage for NEMO-expressing T cells in tail of CXCR4 that prevent interaction with β-arrestin,

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24  Primary Immunodeficiency Diseases 903

thus allowing continuous signaling induced by CXCR4 tion, medical history, and imaging studies are needed to
ligand, CXCL12. This signal retains mature neutrophils evaluate, diagnose, and treat any infections. Controver-
in the bone marrow (myelokathexis) and alters trafficking sial results have been obtained after HSCT.243,244
of B and T lymphocytes, causing lymphopenia.231
Impairment of cellular immunity and defective number AUTOSOMAL RECESSIVE HYPER-
of plasmacytoid dendritic cells (which are the major IMMUNOGLOBULIN E SYNDROME CAUSED
source of IFN-γ) cause warts, and neutropenia and hypo- BY TYK2 MUTATIONS
gammaglobulinemia account for recurrent bacterial infec-
tions that mostly affect the respiratory tract.231,232 The Two distinct forms of autosomal recessive HIES are
number of switched memory B cells is reduced, and there known. Of these, DOCK8 deficiency has been discussed
is oligoclonality of the antibody repertoire.233 Gamma in the preceding section “Other Combined Immunodefi-
globulin replacement therapy generally reduces the rate ciencies with Variable Presentation.” Two patients with
of infection. The CXCR4 antagonist AMD3100 (plerixa- autosomal recessive HIES caused by mutations of TYK2,
for) corrects neutropenia and lymphopenia.234 a member of the JAK family of tyrosine kinases involved
in intracellular signaling, have been reported. The first
HYPERIMMUNOGLOBULIN E SYNDROME CAUSED patient presented with atopy, elevated serum IgE, and
BY STAT3 MUTATIONS susceptibility to infections sustained by S. aureus, BCG,
Salmonella organisms, and viruses.245 The second patient
Hyper-IgE syndrome (HIES, often designated type 1) suffered from disseminated BCG infection, neurobrucel-
was initially described in 1972 in patients with severe losis, and cutaneous herpes zoster but had normal serum
sinopulmonary bacterial infections, severe skin superin- IgE and did not develop atopy.246
fections with S. aureus on a chronic eczematous eruption
(for which the disease is also known as Job syndrome), CHRONIC MUCOCUTANEOUS CANDIDIASIS
and susceptibility to Aspergillus fumigatus pneumonitis
with pneumatocele formation.235 Additional manifesta- CMC affecting the nails, skin, and mucosa is the clinical
tions include asymmetric or coarse facial features, hallmark of three distinct genetic disorders that affect
delayed shedding of primary teeth, bone fragility and IL-17–dependent immunity.247 These include complete,
fractures, scoliosis, and keratoconjunctivitis.236 Patients autosomal recessive deficiency of IL-17 receptor α chain
show increased susceptibility to nonfilamentous molds, (IL17RA),248 partial autosomal dominant IL-17F defi-
such as P. jiroveci pneumonia and in particular chronic ciency,248 and heterozygous gain-of-function mutations
mucocutaneous candidiasis (CMC). There is an increased of signal transducer and activator of transcription 1
rate of malignancies, especially non-Hodgkin lym- (STAT1).249,250 The latter represents the most common
phoma.236 Cardiovascular anomalies have been described cause of isolated CMC. Mutations of caspase recruitment
in recent years and include aneurysms, in particular of domain-containing protein 9 (CARD9) gene, encoding a
the carotids, cerebral arteries, and coronary arteries, and cytosolic adaptor molecule involved in intracellular sig-
may lead to additional complications such as myocardial naling in cells recognizing fungi, also affect development
infarction.237 Inheritance of this form of HIES is autoso- of Th17 cells and cause CMC; however, CARD9-deficient
mal dominant, but many cases represent sporadic pre- patients are also at increased risk of disseminated Candida
sentations. The disease is caused by heterozygous infections as well as of other fungal infections.251 Defi-
dominant-negative mutations of the STAT3 gene that ciency of Th17 cells accounts for CMC also in other
encodes for a transcription factor involved in signaling forms of primary immunodeficiency, including T-cell defi-
from a multitude of receptors.238,239 In particular, STAT3 ciencies, HIES, and autoimmune polyendocrinopathy-
is required for the development of Th17 cells, which candidiasis-ectodermal dystrophy (APECED).
secrete IL-17 and IL-22, two cytokines that play an
important role in defense against candida and in pro- IMMUNODEFICIENCIES WITH SKELETAL
moting secretion of antimicrobial peptides by bronchial ABNORMALITIES
epithelial cells.240
The major immunologic findings are elevated serum Cartilage-hair hypoplasia (CHH) is an autosomal reces-
levels of IgE (3000 to >50,000 IU/mL) and eosinophilia. sive disease characterized by short-limbed dwarfism with
Along with a deficiency of Th17 cells, a reduced number metaphyseal dysplasia, sparse and fair hair, and joint
of memory (CD27+) B lymphocytes also have been hypermotility. Dyserythropoietic anemia and a variable
reported. The diagnosis is established on clinical and degree of immunodeficiency are present in 80% of the
laboratory grounds; a scoring system241 has been devel- patients. A minority of subjects also present with
oped that may be helpful, especially if used in combina- Hirschsprung disease. There is a 6% to 10% rate of
tion with demonstration of lack of Th17 cells.242 malignancies, especially lymphoma and basal cell carci-
Management of HIES caused by STAT3 mutations is noma. The disease has a higher prevalence among Finnish
mainly by skin care and antimicrobial prophylaxis against and Amish populations252 and is caused by mutations
S. aureus. The role of antifungal prophylaxis is contro- in the RMRP gene that encodes for the untranslated
versial, but it may be helpful in patients with CMC. HIES RNA component of the mitochondrial RNA-processing
patients may lack classical signs and symptoms of infec- endoribonuclease253 that is involved in multiple functions,
tion, such as fever. Therefore careful physical examina- including ribosomal and messenger RNA processing,

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904 SECTION VII  IMMUNE SYSTEM

mitochondrial DNA replication, and negative regulation recurrent and severe viral infections (especially those
of target RNA transcripts on interaction with TERT caused by papillomavirus and herpesviruses), and fungal
(telomerase reverse transcriptase).252 infections. There is increased risk of myelodysplasia and
The immunodeficiency of CHH is characterized by malignancies, including acute myeloid leukemia, squa-
increased frequency of infections. Severe and persistent mous cell carcinoma, and EBV-positive leiomyosarcoma.
viral infections (EBV, CMV, HSV, and VZV) and fungal Pulmonary alveolar proteinosis and primary lymphedema
infections may occur, in addition to recurrent respiratory have been observed in several patients.266-269
infections. Granulomatous lesions affecting the skin and Typical laboratory features include profound monocy-
other tissues have been described in several patients.254 topenia, severe reduction in the number of B and NK
Laboratory tests reveal a variable degree of immune dys- lymphocytes (in particular, of the CD56bright subset) and
function that predominantly affects T cells. In rare cases, dendritic cells and elevated levels of fms-like tyrosine
immunodeficiency is very severe and may resemble SCID, kinase ligand (Flt3L).266,267,270 Depletion of regulatory T
“leaky” SCID with reduced number of CD8+ lympho- cells also has been reported.267 Examination of the bone
cytes, or OS.255,256 Irrespective of the severity of the clini- marrow reveals hypocellularity, often associated with
cal phenotype, thymopoiesis is reduced, and there is multilineage dysplasia and cytogenetic abnormalities,
T-cell lymphopenia. Moreover, T lymphocytes show including monosomy 7 and trisomy 8. In vitro IL-12 and
abnormalities of cell cycle progression and an increased IFN-γ production in response to stimulation with LPS is
rate of apoptosis.257 HSCT is an effective form of treat- markedly reduced,267,268 suggesting that disruption of the
ment for patients with a severe clinical phenotype.258 IL-12/IFN-γ axis may contribute to the increased occur-
Schimke immuno-osseous dysplasia is an autosomal rence of mycobacterial disease.
recessive disease characterized by spondyloepiphyseal The disease has been referred to as MonoMAC syn-
dysplasia, focal glomerulosclerosis leading to progressive drome (to indicate the monocytopenia and susceptibility
renal failure, and T-cell immunodeficiency.259 There is T to nontuberculous mycobacterial infections)266,268 or
cell lymphopenia, with an increased proportion of DCML (dendritic cells, monocytes, B and NK lympho-
activated/memory T cells and of TCRγδ-expressing T cytes) deficiency267 and has been shown to be caused by
lymphocytes. The disease is caused by mutations of the heterozygous, loss-of-function mutations of the GATA2
SMARCAL1 gene, which encodes for a chromatin remod- gene.271-273 GATA-2 is a transcription factor that contains
eling protein.260 two highly conserved zinc finger domains that mediate
protein-DNA and protein-protein interactions and is
IMMUNODEFICIENCIES ASSOCIATED required for stem cell homeostasis,274 lymphatic vessel
WITH DISORDERS OF FOLATE AND development,273 and the maturation and homeostasis of
COBALAMIN METABOLISM NK lymphocytes.270 Disease-causing mutations also
include intronic deletions and point mutations in regula-
Inborn errors of folate and cobalamin metabolism may tory regions of the gene that affect GATA2 transcript
associate with varying degrees of immunodeficiency. In levels.275 Both autosomal dominant inheritance and spo-
particular, genetically determined defects in vitamin B12 radic presentation have been reported. If untreated, the
metabolism are associated with megaloblastic anemia, disease has a severe prognosis, with death occurring in
neutropenia, and neurologic symptoms with seizures and adulthood as a result of infections or malignancies. Non-
developmental delay.261 Transcobalamin II (gene TCN2) myeloablative HSCT has been successfully performed in
deficiency causes neutropenia leading to recurrent bacte- several patients, with reconstitution of the number of
rial infections.262 Severe lymphopenia is observed in monocyte, B-cell, and NK-cell populations and reversal
patients with deficiency of methionine synthase, causing of the clinical phenotype.276
a SCID-like phenotype with severe viral and bacterial
infections.263 Mutations of proton-coupled folate trans- IMMUNODEFICIENCIES WITH IMMUNE
porter that impede folate absorption through the gastro- DYSREGULATION
intestinal mucosa are also associated with extreme
lymphopenia and clinical features of SCID.264 Mutations Although autoimmune and inflammatory manifestations
of the MTHFD1 gene that encodes for a trifunctional may be seen in a large number of primary immunodefi-
protein essential for processing of single-carbon folate ciencies, they represent the main feature in some. The
derivatives cause SCID with decreased number of T, B, pathophysiology of these disorders may reflect a variety
and NK lymphocytes, which is associated with megalo- of mechanisms, including impairment of central and
blastic anemia, leukopenia, atypical hemolytic uremic peripheral tolerance and chronic immune activation asso-
syndrome, and neurologic abnormalities. Parenteral sup- ciated with the inability to clear infections. These disor-
plementation therapy is beneficial.265 ders and their associated genes are listed in Table 24-5.

GATA2 DEFICIENCY AUTOIMMUNE POLYENDOCRINOPATHY-


CANDIDIASIS-ECTODERMAL
In 2010 Vinh and coworkers266 reported on a series of DYSTROPHY SYNDROME
patients with a distinct clinical phenotype characterized
by onset in late childhood or adulthood, susceptibility APECED syndrome represents the prototypic disorder
to disseminated nontuberculous mycobacterial disease, associated with impairment of central T-cell tolerance.

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24  Primary Immunodeficiency Diseases 905

TABLE 24-5  Immunodeficiency Syndromes with IPEX require immune suppression, but the only
Associated with Dysregulation definitive treatment currently available is allogeneic
HSCT.289
Syndrome Gene
Autoimmune AIRE DEFECTS OF IL-2–MEDIATED SIGNALING
polyendocrinopathy
candidiasis ectodermal IL-2–mediated signaling is important to maintain immune
dystrophy (APECED) homeostasis and support the function of Treg lympho-
Immune dysregulation FOXP3 cytes. Mutations in the IL2RA gene, which encodes
polyendocrinopathy X-linked CD25, the α chain of the IL-2R, cause immunodeficiency
(IPEX) with IPEX-like immune dysregulation.290,291 The clinical
Defects of IL-2 signaling IL2RA, STAT5B phenotype is marked by severe diarrhea, failure to thrive,
CMV infection, chronic lung disease, lymphadenopathy,
Autoimmune CASP8, CASP10, FAS, FASLG, splenomegaly, and autoimmunity (diabetes mellitus,
lymphoproliferative KRAS, NRAS
syndrome (ALPS) autoimmune hepatitis). Poor in vitro T-cell function that
could not be corrected with exogenous IL-2 was demon-
Other ITCH
strated. The number of FOXP3+ cells was preserved in
patients with CD25 deficiency; however, secretion of
IL-10, a cytokine with immunosuppressive activity, was
impaired,290 possibly accounting for the autoimmune
manifestations of the disease.
APECED is inherited as an autosomal recessive trait and Mutations of the signal transduced and activator of
is characterized by autoimmune hypoparathyroidism, transcription 5B (STAT5B) gene, which encodes a tran-
Addison disease, and CMC. Patients are also prone to scription factor activated by IL-2 signaling, cause an
other autoimmune manifestations, such as hepatitis, alo- autosomal recessive form of immunodeficiency with
pecia, ovarian failure, and hypothyroidism. There is an immune dysregulation. Because STAT5B is also activated
increased incidence of oral squamous cell carcinoma, in response to growth hormone receptor stimulation,
and fulminant autoimmune hepatitis. The disease is patients with STAT5B deficiency also show growth failure
caused by mutations in the gene AIRE (autoimmune with growth hormone insensitivity.292,293
regulator) encoding a transcription factor expressed by
medullary thymic epithelial cells (mTECs).277,278 AIRE AUTOIMMUNE LYMPHOPROLIFERATIVE
promotes expression of tissue-specific antigens that are SYNDROME
presented by mTECs and thymic dendritic cells to
nascent T lymphocytes.279 High-affinity recognition of Apoptosis of self-reactive lymphocytes is another impor-
self peptides leads to deletion of self-reactive T cells. tant mechanism to prevent autoimmunity in the periph-
Therefore mutations of the AIRE gene compromise the ery and may be induced either through the extrinsic,
mechanism of central tolerance and result in APECED, Fas-dependent pathway or through induction of the mito-
which is associated with production of multiple autoan- chondrial pathway in response to cell damage and cyto-
tibody specificities.280 Interestingly, autoantibody pro- kine (e.g., IL-2) starvation. Both pathways converge on
duction in patients with APECED is not restricted to caspase 9 and downstream effector caspases 3 and 7,
AIRE-dependent self-antigens but also includes antibod- causing apoptosis. Autoimmune lymphoproliferative syn-
ies to interferon-α and β281 as well as IL-17 and drome (ALPS) is characterized by lymphadenopathy, sple-
IL-22.282,283 Defective Th17-dependent immune responses nomegaly, and autoimmune cytopenias and an increased
may account for chronic mucocutaneous candidiasis in risk of developing lymphoma. Infiltrative lymphoprolif-
this disease. erative disease may also cause organ-specific complica-
tions (glomerulonephritis, hepatitis, encephalitis, uveitis,
IMMUNE DYSREGULATION interstitial pulmonary disease). There is a characteristic
POLYENDOCRINOPATHY ENTEROPATHY expansion of CD3+TCRαβ+CD4−CD8− double-negative
X-LINKED SYNDROME T cells (DNTs).294
Most patients are heterozygous for a mutation in the
Treg cells maintain peripheral T cell tolerance by sup- FAS gene; in such families the disease is inherited as an
pressing self-reactive T lymphocytes that have escaped autosomal dominant trait with variable penetrance.
central tolerance.284 Generation of Treg cells is controlled Somatic mutations in FAS are another common cause of
by the transcription factor FOXP3.285 Mutations of the the disease.295,296 More rarely, patients may show biallelic
FOXP3 gene cause immune dysregulation, polyendocri- mutations.
nopathy, enteropathy, X-linked (IPEX) syndrome.286,287 Other rare causes of ALPS are represented by muta-
IPEX is characterized by severe early-onset autoimmune tions of genes encoding Fas ligand (FasL),297 FADD,298
manifestations that involve the gut (causing intractable caspase 8,299 and caspase 10,300 all of which are involved
diarrhea), pancreas (diabetes), the skin, and other organs. in the Fas-mediated signaling pathway leading to apop-
Lymphoproliferation and cytopenias are also very common. tosis. The number of DNTs is only marginally elevated
Delayed presentations have been also observed.288 Patients in patients with caspase 8 deficiency.

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906 SECTION VII  IMMUNE SYSTEM

In addition to an increased proportion of DNTs, other TABLE 24-6  Immunodeficiency Syndromes with
biomarkers that may facilitate the diagnosis of ALPS and Impaired Cytotoxicity
that are associated especially with FAS mutations include
elevated serum levels of vitamin B12, soluble FasL, IL-10, Syndrome Gene
and IL-18. Hypergammaglobulinemia is common. More-
Familial hemophagocytic PRF1, STX11,
over, patients with ALPS caused by FAS mutation fre- lymphohistiocytosis STXBP2, UNC13D
quently have a reduced number of memory (CD27+) B
lymphocytes.301 X-linked lymphoproliferative syndromes BIRC4, SH2D1A
Defects of the “intrinsic” (mitochondrial) pathway of Other CD16, CD27, ITK
apoptosis leading to ALPS include gain-of-function muta-
tions of NRAS302 and somatic mutations of KRAS,303,304
but these variants do not result in an increased number FAMILIAL HEMOPHAGOCYTIC
of DNTs. LYMPHOHISTIOCYTOSIS
Management of ALPS includes use of immunosuppres-
sive drugs (steroids, mycophenolate mofetil, sirolimus) to Familial hemophagocytic lymphohistiocytosis (FHL)
control autoimmune manifestations and regular monitor- includes a heterogeneous group of monogenic disorders
ing of lymphoproliferation by computed tomography characterized by impaired cell-mediated cytotoxicity. In
scanning or positron emission tomography for surveil- patients with FHL, the inability to clear viral infections
lance of lymphoma. Splenectomy may improve the cyto- causes persistent activation of CD8+ and NK lympho-
penias but is associated with a marked increase of sepsis. cytes, with production of high amounts of IFN-α and -β
Chronic cytopenias tend to improve over time; HSCT and of proinflammatory cytokines (tumor necrosis factor-
should be reserved for very severe clinical presentations alpha [TNF-α], IL-6).309 Clinical features of FHL include
with autoimmune disease refractory to treatment.305 recurrent episodes of high fever, pancytopenia, liver and
spleen enlargement, and signs of neurologic involvement.
The diagnostic criteria were revised in 2007.310 Elevated
ITCH DEFICIENCY serum levels of triglycerides, ferritin, and soluble CD25
Mutations of the E3 ubiquitin ligase ITCH have been and decreased levels of fibrinogen and poor NK function
shown to cause multisystem autoimmune disease in are typical laboratory findings. If left untreated, FHL is
affected individuals from a large Amish kindred.306 Char- rapidly fatal. Severe bacterial and fungal infections and
acteristic clinical features include failure to thrive, hepa- multiple organ failure are the main causes of death. Treat-
tosplenomegaly, multiorgan autoimmune manifestations ment should be aimed at eradicating the underlying infec-
(hypothyroidism, hepatitis, diabetes, enteropathy), tion while suppressing immune activation at the same
chronic lung disease, developmental delay, dysmorphic time. Corticosteroids, cyclosporine A, etoposide, and
features, and hypotonia. Dysfunction of E3 ubiquitin antithymocyte globulin are often effective in tempering
ligases have been shown to lead to indiscriminate T cell immune activation.311 However, relapses are common,
activation, loss of tolerance to self-antigens and accumu- and the only curative treatment is represented by HSCT.
lation of autoreactive B lymphocytes.307 In particular, reduced intensity conditioning has shown
excellent efficacy and limited toxicity.312
IMMUNODEFICIENCIES WITH IMPAIRED CELL- The genetic defect has been identified for four forms
MEDIATED CYTOTOXICITY of FHL so far, and all of them are inherited as autosomal
recessive traits. Perforin deficiency accounts for approxi-
CD8+ cytotoxic T lymphocytes (CTLs) and NK cells play mately 30% of all cases of FHL. It is caused by mutations
a critical role in antiviral immune defense through two of the PRF1 gene that prevent expression or correct
mechanisms: Fas-mediated apoptosis of virus-infected cells assembly of perforin multimers that form pores through
and release of cytolytic granules. In resting CTLs and NK which cytolytic enzymes are released into target cells.313
lymphocytes, cytotoxic proteins are contained in endo- Mutations of the UNC13D gene, encoding for Munc13-
somal secretory granules. On activation of CTLs and NK 4, impair priming of the cytolytic granules, which is nec-
lymphocytes, lytic granules polarize toward the immune essary for their fusion with the cell membrane. UNC13D
synapse, dock, and fuse with the cell membrane of the effec- mutations represent the most common form of FHL
tor cell. Multimers of perforin form pores through which (30% to 40% of all cases).314 Defects of the Syntaxin 11
CTLs and NK cells release cytotoxic proteins (granzyme B, (STX11) gene affect granule exocytosis.315 Finally, FHL
granulolysin) into virus-infected target cells, causing activa- may also be caused by defects of Munc18-2, a protein
tion of caspases and apoptosis of target cells.308 partner of STX11 encoded by the Syntaxin binding
Defects in this process are responsible for various protein 2 (STXBP2) gene.316
forms of familial hemophagocytic lymphohistiocytosis.309
Defective cell-mediated cytotoxicity is also observed in X-LINKED LYMPHOPROLIFERATIVE DISEASE
several forms of pigmentary dilution disorders (discussed
previously). Finally, selective susceptibility to EBV infec- X-linked lymphoproliferative (XLP) disease is character-
tion is at the basis of various forms of lymphoprolifera- ized by unique susceptibility to severe complications after
tive syndrome. These diseases and their associated genes EBV infection in male subjects. Two genetically distinct
are listed in Table 24-6. forms are known. In XLP1 the disease is caused by

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24  Primary Immunodeficiency Diseases 907

mutations of the SH2 domain containing protein 1 A subsets. By interacting with CD70, it promotes genera-
(SH2D1A) gene, encoding for a small adapter protein tion and maintenance of T-cell memory. It is also com-
(SLAM-associated protein, or SAP) involved in intracel- monly used as a marker of memory B lymphocytes. CD27
lular signaling in T and NK lymphocytes.317,318 In particu- deficiency has been identified in some patients presenting
lar, SAP binds to CD244 (a SLAM family member) with severe EBV infection. Lymphoma and secondary
expressed by NK lymphocytes. EBV-infected B cells hypogammaglobulinemia have been reported in some of
express high levels of CD48, the CD244 ligand. On these patients. HSCT represents a curative form of
CD244/CD48 binding, SAP participates at intracellular treatment.327,328
signaling and promotes NK cytolytic activity against
EBV-infected target cells. In the absence of SAP, NK cyto- CD16 DEFICIENCY
lytic activity is impaired.319 SAP is also important for the
function of follicular helper T cells that promote matura- One of the mechanisms by which NK lymphocytes
tion of antibody responses.320 XLP2 is caused by muta- mediate killing of target cells is antibody-dependent cel-
tions of the BIRC4 gene, which encodes for the X-linked lular cytotoxicity (ADCC), whereby antibody-bound
inhibitor of apoptosis (XIAP) protein.321 target cells come in contact with NK lymphocytes through
XLP1 and XLP2 have partially overlapping clinical binding of the Fc region of IgG molecules to a specific
features. Hemophagocytic lymphohistiocytosis (HLH) receptor (FcγRIIIa, also known as CD16) expressed on
subsequent to primary EBV infection is a prominent sign the surface of NK lymphocytes. Homozygosity for the
at clinical presentation in both diseases. XLP1 may mani- Leu66His amino acid substitution in CD16 causes defi-
fest with fatal infectious mononucleosis, aplastic anemia, cient spontaneous NK cell-mediated cytotoxicity but sur-
pulmonary lymphoid granulomatosis with vasculitis, and prisingly leaves ADCC intact. Expression of CD2, a
lymphoma.322 A proportion of XLP1 patients who survive co-activating NK cell receptor, is decreased, affecting
primary EBV infection will develop hypogammaglobu- intracellular signaling in NK lymphocytes. Recurrent and
linemia, which in some cases is associated with elevated severe herpesvirus infections are the clinical hallmark of
levels of IgM or IgA. Some patients may have a clinical this condition.329
and laboratory phenotype consistent with common vari-
able immunodeficiency (CVID, discussed later). Func- IMMUNODEFICIENCIES WITH SELECTIVE
tional activity of NK and CTLs is impaired. Finally, PREDISPOSITION TO PATHOGENS
patients with XLP1 lack NKT lymphocytes.323 Without
HSCT, 62.5% of the patients survive (and most of them Most forms of primary immunodeficiencies are charac-
require Ig replacement); however, poor survival rates (less terized by susceptibility to a broad range of pathogens,
than 20%) have been observed in patients without trans- whose nature (bacteria, viruses, fungi, protozoa) reflects
plants who have features of HLH. HSCT may cure the underlying immune defect. However, in the last two
approximately 80% of XLP1 patients, but poorer decades it has become clear that certain gene defects
outcome (50% survival) has been observed if HLH is that affect the immune system may lead to selective pre-
present.322 disposition to a narrow group of pathogens. These find-
In contrast, XLP2 causes recurrent episodes of HLH, ings have supported the genetic theory of infectious
with or without EBV infection.323 Patients with XLP2 are diseases, whereby life-threatening infections early in life
not at increased risk of lymphoma; on the other hand, may in fact be caused by inborn errors of immunity.330
inflammatory bowel disease is frequently observed.324 These disorders and their associated genes are listed in
Definitive treatment of XLP2 is also based on HSCT; Table 24-7.
however, use of a myeloablative conditioning regimen is
associated with high mortality.325 Mendelian Susceptibility to Mycobacterial Diseases
The designation Mendelian susceptibility to mycobacte-
rial diseases (MSMD) refers to a group of PIDDs char-
IL-2 INDUCIBLE TYROSINE KINASE DEFICIENCY acterized mainly by selective susceptibility to infection
Interleukin-2 inducible tyrosine kinase (ITK) is a nonre- with mycobacteria including both Mycobacterium
ceptor tyrosine kinase that modulates the strength of tuberculosis and many atypical species.331-334 Patients
intracellular signaling in T lymphocytes on TCR-induced
activation. Patients with ITK deficiency are susceptible to
EBV-driven lymphoproliferative disease (often involving
the lungs as well), Hodgkin lymphoma, hypogamma-
globulinemia, autoimmunity, and HLH.326 The disease is TABLE 24-7  Immunodeficiencies with Selective
inherited as an autosomal recessive trait. There is a Predisposition to Pathogens
reduced number of naïve CD4+ lymphocytes and of NKT
cells. Allogeneic HSCT may cure the disease. Syndrome Gene
Mendelian susceptibility to IFNGR1, IFNGR2, IL12B,
mycobacterial disease IL12RB1, STAT1
CD27 DEFICIENCY
Epidermodysplasia verruciformis TMC6, TMC8
CD27 is a member of the TNF receptor family and is
Trypanosomiasis APOL1
broadly expressed on the surface of various lymphocyte

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908 SECTION VII  IMMUNE SYSTEM

are also susceptible to disseminated infections with Sal- Inheritance varies according to the genes and the spe-
monella species. There are no other consistent clinical cific mutations involved. Thus far, mutations in
manifestations, and all routine screening tests of UNC93B1 have shown exclusively autosomal recessive
humoral and cellular immunity are normal. The vast inheritance, whereas mutations of TRAF3 and TBK1
majority of these patients harbor mutations in one of have exhibited exclusively autosomal dominant inheri-
five genes that encode elements in a signaling cascade tance. Mutations of TLR3 and TICAM1 have shown
involving IFN-γ and IL-12. IL-12 is produced by mono- either dominant or recessive inheritance depending on
nuclear cells in response to stimulation by way of TLRs the specific lesion.
and other pattern recognition receptors. IL-12 stimu-
lates Th1 differentiation, and mature Th1 cells and NK Susceptibility to Trypanosomiasis
cells produce IFN-γ. IFN-γ then acts on mononuclear Trypanosomes are single-cell (protozoan) organisms
cells to promote intracellular killing of phagocytosed causing endemic infections in many parts of the world.
organisms. In the absence of the normal operation of Trypanosoma cruzi is the causative agent of Chagas
this sequence, macrophages are not able to kill ingested disease, and it is estimated that approximately 10
mycobacteria or Salmonella organisms, and severe million people in South America harbor this parasite,
infection results. Thus far, mutations have been found most being asymptomatic. Subspecies of Trypanosoma
in the genes encoding the IL-12 p40 subunit (IL12B), brucei are responsible for sleeping sickness, and it is
the β1 chain of the IL-12 receptor (IL12RB1), both estimated that more than 60 million individuals in
chains of the IFN-γ receptor (IFNGR1, IFNGR2), and Africa harbor this organism. Most individuals are pro-
the STAT1 signal transducing molecule which mediates tected from progression of disease by apolipoprotein
signaling of the IFN-γ receptor.331-334 Most cases show L1 (APOL1), which can lyse the T. brucei plasma
autosomal recessive inheritance, but a few specific membrane and kill the organism. Some strains of try-
mutations of IFNGR1 may exhibit autosomal dominant panosomes have become more pathogenic by virtue
inheritance. Acquired forms of susceptibility to myco- of their resistance to APOL1 lysis.344-348 Conversely,
bacterial infection have been ascribed to autoantibodies individuals who have mutations in their APOL1 genes
to IFN-γ. are more susceptible to trypanosome infection and
Therapy for MSMD is mainly through aggressive severe disease. There are no known clinical conse-
treatment of infections when they occur and prophy- quences of deleterious APOL1 mutations beyond sus-
laxis for selected individuals who may relapse frequently. ceptibility to T. brucei. However, isoforms of APOL1
For patients with hypomorphic (partly functional) muta- selected through evolution for higher trypanosome lytic
tions of IFNGR1, IFN-γ supplementation may be activity are risk factors for nondiabetic kidney disease
beneficial. in African-Americans.349
Epidermodysplasia Verruciformis
HUMORAL IMMUNODEFICIENCY
Mutations in the genes TMC6 (transmembrane channel-
like 6) and TMC8 give rise to epidermodysplasia verru- The humoral immunodeficiencies and their associated
ciformis (EV). These genes were previously called gene defects are listed in Table 24-8. These disorders are
EVER1 and EVER2, respectively. EV exhibits autoso- characterized by hypogammaglobulinemia or dysgamma-
mal recessive inheritance, and affected individuals are globulinemia, often together with relative deficiency of
susceptible to persistent skin infection only by HPV.335,336 antibody responses to various forms of antigenic chal-
There is a high rate of malignant transformation in the lenge.3,4 Cellular immunity is generally intact. Humoral
skin, but there are no other infectious susceptibilities or immunodeficiency is most commonly manifested by
clinical manifestations of the disease. Acquired EV has recurrent bacterial and viral infections of the upper and
been associated with human immunodeficiency virus lower respiratory tract. Pyogenic skin infections, as well
(HIV) infection.337,338 as meningitis, osteomyelitis, and other foci of infection,
are also seen frequently. These infections are generally
Herpes Simplex Encephalitis caused by the same organisms that are virulent in immu-
HSVs are prevalent in the general population and are nocompetent hosts, predominantly encapsulated bacteria
capable of causing disseminated severe and even fatal such as Streptococcus pneumoniae, Hemophilus influen-
infections in patients with profound T-cell defects (dis- zae, S. aureus, and Neisseria meningitidis. Viral infections
cussed earlier). However, in rare cases individuals are usually resolve normally in these patients, although a
susceptible specifically to encephalitis caused by HSV, in higher rate of recurrence with the same agent may be seen
the absence of any other organ or system involve- because there is impaired production of neutralizing anti-
ment.339-343 To date, mutations in five distinct genes have bodies or B-cell memory. The results of physical examina-
been associated with this clinical entity: TLR3 (TLR3), tion are not specific and show only the presence or
UNC93B1, TRAF3, TICAM1 (previously known as sequelae of microbial infections. A relative paucity of
TRIF), and TBK1. All of the proteins encoded by these peripheral lymphoid tissue may be noted in some patients,
pathways interact in transducing responses by way of especially areas rich in B cells (e.g., tonsils). Studies of
TLR3 (and in some cases also TLR4) with the common peripheral blood lymphocyte subsets are often normal;
result of a failure to produce sufficient amounts of type the number of B cells may be reduced in certain
1 interferons in response to HSV infection in the brain. syndromes.

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24  Primary Immunodeficiency Diseases 909

TABLE 24-8  Humoral Immunodeficiencies and erythroid cells. A variety of BTK gene defects such as
Associated Gene Defects point mutations, deletions, and insertions have been
described in patients with XLA. In most patients B-cell
Syndrome Gene development is impeded at an early stage (the pro–B-cell
to pre–B-cell transition).
X-linked (Bruton) BTK
agammaglobulinemia BTK mutations account for approximately 85% of all
cases of agammaglobulinemia.354 BTK mutations have
Autosomal recessive CD79A, CD79B, BLNK, also been described in patients with “atypical” XLA who
agammaglobulinemias IGHM, IGLL1, LRRC8,
PIK3R2 have low numbers of B cells and low-level antibody
production.351-353 In some patients with atypical XLA,
Monogenic common variable BAFFR, CD19, CD21, CVID was misdiagnosed (discussed later) before discov-
immunodeficiency CD81, ICOS
ery of the BTK defect.355 In general, BTK mutations that
Common variable Undefined permit the expression of small amounts of functional or
immunodeficiency partially functional Btk protein are associated with milder
Good syndrome Undefined clinical phenotypes and slightly higher numbers of B cells
Selective IgA deficiency Undefined in the circulation. 351-353 However, even siblings with iden-
tical mutations may show quite divergent phenotypes.
IgG subclass deficiency Undefined Female carriers of XLA show nonrandom X-chromosome
Specific antibody deficiency with Undefined inactivation in their B cells.
normal immunoglobulins
Autosomal Recessive Agammaglobulinemias
Transient Undefined
hypogammaglobulinemia of Female patients with agammaglobulinemia and no B cells
infancy and males with a similar phenotype lacking BTK muta-
Class-switch defects: tions have been described. These patients have forms of
 CD40 ligand deficiency TNFSF5 agammaglobulinemia with autosomal recessive inheri-
(X-linked HIM) tance that result from several distinct molecular defects,354
 CD40 deficiency TNFRSF5 including mutations of the Igµ heavy-chain locus, which
  B-cell–specific defects AICDA, UNG
prevents formation of the IgM heavy chain required for
formation of the Ig receptors on pre-B cells and mature
B cells (see Fig. 24-7). Defects of λ5 (a component of the
The Agammaglobulinemias
X-Linked Agammaglobulinemia
X-Linked agammaglobulinemia (XLA) is also known as Pre-BCR
Bruton agammaglobulinemia because Bruton provided Surrogate light chain
the classic description of the disease in 1952.350 Affected
IgM heavy chain
male subjects are often asymptomatic during the first
months of life while they are protected by transplacen- Igα
tally acquired maternal antibodies. These antibodies fall α β α β
to low levels by 6 to 9 months of age, and patients begin
to experience recurrent bacterial infections.351-353 Physical
Signal
examination at any age often reveals a striking absence
of tonsils and palpable lymphoid tissue. Serum Ig is ITAMs
absent or the level is extremely low; in addition, no B Lyn Btk PLC-γ 2 IP3
cells are found or their numbers are extremely low. Cel-
lular immunity is completely intact. However, these Ca++
DAG
patients are prone to the development of chronic entero-
viral meningoencephalitis and vaccine-associated para-
lytic poliomyelitis, which suggests an important role for PKC
humoral immunity in the control of these infections.
Moreover, patients may have arthropathy resembling Syk BLNK Vav MAPK
rheumatic disease, which may be due to infection with
Mycoplasma or Ureaplasma organisms. Other opportu- Figure 24-7 Signaling via the pre–B-cell receptor (Pre-BCR). The
nistic infections, such as P. jiroveci pneumonia, are seen Pre-BCR is composed of an IgM heavy chain with a surrogate light-
chain heterodimer (VpreB and λ5), along with a signaling heterodimer
only rarely. of Igα and Igβ. The immunoreceptor tyrosine-based activating motifs
XLA is another example of an immunodeficiency (ITAMs, see Fig. 24-5) recruit tyrosine kinases (Lyn, Syk, Btk) that initi-
caused by a defect in a signal transduction molecule. In ate downstream signaling. The adapter proteins BLNK and Vav recruit
fact, this protein tyrosine kinase is now known as Bruton additional signaling intermediates. Defects in components shown in
blue lead to agammaglobulinemia by blocking pre-BCR signaling and
tyrosine kinase ([Btk], Fig. 24-7).351-353 It is expressed in interrupting B-cell development. DAG, Diacylglycerol; IP3, inositol
B cells at all stages of development, as well as in cell lines triphosphate; PKC, protein kinase C; PLC, phospholipase C; MAPK,
derived from monocytes, macrophages, mast cells, and mitogen-activated protein kinase.

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910 SECTION VII  IMMUNE SYSTEM

surrogate light chain) also prevent formation of the pre– of patients and has been linked in some patients to HHV-8
B-cell Ig receptor required for B-cell development. Igα infection.365,366 More diffuse noncaseating granulomatous
(CD79a) and Igβ are transmembrane molecules required disease resembling sarcoidosis may be encountered in the
for signal transduction by way of the pre–B-cell and skin or viscera. Additional manifestations include lung
mature B-cell Ig receptors. Lesions in these genes prevent disease resembling asthma, chronic rhinitis, chronic giar-
Ig receptor signaling and B-cell development.356 Defects diasis, and recurrent or chronic arthropathy. The appar-
in the signal transduction proteins BLNK (B-cell linker ent “atopic” symptoms usually occur in the absence of
protein) and the p85 (β-regulatory) subunit of phos- allergen-specific IgE.367 Malabsorptive inflammatory
phoinositide 3′ (PI3) kinase (gene PIK3R2) have also bowel disease may occur.368 A broad spectrum of autoim-
been found.354,357 Mutations in these molecules prevent mune diseases may be associated, including a variety of
intracellular signaling after ligation of the B-cell receptor. cytopenias, arthritides, and vasculitides.369,370 Widespread
All these mutations arrest B-cell development at early lymphoproliferation may cause splenomegaly, adenopa-
stages in bone marrow. thy, and intestinal lymphonodular hyperplasia.371-373
One patient has been described with an apparent dom- Patients with CVID also have a higher incidence of gas-
inantly expressed translocation abrogating the function trointestinal and lymphoid malignancies.364 The relative
of the LRRC8) gene.358 The function of the LRRC8 risk for lymphoma has been estimated to be as much
protein is not yet known; it is a member of a growing as 30- to 400-fold greater than that in the general
family of proteins of unknown function called the LRRC8 population.
family, within the much larger and very diverse superfam- Memory B-cell subpopulations may be useful diagnos-
ily of leucine-rich repeat proteins. The female patient has tic and potentially prognostic markers in CVID.363,374-379
agammaglobulinemia with arrest of B-cell development Memory B cells express the CD27 (TNFRSF7) molecule.
in bone marrow. Naïve B cells express IgM and IgD but not CD27.
Unswitched memory B cells (also called marginal zone
cells) express IgM, IgD, and CD27. After class-switching
Other Predominantly Antibody Deficiency Syndromes
in germinal centers, B cells cease expressing IgM and IgD
Common Variable Immunodeficiency and subsequently express “downstream” Ig isotypes such
The diagnostic label of CVID encompasses an unknown as IgG, IgA, and IgE (Fig. 24-8). Memory B cells after
number of conditions that are genetically and etiologi- class-switching (switched memory B cells) are
cally distinct but have in common late-onset humoral IgM−IgD−CD27+. Additional subsets of B cells include
immunodeficiency, most often in the first or third decades transitional B cells (IgMhighCD38high) and CD21low B cells.
of life.359-363 Hypogammaglobulinemia and impaired spe- Proportions of these peripheral B cell subtypes enumer-
cific antibody production are universal, by definition. ated by flow cytometry correlate with clinical pheno-
Deficiency of IgA is very common in CVID.364 IgM is types. A more severe clinical phenotype with lower Ig and
also frequently affected; the pattern varies from one worse infections and increased granulomatous disease
individual to another. The levels of particular isotypes in correlates with a decreased number of marginal zone and
any patient are often static over time, but fluctuations class-switched B cells. Granulomatous disease and sple-
may occur. nomegaly also correlate with an expansion of CD21low B
Patients with CVID resemble individuals with XLA cells. Increase in transitional B cells is associated with
(and other humoral immunodeficiencies) because they lymphadenopathy. Specific B cell subsets are developmen-
also have recurrent sinopulmonary bacterial infections. tally regulated, and age-adjusted values should be used in
Chronic enteroviral infections, including meningoenceph- these instances.380-382
alitis, may also be seen in CVID. A form of granulocytic/ Although cellular immune function is grossly preserved
lymphocytic interstitial lung disease occurs in a subset in the majority of patients with CVID, a variety of

– M – – D – – G3 – – G1 – – psE – – A1 – – psG – – G2 – – G4 – – E – – A2

x x I
x x II
x x III
x x IV
x x V
x x VI

Figure 24-8  Immunoglobulin (Ig) heavy-chain gene deletion haplotypes. The top line shows the order of the Ig constant region genes (e.g., M =
IgM, etc.). The letters ps designate a pseudogene that is not expressed; numbers indicate subclasses. Six haplotypes have been defined (Roman
numerals). In each haplotype the entire region indicated by the Xs is missing. (Data from Lefranc MP, Hammarstrom L, Smith CI, Lefranc G:
Gene deletions in the human immunoglobulin heavy chain constant region locus: molecular and immunological analysis. Immunodefic Rev 2:265–
281, 1991.)

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24  Primary Immunodeficiency Diseases 911

functional and phenotypic T-cell abnormalities are found


in some.359,382-385 These include reductions in peripheral CD19, CD21, and CD81 Deficiencies
blood T-cell populations, as well as functional defects CD19 is expressed on B cells and is a component of a
such as reduced in vitro proliferative responses, defects receptor complex that contains CD21, a receptor for the
in cytokine production, decreased T-helper cell function, complement fragment C3dg (it is also called complement
abnormalities in T-cell signaling, diminished expression receptor 2, or CR2, and it is the cellular receptor for EBV)
of the costimulatory molecule CD40L, decreased numbers along with a tetraspan molecule called TAPA1 (also
of naïve T cells, increased suppressor T-cell function, and CD81). Simultaneous cross-linking of the CD19/CD21/
decreased numbers of regulatory T cells. CD81 complex and the B-cell Ig receptor lowers the
The genetic heterogeneity of CVID is beginning to threshold for B-cell activation. Patients with defects of
yield to molecular biologic analysis. Several single-gene the CD19,396,397 CD21,398,399 or CD81400 genes exhibit
defects have been found in varying (small) proportions recurrent infections, hypogammaglobulinemia, and low
of patients with CVID (discussed later). It may also levels of switched memory B cells. Autoimmunity and
happen that individuals classified as having CVID (or lymphoproliferation do not appear to be elements of the
a phenotype consistent with CVID) on clinical and labo- clinical presentations of these disorders.
ratory grounds may be found to have mutations in
genes characteristically associated with other primary BAFF Receptor Deficiency
immunodeficiencies. Such has been the case with Two siblings have been described with homozygous dele-
some individuals with mutations in BTK (causative in tions in the BAFFR gene encoding the BAFF (B cell acti-
XLA),355 SH2D1A or XIAP (XLP disease),386,387 and vating factor) receptor.401 Both had low IgG, poor
TNFSF5 (CD40L, X-linked hyper-IgM syndrome).388 polysaccharide antibody response, and low memory B
Functionally relevant polymporphisms in TNFRSF13B cells. However, only one sibling had recurrent infections.
(encoding TACI) occur in approximately 1% of the It is not clear why only one sibling was affected clinically,
general population. The most common are Cys104Arg but variable penetrance is frequently observed in all forms
(cysteine 104 replaced by arginine) and Ala181Glu. of immunodeficiency.4
Approximately 10% of patients with CVID are heterozy-
gous, and 1% are homozygous for these.389-392 TACI is Good Syndrome
expressed on B cells and interacts with the ligands BAFF The occurrence of thymoma in the context of a clinical
and APRIL expressed on macrophages and dendritic and immunologic picture very similar to that of CVID
cells. These interactions have important roles in B-cell with low numbers of B cells and generally more severely
activation and Ig class switching. TACI polymorphisms impaired T-cell function has been designated Good
are not entirely disease causing by themselves, but the syndrome.402-406 The spectrum of bacterial sinopulmonary
presence of one of these TACI polymorphisms does infections and pathogens is similar to those associated
appear to confer increased risk of lymphoproliferation with the more prevalent forms of CVID. However, Good
and autoimmunity.393 syndrome is associated more frequently with opportunis-
The genetic determinants of CVID in the majority of tic infections, including mucocutaneous candidiasis,
patients may be more complex. A recent genome-wide severe varicella-zoster virus infection, P. jiroveci, CMV,
association study revealed complex patterns.394 The and recurrent HSV. Lymphadenopathy and splenomegaly,
strongest associations were with the MHC locus and a commonly seen in CVID, are not characteristic features
family of disintegrin/metalloproteinase genes. However, of Good syndrome. Autoimmune disease is a frequent
there were at least 16 associated gene duplications or complication of Good syndrome, most notably pure red
deletions together with many (≈100) unique intraexonic cell aplasia and neutropenia. Patients with Good syn-
duplications or deletions. Furthermore, a complex genetic drome also often suffer from chronic diarrhea of unclear
signature composed of more than 1000 single nucleotide etiology.
polymorphisms was highly predictive of the CVID phe- Panhypogammaglobulinemia is a consistent finding in
notype. How this heterogeneous genetic picture relates to Good syndrome.402-406 Unlike the majority of patients
the clinic manifestations of CVID is unknown. with CVID, immunophenotypic analysis of peripheral
blood lymphocytes frequently shows absent or very low
Deficiency of Inducible T-Cell Costimulator numbers of B cells, reduced CD4+ T cells, absent cutane-
The inducible T-cell costimulator (ICOS) is expressed on ous delayed hypersensitivity responses, and reduced in
T cells after stimulation. It interacts with a member of vitro T-cell response to mitogen. It is not clear whether
the B7 family of molecules known as ICOS ligand. Fewer patients with Good syndrome exhibit as yet undiscovered
than 20 patients worldwide have been found to have specific genetic or immunologic abnormalities that clearly
CVID associated with ICOS deficiency.395 These patients distinguish them from CVID.
may manifest recurrent respiratory and gastrointestinal
infections in adulthood, panhypogammaglobulinemia Selective IgA Deficiency
and impaired vaccine responses, autoimmune disease There are two subclasses of human IgA: IgA1 and IgA2.
(neutropenia), lymphoproliferation, and cancer (carci- They are encoded by separate genes on the heavy-chain
noma of the vulva). Lymphoid tissues exhibit poorly C region locus on chromosome 14 (see Fig. 24-8). IgA1
formed germinal centers, and circulating switched predominates in serum (80% to 90%), whereas IgA1 and
memory B cells are markedly reduced. IgA2 are equally prevalent in secretions. Both subclasses

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912 SECTION VII  IMMUNE SYSTEM

are equally affected in selective IgA deficiency (SIGAD). SIGAD may occur as a drug side effect and has been
SIGAD is defined as a serum IgA level of less than 0.07 g/L reported with phenytoin, carbamazepine, valproic acid,
with normal serum IgG and IgM in a child older than 4 zonisamide, sulfasalazine, gold, penicillamine, hydroxy-
years of age in whom other causes of hypogammaglobu- chloroquine, and nonsteroidal antiinflammatory drugs.418
linemia have been excluded.4 Note that this definition is The IgA level may normalize after cessation of the drug.
restricted to the absence of serum IgA. There is no known
clinical association with IgA levels between the lower Immunoglobulin G Subclass Deficiency
limit of detection and the lower limit of the normal range. Four subclasses of IgG exist in humans: IgG1, IgG2,
It is not appropriate to refer to patients with these nonzero IgG3, and IgG4. Their designations order their preva-
low IgA values as being IgA-deficient. lence in serum, with each constituting roughly 67%,
SIGAD is seen in approximately 1 in 700 Caucasians 23%, 7%, and 3% of the total, respectively. A different
in the United States.407 In contrast, its incidence among gene encodes the heavy-chain constant region of each
Japanese is only 1 in 18,500. This presumably reflects subclass (see Fig. 24-8). Each subclass has unique struc-
population genetic differences, possibly related to the tural properties and plays a different role in immune
HLA complex. SIGAD has been associated with extended responses as a result of different interactions with the
HLA haplotypes similar to those observed in CVID.408,409 complement system and with receptors for IgG on phago-
The majority of individuals with SIGAD are completely cytic cells and lymphocytes. In addition, IgG subclasses
asymptomatic. Some may have a clinical course similar are produced in different relative amounts depending on
to that seen in CVID or in IgG subclass deficiency (dis- the antigenic stimulus.422 Mainly IgG1 is produced in
cussed later). The proportion of patients with SIGAD is response to soluble protein antigens. Viral antigens also
increased in a population of people with chronic lung elicit predominantly IgG1 responses and often significant
disease, and 20 years’ observation of blood donors with amounts of IgG3 as well. Particular viruses (e.g., hepati-
SIGAD has documented an increased incidence of respi- tis, herpes simplex, and varicella) also elicit IgG4. The
ratory infections and autoimmune disease.410-413 pneumococcal capsular polysaccharide response is almost
The spectrum of autoimmune syndromes associated exclusively of the IgG2 subclass, whereas H. influenzae
with SIGAD is similar to CVID.410-413 In addition, atopic type B (HIB) polysaccharide elicits mainly IgG2, with
diseases appear to be more prevalent among those with some IgG1 (the latter is found in younger children par-
SIGAD, and some have also noted an increased incidence ticularly). Note that the current HIB and pneumococcal
of the type of malignancies encountered in CVID. In rare (Prevnar) vaccines are protein conjugates and elicit
cases, SIGAD has evolved into CVID, or levels of IgA responses characteristic of protein antigens.
have increased over time.414,415 Treatment of SIGAD has IgG subclass deficiency (IGGSD) is defined as a level
generally focused on management of complications as of one or more IgG subclasses greater than 2 SD below
they occur. In some instances, gamma globulin infusions the age-adjusted mean with a normal total level of IgG.
may be helpful, especially if an associated IgG subclass Precise criteria for diagnosis are difficult to establish
or specific antibody deficiency is present (discussed later). because of variability in Ig measurements by various
However, researchers in one study did not find an associa- techniques (e.g., nephelometry and radial immunodiffu-
tion between a history of infections and lower antibody sion) and the wide variability in normal ranges with
responses to pneumococcal polysaccharides.411 Some respect to age and ethnicity. The significance of decreased
studies do show an association of increased infections if levels of IgG subclasses in patients with recurrent infec-
there is an IgG subclass deficiency or mannose-binding tions is further clouded by the fact that the majority of
lectin (MBL) deficiency together with SIGAD.416 individuals with isolated subclass deficiencies are asymp-
Apart from the absence of IgA itself and its occasional tomatic. These factors make the diagnosis of IGGSD
association with abnormalities of IgG subclasses, there controversial.423
are few other characteristic immunologic abnormalities. Patients with IGGSD commonly present with recur-
Some researchers have found low levels of switched rent sinopulmonary infections of varying severity caused
memory B cells in some patients and observed correla- by common respiratory bacterial pathogens.424-428 Some
tions with disease severity and autoimmune complica- may also have recurrent diarrhea, often of infectious
tions similar to those in CVID.417 origin. Furthermore, atopic diseases such as asthma and
Molecular genetic defects have not been described in allergic rhinitis are more prevalent in patients with
SIGAD. Lesions in IgA C region genes are not found, IGGSD. Deficiency of the IgG2 subclass is detected most
except in rare instances associated with other deletions commonly in symptomatic patients. It may occur in isola-
(discussed later). SIGAD and CVID have been associated tion but is also usually associated with deficiency of
with the HLA haplotype A1, B8, DR3 in Caucasians.409,418 IgG4, IgA, or both. Selective deficiency of IgG3 alone is
A SIGAD susceptibility locus (IGAD1) has been mapped likewise observed (most often in adult women) and is
to the boundary region between HLA class II and class associated with the same clinical picture described
III.419,420 A more detailed analysis identified a positive earlier.424,425 The lowest IgG4 levels are usually associated
association of SIGAD with HLA-DRB1*0301, DQB1*02 with IgG2 deficiency. Recurrent infections have been
and a negative association with DRB1*1501, DQB1*0602. described in some patients with only IgG4 deficiency,
Another study identified an association of SIGAD with although a diagnosis of isolated IgG4 deficiency is con-
DRB1*0102, DQB1*0501.421 The significance of these sidered most controversial because normal ranges for
associations requires clarification. IgG4 are poorly defined.

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24  Primary Immunodeficiency Diseases 913

Several studies have shown an increased proportion deficiency is usually slow spontaneous resolution.415 Most
of individuals with subclass deficiencies among patients children have a greatly reduced incidence of infections by
with recurrent infections.4 Not all of these patients have late childhood.
demonstrably impaired responses to vaccines, however.
Thus the relationship between lack of an antibody Transient Hypogammaglobulinemia of Infancy
isotype and susceptibility to infection is far from straight- Transient hypogammaglobulinemia of infancy (THI) is,
forward. Assessing the response to antigen challenge as its name suggests, an antibody deficiency beginning in
is an important element in the evaluation of these infancy that resolves spontaneously, usually by 4 to 5
patients. Assessment of memory B-cell subsets may years of age.443-447 It is defined as the occurrence of an
become a useful diagnostic tool for IGGSD; some studies IgG level more than 2 SD below the age-adjusted mean.
suggest that reduced switched memory B cells have Many patients also have low IgA, and some also have
better a correlation with risk for infection than antibody low IgM. Vaccine antibody responses are usually intact,
responses do.429 but this is not always the case. Peripheral lymphoid tissue
The C region genes determining antibody classes and is sparsely populated with small or no germinal centers
subclasses are arranged in the same transcriptional ori- and markedly reduced plasma cell contents. Numbers of
entation on chromosome 14 (see Fig. 24-8). As with circulating B and T cells are generally normal, as are in
SIGAD, only rarely is clinically significant IGGSD asso- vitro assays of lymphocyte function (e.g., mitogen
ciated with genetic lesions of IgG C region genes. This response). One recent study documented higher B-cell
has been observed in a single reported patient with IgG2 counts than in an age-matched group.448
deficiency, in whom mutation prevented expression of Ig levels in THI gradually increase over time, and the
cell surface IgG2.430 In fact, large deletions of Ig C region majority of patients have normal levels by the age of 4
genes are surprisingly common; six multigene deletion or 5, rarely later.443-447 Thus the diagnosis can be con-
haplotypes have been identified (see Fig. 24-8).431 In one firmed only after Ig levels normalize. Prospective studies
population with a high degree of consanguinity, individ- show a preponderance of the diagnosis in male subjects
uals were found to be homozygous for one haplotype or and normalization of Ig levels at a median of approxi-
heterozygous for two different haplotypes. Fifteen of 16 mately 2 years, with an upper limit of approximately 5
people with deletions on both chromosomes were years. Female subjects and patients with lower IgG levels
entirely healthy despite a complete lack of one or more tend to take longer to normalize.
IgG subclasses or IgA1; one person had recurrent infec-
tions.432 Similarly, two healthy siblings have been Immunoglobulin Class-switch Defects
described, each having homozygous deletions of IgA1, As mentioned previously, naïve B cells express IgM and
IgG2, IgG4, and IgE.433 Another group described a IgD on the cell surface. These different isotypes are gener-
healthy 50-year-old man who had deletions encompass- ated by way of differential splicing of mRNA transcripts.
ing the heavy-chain genes encoding IgG1, IgG2, IgG4, When B cells are activated by antigen and interaction
and IgA1.434 This individual did not produce polysac- with helper T cells in germinal centers, they initiate a
charide antibody but did produce IgG3 to protein anti- process of class-switching whereby the DNA intervening
gens, including pneumococcal surface proteins. Finally, between the variable region gene and a downstream
an analysis of the Ig heavy-chain loci of 33 patients with isotype is excised. In this manner, B cells begin to express
CVID revealed only two patients who were heterozy- IgG, IgA, or IgE. When this process is impeded, the
gous for C gene deletions.435 amount of these isotypes produced is very low, while the
amount of IgM may be normal or very high. These dis-
Specific Antibody Deficiency with Normal Immunoglobulins orders are often referred to as hyper-IgM syndromes.
A population of patients with recurrent infections and However, there are many important differences among
poor antibody responses (mainly to polysaccharide anti- the disorders often placed in this group.449
gens) have completely normal levels of antibody classes
and subclasses. This condition has been called specific X-Linked Immunodeficiency with Normal or Elevated IgM
antibody deficiency with normal immunoglobulins As its name implies, X-linked immunodeficiency with
(SADNI) or functional antibody deficiency.436-438,439-441 In normal or elevated IgM (XHIM, also HIM1) denotes a
one retrospective compilation of 90 patients in a tertiary- form of selective hypogammaglobulinemia G and A,
care institution with newly diagnosed immunodeficiency, together with normal or elevated amounts of IgM.450-454,455
specific antibody deficiency with normal Igs was the most These patients are seen in the first 1 or 2 years of life with
common diagnosis, made in 23% of patients.442 Repeated the recurrent sinopulmonary bacterial infections often
immunization may lead to measurable antibody responses, found in those with hypogammaglobulinemia, together
although even protein conjugate pneumococcal polysac- with opportunistic infections by organisms such as P.
charide vaccines may not be as effective as in healthy jiroveci, Cryptosporidium, and Histoplasma. Affected
individuals.440 Measurement of memory B-cell popula- patients are also prone to the development of neutrope-
tions may correlate better with infection risk in these nia, anemia secondary to parvovirus, stomatitis, scleros-
patients, although further study is required.429 SIGAD, ing cholangitis, and liver and hematologic malignancies.
IGGSD, SADNI, and a subset of CVID may be entities in A variety of autoimmune manifestations may be seen,
a spectrum with similar pathophysiologic characteristics. including cytopenias, arthropathy, and inflammatory
The natural history of IGGSD and specific antibody bowel disease.456

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914 SECTION VII  IMMUNE SYSTEM

The number of circulating B cells is normal, but they lack of which may underlie the predisposition to opportu-
express IgM exclusively (in association with IgD) on their nistic infection and malignancy seen in patients with CD40
surface. Immune responses are varied. Isohemagglutinins ligand deficiency.
are often present, and vaccination may elicit specific IgM Perhaps not too surprisingly, a clinically and immuno-
responses. No other isotypes are produced; there is no logically identical immunodeficiency syndrome arises
B-cell memory. Secondary lymphoid tissues are sparsely from mutations in the gene TNFRSF5, which encodes
populated and do not contain germinal centers. In spite CD40.451,454,457,458 Only a few patients with this defect
of the important defects in T-cell function for B-cell help, have been found so far.
screening studies such as flow cytometric measurement of These defects in CD40L and CD40 (TNFSF5 and
T-cell populations or in vitro proliferation tests are often TNFRSF5) are discussed here together with the humoral
normal.450-455 immunodeficiencies because of the prominence of the
The genetic lesion in XHIM is in TNFSF5 (tumor class-switch defect in the clinical expression. However,
necrosis factor superfamily member 5), also known as they are truly combined immunodeficiencies with impor-
CD40 ligand (CD40L) or CD154. 450-455 This is an inte- tant defects of T-cell function. In addition to IgG therapy
gral membrane protein that is mainly expressed on T cells and infection prophylaxis, these patients are candidates
after an activating stimulus, such as interaction of the for HSCT.
TCR with an MHC-peptide complex on the surface of a
B cell or APC (Fig. 24-9). The signal delivered by T-cell Mutations in Activation-Induced Cytidine Deaminase and Uracil
CD40L to CD40 is critical for Ig class switching, the Nucleoside Glycosylase
development of B-cell memory, affinity maturation of the Activation-induced cytidine deaminase (AID) and uracil
antibody response (somatic hypermutation of Ig V nucleoside glycosylase (UNG) defects exclusively affect
regions), and the expression of important costimulatory B-cell function while T-cell number and function are com-
molecules such as those of the B7 family by B cells and pletely normal. They were originally defined in the
APCs (see Fig. 24-9). medical literature as forms of hyper-IgM (HIM) syn-
The CD40 system has additional roles in the interaction drome, which leads to some confusion insofar as other
of T cells with monocytes. Several T-cell–derived cytokines forms of HIM are combined immunodeficiencies with
(granulocyte-macrophage colony-stimulating factor, IL-3, important T-cell dysfunction (discussed previously). AID
and IFN-γ) induce the expression of CD40 on monocytes. deficiency has been called HIM2454,459-461 and UNG defi-
Furthermore, engagement of monocyte CD40 induces ciency has been called HIM5454,462 (see Table 24-8). The
cytokine synthesis and activates tumoricidal mechanisms. AID and UNG enzymes are RNA modifiers expressed in
These phenomena suggest an important interaction, the B cells that act during class-switch recombination. In the

T-B Cell Interactions


Allergen
IL-4
IL-4R

CD28
*B7
CD3
Class II

TCR
IL2/IL4

T B
CD40L CD40
Activation of
* switching

TCR + CD28 CD40 + IL4R

Proliferation Cytokine synthesis IgE isotype switching Proliferation


Figure 24-9 Signals required for T-cell activation by antigen-presenting cells (APCs), B-cell activation by the T cell, and B-cell immunoglobulin
class-switching. The T-cell receptor (TCR) interacts with MHC + peptide. Subsequent to this interaction, the T cell expresses CD40 ligand (CD40L)
and begins producing IL-2 and IL-4. CD40L interacts with CD40 on the APC (or B cell) inducing expression of B7-1 (also called CD80) and B7-2
(CD86). This interaction leads to full activation of APC function, macrophage killing capacity, or B-cell activation, depending on the cells involved.
Binding of B7 molecules to CD28 on the T-cell surface provides an important costimulatory signal leading to full T-cell activation and increased
cytokine production. IL-4 produced by the T cell interacts with its receptor on B cells to induce class-switching. Other cytokines act on other cell
types to modulate their activities in the immune response.

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24  Primary Immunodeficiency Diseases 915

absence of their activity, B cells cannot switch from pro- A high index of suspicion for antibody deficiency
duction of IgM and IgD to production of downstream Ig should be maintained in patients with recurrent, refrac-
isotypes (see Fig. 24-8). Somatic hypermutation is also tory, or severe infections. One study of primary antibody
affected. These processes normally occur during B-cell deficiency in the United Kingdom found that the median
activation in germinal centers. delay in diagnosis after the onset of symptoms (infec-
Another form of HIM syndrome with an unknown tions) was 2 years (mean, 4.4 years), even after the intro-
gene defect leads to impaired Ig class-switching duction of a set of national guidelines intended to reduce
recombination.463-466 This has been called HIM4. All these this delay.471
disorders are very similar clinically and immunologically.
Patients suffer mainly from respiratory tract bacterial IgG Replacement Therapy
infections and lymphadenopathy, and cellular immuno- The mainstay of therapy for significantly impaired ability
deficiency is not seen. IgG, IgA, and IgE levels are all low to produce antibody is IgG replacement.4,472 As men-
or absent; IgM levels tend to be higher than in the tioned earlier, this therapy is also important for the treat-
X-linked HIM syndrome. Patients tend to do well with ment of any combined immunodeficiency in which
IgG replacement. defective antibody production may occur. Patients with
XLA were the first to receive human gamma globulin
therapy. The effect of intramuscular injections of gamma
Management of Humoral Immunodeficiency
globulin was prompt and dramatic, with a reduction in
Diagnostic Approach the occurrence of infections. With the advent of prepara-
Patients with recurrent infections, regardless of antibody tions suitable for intravenous administration in the 1970s,
class or subclass levels, should undergo thorough evalu- this became the most common route of administration
ation to rule out other potential predisposing factors worldwide. A retrospective study of bacterial infections
(e.g., anatomic defects or environmental allergies).4 The in patients with XLA showed a reduction in incidence
amounts of one or more antibody isotypes are reduced in from 0.4 to 0.06 per patient per year with IVIG therapy.473
many of these diseases.3,4 The severity of the phenotype At present, administration of IVIG provides these patients
often correlates with the degree of hypogammaglobu- with an almost normal lifestyle.474-479 Many immunolo-
linemia. The predisposition that patients have to particu- gists also apply chronic antibiotic prophylaxis in addition
lar types of infections may also depend on the affected to IgG for patients with XLA, but this practice is not
isotypes (discussed later). It is always of the utmost universal. All patients with CVID and with class-switch
importance to use age-adjusted reference ranges. Ig levels defects should also be treated with IgG infu-
are low in infancy and rise throughout childhood. Most sions.4,472,474,477,480-483 For these patients, as with XLA,
isotypes reach fully adult levels between the ages of 5 and many immunologists also apply chronic antibiotic
10 years. prophylaxis.
Antibody titers to specific antigens may be measured In most countries gamma globulin replacement is
before or after immunization (often both). The specific administered predominantly by the intravenous route
antibodies most commonly assayed for protein antigens every 3 to 4 weeks. However, IgG can also be adminis-
are tetanus and diphtheria toxoids. With respect to poly- tered by subcutaneous infusion.477,480,481,484 Smaller subcu-
saccharide antigens, measurement of antibodies to pneu- taneous doses are given weekly or twice weekly or even
mococcal serotypes is frequently undertaken. If a child has daily. Intravenous infusion is generally well tolerated but
had a particular illness (e.g., varicella), a specific viral requires intravenous access and is associated with fre-
antibody titer may be useful. Note that the HIB vaccines quent mild (10% to 20% of patients) or moderate (5%)
and newer pneumococcal vaccines (e.g., Prevnar-13) cur- side effects. Subcutaneous infusions may be administered
rently in use for primary immunization in children are by patients themselves at their own convenience with a
protein conjugates. Thus measuring a polyribosylribitol much lower rate of systemic effects at the cost of gener-
phosphate or pneumococcal serum antibody concentration ally mild and transient (24-hour) local irritation. The
in children who have received these vaccines does not general efficacy of intravenous versus subcutaneous
necessarily reflect a “pure” polysaccharide antibody administration appears to be equivalent. Subcutaneous
response. The adequacy of carbohydrate responses may be infusion is becoming increasingly popular.
tested by challenge with 24-valent pneumococcal polysac-
charide vaccines (e.g., Pneumovax).438,439,467-469 This vaccine Antibiotic Prophylaxis
produces reliable results in normal children as young as 1 For milder forms of antibody deficiency such as SIGAD,
year.470 An unconjugated meningococcal vaccine (Meno- IGGSD, SADNI and THI, antibiotic prophylaxis is the
mune) may also be used to assess ability to respond to more common first-line approach for infection prophy-
polysaccharides. In children who are not fully immunized laxis.4 However, regimens are not standardized. Com-
or who are too young to immunize, isohemagglutinins may monly used agents include amoxicillin and trimethoprim-
be measured as an indicator of the ability to generate sulfamethoxazole. Depending on specific circumstances,
polysaccharide antibody.4 other antibiotics may be chosen, such as clarithromycin
Most children have been immunized with tetanus or azithromycin, amoxicillin-clavulanate, or doxycycline.
toxoid, HIB, and Prevnar, and antibody titers may be Also depending on circumstances, therapeutic dose or
determined at the first visit. If titers are low, response to half-dose regimens may be applied. For any of these dis-
booster immunization may be assessed. orders (with the possible exception of SIGAD), IgG

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916 SECTION VII  IMMUNE SYSTEM

therapy may ultimately be prescribed if the response Classical Lectin Alternative


to antibiotic prophylaxis is poor, or if intolerable side pathway pathway pathway
effects or hypersensitivity precludes their continued Extracellular
use.424,426,477,485,486 In these circumstances, there is usually IgG, IgM MBL, ficolins matrix
a clearly observable reduction in the frequency of infec- C2, C4
tions. IgG replacement for SIGAD is especially controver- C1qrs MASP1, 2, 3 C3b
sial because experience has not demonstrated consistent
fB, fD, P
benefit. C3
General Care C4b2a C3bBbP

Patients with antibody deficiency require regular moni- C3a


+
toring for occurrence or progression of complications and C3b
adequacy of therapy.4 Lung function should be measured
C5
regularly along with periodic assessment of hematologic
parameters, liver and kidney function, and Ig levels. C4b2a3b C3b2BbP
Therapy for autoimmune inflammatory complications in C5a
CVID and other antibody deficiencies generally follows +
regimens applied in similar situations in the absence of C5b
the immunodeficiency.365,369,371,392,480 However, patients C6, C7, C8 C9 x n
with primary immunodeficiency who are treated with C5b6789n
immunosuppression for autoimmune or lymphoprolifera- MAC
tive disorders may be more susceptible to infectious
Figure 24-10 Complement activation pathways. The alternative
complications. pathway is initiated when the C3b fragment with factor B (fB) and
properdin (P) bind to the extracellular matrix or some microbial poly-
saccharides. Factor D (fD) cleaves fB to yield the C3 convertase BbC3b.
COMPLEMENT DEFICIENCIES Addition of C3b creates the C5 convertase BbC3b2. The classical
pathway begins when IgG or IgM bound to a surface forms a complex
The complement system is composed of some 20 serum with C1qrs. The lectin pathway is initiated when mannose-binding
proteins, 5 complement receptors with varied distribu- lectin (MBL) or other initiators such as the ficolins and MBL-associated
tion among leukocytes, and several integral membrane serine protease 2 (MASP2) bind to microbial polysaccharides. Activated
regu­lators found on most cells of the body.487,488 The C1qrs and MBL/MASP2 are both capable of cleaving C2 and C4 to
latter group of molecules limit cell damage as a result of yield the C3 convertase C4b2a. Addition of C3b to this complex yields
the C5 convertase C4b2a3b. The C5 convertases generate C5b, the
a low constitutive level of complement activation. There nucleus for the membrane attack complex (MAC), which is formed by
are three distinct modes of complement activation: the the addition of one each of C6, C7, and C8 and several molecules of
classical pathway, the alternative pathway, and the lectin C9.
pathway. These pathways are shown in Figure 24-10.
Soluble or surface-bound antigen-antibody complexes
initiate the classical pathway; the alternative pathway is
activated when complexes of C3b, factor B, and proper-
din are deposited on bacterial surfaces or extracellular TABLE 24-9  Clinical Associations with
matrix components. The lectin pathway is initiated by Complement Deficiencies
binding of MBL to mannose-containing microbial poly-
saccharides. The activation of the complement system Symptoms/Syndrome Associated with
by way of any of these pathways consists of sequential Component Deficiency
proteolytic interactions having a common outcome: C1q, C1r Systemic lupus erythematosus–like
cleavage (activation) of the C3 complement component syndrome
to yield the anaphylatoxin C3a and the C3b fragment. C2 Systemic lupus erythematosus–like
C3b attaches to cell membranes (e.g., bacteria) and is syndrome, vasculitis, polymyositis
the principal opsonin for phagocytosis. After cleavage of
C4 Systemic lupus erythematosus–like
the C5 component (yielding the anaphylatoxin C5a), syndrome
additional reactions are nonenzymatic aggregation of
C5b, C6, C7, C8, and C9 to form the macromolecular C3 Recurrent pyogenic infections
membrane attack complex (MAC). The MAC is an C5, C6, C7, C8, C9 Neisserial infection, systemic lupus
amphiphilic cylinder; its hydrophobic end inserts into erythematosus–like syndrome
target cell membranes and permits free flow of ions and C1-INH Hereditary angioedema
other solutes, which leads to metabolic derangement or
lysis.489 Genetic defects of almost all complement com- Factor I, Factor H Recurrent pyogenic infections, atypical
hemolytic uremic syndrome
ponents are known. The clinical manifestations of these
defects are categorized in Table 24-9. Complement defi- Factor D, Properdin Neisserial infections
ciencies are among the rarest of primary immunodefi- MBL, MASP-2 Recurrent pyogenic infections
ciencies, accounting for fewer than 1% of all patients
Ficolin 3 Atopy (possibly also infection)
diagnosed.

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24  Primary Immunodeficiency Diseases 917

Deficiency of Classical Complement genes encoding C4 are also located in the class III region
Pathway Components of the HLA complex. There are two copies on each chro-
mosome, C4A and C4B. Each encodes proteins that differ
C1 Deficiency in structure only minimally, although their biologic activi-
C1 is a large complex multimer consisting of three major ties are distinct. Null alleles at these loci occur frequently;
subunits: C1q, C1r, and C1s. C1q is itself a complex of 35% of people have one copy of either C4AQ0 or
18 separate polypeptides, 6 molecules each of C1qA, C4BQ0. Ten percent of the population have two null
C1qB, and C1qC. The C1 complex is completed by the alleles, and 1% have three. The presence of four null
addition of two molecules each of C1r and C1s, which alleles (complete C4 deficiency) is rare. All of these partial
brings the total to 22 polypeptides. Patients with defects deficiency states are often asymptomatic. One study has
in any of the major subunits of C1 have a syndrome found an association of C4B null alleles with Henoch-
resembling systemic lupus erythematosus (SLE) and sus- Schönlein purpura.507 Older studies have found HLA
ceptibility to recurrent infections.490-493 Deficiency of C1q haplotypes containing C4 null alleles frequently in
may be caused by antigenically normal nonfunctional patients with SLE.508 However, more recent studies
protein or complete absence of C1q. The C1QA, C1QB, suggest that this association arises by linkage disequilib-
and C1QC genes are closely linked on chromosome 1; rium of C4 with the MHC locus rather than by the C4
defects in the C1QB and C1QC genes have been genes themselves.509 The relatively high rate of occurrence
described. The genes encoding C1r and C1s are closely of C2 and C4 null alleles leads to combined heterozygous
linked on chromosome 12, and mutations of both C1r partial deficiencies of both in about 1 in 1000 Cauca-
and C1s have also been described. In addition to geneti- sians. Approximately one third of these patients have SLE
cally determined or primary C1q deficiency, autoantibody- and other autoimmune diseases.510 It is possible that this
mediated depletion of C1q has been associated with association also may be the result of linkage disequilib-
SLE.494-497 rium with MHC.
C2 Deficiency C3 Deficiency
The monomeric C2 component of complement is the The C3 component sits at the confluence of all three
substrate for the activated C1s component of the C1q pathways of complement activation. The various frag-
complex. Two fragments are generated in this reaction: ments of C3 generated through the action of C3 conver-
The C2a fragment associates with C4b on a cell surface tases (C4b2a and C3b2Bb), as well as other serum
and becomes an activator for C3 (“C3 convertase”); the proteases, have diverse influences within the immune
C2b fragment is a substrate for plasmin and releases a system. C3a is a potent anaphylatoxin, whereas C3b is
vasoactive peptide that may play a role in hereditary the principal opsonin for phagocytosis and is a compo-
angioedema (HAE, discussed later). Approximately 50% nent of enzyme complexes in the alternative pathway of
of individuals with C2 deficiency are asymptomatic. The complement activation. Additional C3 fragments influ-
rest have one or more of the following: various forms of ence lymphocyte function. For example, C3d is an impor-
vasculitis such as discoid lupus erythematosus or SLE, tant regulator of B-cell activation.511 Patients with C3
chronic Henoch-Schönlein purpura, polymyositis, or deficiency are susceptible to recurrent pyogenic infections
recurrent pyogenic infections.498-501 Only approximately affecting any organ system, and this condition is often
25% of C2-deficient patients are prone to infections. C2 clinically indistinguishable from hypogammaglobu-
deficiency is associated with low levels of IgG subclasses, linemia. These patients also may exhibit skin, kidney, and
and low levels of IgG4 and IgA may play a role in deter- joint inflammation caused by immune complex deposi-
mining susceptibility to infection. tion as well as a variety of autoimmune diseases.512-514
The gene encoding C2 resides in the class III region of
the HLA complex on chromosome 6. Between 1% and Deficiency of Alternative Complement
1.5% of Caucasians are heterozygous for a null C2 allele
Pathway Components
(C2Q0). Thus approximately 1 in 10,000 will be homo-
zygous for C2Q0 and have a complete deficiency of Properdin Deficiency
C2.498-501 Two forms of C2 deficiency independent of Properdin stabilizes the alternative pathway C3 conver-
C2Q0 have been identified. In type I, a mutation results tase. The properdin gene is located on the X chromo-
in loss of a mRNA splice site and C2 cannot be trans- some. Lack of properdin does not cause any changes in
lated. In type 2 deficiency C2 is not secreted, but the basis serum levels of complement components; activation
for this is unknown. through the alternative pathway is inefficient. Susceptibil-
ity to respiratory bacterial infections, Neisseria infec-
C4 Deficiency tions, and SLE has been associated with properdin
The C4 component is another substrate for activated C1s. deficiency.510,515-518
The C4a fragment is a very weak anaphylatoxin, and the
C4b fragment associates with C2a on a cell membrane to Factor D Deficiency
constitute C3 convertase. Complete deficiency of C4 is Factor D cleaves factor B after it associates with C3b.
rare. Virtually all such individuals with C4 deficiency Factor D deficiency is associated with recurrent respira-
have SLE and severe glomerulonephritis.502-506 Renal tory bacterial infections, pneumococcal sepsis, Neisseria
failure and infection are the leading causes of death. The infections, and glomerulonephritis.519-522

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918 SECTION VII  IMMUNE SYSTEM

Deficiency of Lectin Pathway Complement Components MBL in this study. Similarly, low blood MBL levels may
also increase the severity of primary immunodeficiency,
Mannose-Binding Lectin Deficiency such as in CVID or with IgA/IgG subclass deficiencies or
MBL is a member of the collectin protein family, which properdin deficiency.416,536-538
also includes lung surfactant proteins A and D.523 MBL MBL levels may also impact certain inflammatory
has a structure similar to C1q and interacts with polysac- states. A low level of MBL has been associated with a
charides containing mannose, glucose, and fucose, as well lower rate of acute rejection after heart transplantation539
as acetylated derivatives of these sugars. Thus MBL may and smaller infarct size and better outcome after cerebral
interact with members of virtually all classes of infectious infarction.540 However, another study reported a higher
microbes. Three proteins called MBL-associated serine risk for myocardial infarction in adults with MBL defi-
proteases (MASPs) 1 to 3 are similar to C1r and C1s. ciency.541 MBL deficiency has also been reported to predis-
MASP-2 may have the most important role in catalyzing pose to or worsen autoimmune or inflammatory diseases
cleavage of C2 and C4 in a manner analogous to C1s. such as rheumatoid arthritis, SLE, and celiac disease.542
Once this is accomplished, the classical pathway C3 con- There are also examples of studies reporting negative
vertase has been created and further reactions are identi- findings regarding disease susceptibility and MBL levels.
cal to the classical pathway. There are polymorphisms of For example, a recent study in 105 HIV patients did not
the gene encoding MBL that affect both structure and find a significant association between low MBL levels and
expression. Structural polymorphisms may impair the the occurrence of infection.543 Another study did not find
ability of MBL to form functional oligomers that bind correlation of MBL levels with outcomes in cystic fibrosis
effectively to carbohydrates and may also impair the patients544 (whereas earlier studies had reached opposite
association with MASP-2 and subsequent activation of conclusions544-548). The situation may be even more
the remainder of the classical pathway. Promoter poly- complex because of discrepancies between studies based
morphisms lead to variation in blood MBL levels of on measuring MBL levels versus those based on genetics.
greater than 1000-fold from 5 ng up to 10 µg/mL. A For example, MBL genotypes generally thought to be
clinically relevant lower limit is not well established. predictive of serum level and function did not correlate
Many studies use values of approximately 100 to 200 ng/ with infection rates in patients with colorectal cancer, in
mL, although slightly different values are occasionally contrast to a prior study that had found significant asso-
used. MBL levels also vary among ethnic groups. The ciations with the serum levels of MBL.549
genotype or functional tests may be more informative In spite of the controversy surrounding the clinical
than the serum level alone because it is possible to have significance of MBL levels, recombinant human MBL is
normal serum levels of a nonfunctional protein. under development as a therapeutic agent; one phase I
The clinical significance of MBL measurement is con- trial has shown no adverse effects of administration to
troversial. Low blood MBL level or function does not by healthy MBL-deficient individuals.550
itself clearly predispose to disease, except possibly during The ficolins 1-3 are also members of the collectin
infancy, when it may be associated with a higher rate of family of molecules and can interact with MASPs 1 to 3
bacterial respiratory tract infections.523 One study sug- and initiate the lectin pathway of complement activation.
gests that the (possible) increased susceptibility to pneu- Deficiency of ficolin 2 (also called L-ficolin) has recently
mococcal infections in MBL deficiency may be serotype been associated with recurrent respiratory infections
specific.524 In other words, MBL-determined host defense and atopy in children.551 However, a more recent report
is more important for some serotypes than for others. A from the same group suggests that the main clinical asso-
variety of other types of conditions have been reported ciation of low ficolin levels is with atopy rather than with
to be associated with MBL-deficiency, including pertus- infection.552 The significance of these findings requires
sis,525 cryptococcal meningitis,526 cryptosporidiosis,527 clarification.
recurrent vulvovaginal candidiasis,528 and the occurrence
of septic shock in pyelonephritis as a result of E. coli529 MASP-2 Deficiency
or severe course and fatality in adults with community- Abrogation of MASP-2 function is expected to have the
acquired pneumonia.530 same consequence as the absence of MBL function: failure
Some reports also suggest that in the setting of other to activate complement by way of the lectin pathway.
disease processes or stresses on the immune system, MBL Patients homozygous for MASP2 mutations have been
deficiency predisposes to a higher rate of a variety of reported to have similar clinical associations as described
infectious complications. For example, one study reported for MBL deficiency.524,530,549,553-555 All of the controversy
a higher rate of invasive aspergillosis in MBL-deficient regarding the clinical importance of MBL levels and
patients with secondary immune compromise resulting genetics applies equally to a discussion of functional
from acquired immunodeficiency virus or treatment with MASP2 polymorphisms or mutations.
steroids or cancer chemotherapy.531 Another report found
a higher rate of bacterial infections in patients with low Deficiency of Terminal Complement Components
MBL and hepatic cirrhosis532 or patients who underwent Recurrent neisserial and pneumococcal infections and
liver transplantation533 or HSCT.534 Another group rheumatic disease have been reported in patients with
reported a higher rate of CMV reactivation in MBL- C5,556,557 C6,558,559 and C7560 deficiencies. C6 deficiency
deficient patients after lung transplantation.535 Interest- has been found in approximately 1 in 1600 African-
ingly, overall survival was superior in those with low Americans in the southeastern United States in

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24  Primary Immunodeficiency Diseases 919

association with a higher incidence of meningococcal gene, patients have inadequate levels of C1-INH, well
meningitis.561 below the 50% one would expect to be due to a simple
The C8 molecule is a heterotrimer of chains designated gene dosage effect. The mechanism that leads to inhibi-
α, β, and γ. The C8A and C8B genes are on chromosome tion of transcription of the normal gene is unknown.
1, whereas the C8G gene resides on chromosome 9. C8 Although inheritance is autosomal dominant, as many as
deficiency is also associated with recurrent neisserial infec- 10% to 25% of patients may express new mutations.
tion; patients have been identified with lesions of C8A or Acquired forms of HAE have also been described. In
C8B.562-565 Patients with lesions in the C8A genes also lack acquired angioedema (AAE) type 1, C1-INH levels
C8 γ protein, even though the latter genes are normal, decrease by an unknown mechanism, usually as a
because C8 α and γ are normally covalently linked. C9 paraneoplastic process associated with lymphoma and
deficiency is usually asymptomatic566; a few patients with lymphoproliferative disorders.576-581 In AAE type 2, auto-
recurrent neisserial infections have been described.567,568 antibodies against C1-INH deplete it from serum.582-584
One patient with IgA nephropathy associated with C9 These antibodies may arise sporadically, in the context of
deficiency has been reported.569 C9 deficiency has also other autoimmune syndromes, or in association with
been found in one patient with dermatomyositis.570 Allo- lymphoproliferation.
typy at IgG Fc receptor gene loci may have an impact on There are three distinct problems in the management
the susceptibility to infection in patients with deficiencies of HAE or AAE. These are the control of acute attacks
of terminal complement components.571 when they occur and the short-term (i.e., preprocedure)
and long-term prophylaxis of acute attacks.585,586-588 For
management of acute attacks in patients with HAE, medi-
Deficiency of Complement Regulatory Factors
cations such as epinephrine, antihistamines, and cortico-
C1 Inhibitor Deficiency (Hereditary Angioedema) steroids, used to treat angioedema subsequent to
HAE exhibits autosomal dominant inheritance. The hypersensitivity reactions, are entirely useless because the
symptoms of this disease are unpredictable recurrences of mechanism of swelling in HAE is unrelated. Analgesia is
acute and profound subepithelial edema in a variety of indicated for painful abdominal crises. Airway protection
anatomic locations.572,573 Physical trauma may be a pre- is vital and may require a tracheostomy.
cipitating factor. The distal ends of the extremities, face, Recently, several new products have been approved by
intestines, and pharynx are often affected. Extremity the U.S. Food and Drug Administration (FDA) for the
edema is painless but impedes function. Intestinal edema treatment of acute attacks of angioedema. These include
causes excruciating pain and is associated with abdomi- the human plasma–derived purified C1 inhibitor Beri-
nal distention, vomiting, and diarrhea. Pharyngeal edema nert,589,590 a recombinant kallikrein inhibitor,591-594 and a
may lead to fatal airway obstruction.574 Attacks evolve peptidomimetic bradykinin receptor 2 inhibitor.595-597 All
over a period of approximately 12 hours and resolve in of these drugs have proved effective for the treatment of
24 to 48 hours. Attacks in childhood are not uncommon acute HAE attacks, reducing the intensity of angioedema
but occur less frequently than in adulthood. An increase and shortening the time to resolution. Other medications
in incidence and severity often occurs during puberty and may be used if these are not available. Fresh frozen
is sustained thereafter. Attacks may be associated with plasma has been used in attempts to replace C1-INH.
menses in females. Patients may become symptomatic or There are several anecdotal reports of efficacy of this
may have more frequent symptoms when receiving estro- therapy.598 However, this is not considered first-line
gen replacement or contraceptive therapy. therapy for acute attacks with the availability of newer
C1 esterase inhibitor (C1-INH) is a serum serine pro- agents. Tranexamic acid may also be effective, but this is
tease inhibitor (Serpin G1) that limits activities of the also a second-line agent.585-588
complement proteases C1r and C1s, as well as those of Several strategies are available for short- and long-
kallikrein, coagulation factors XIa and XIIa, and term prophylaxis of angioedema attacks. Short-term pro-
plasmin.572,573 In type I HAE (≈85% of patients), levels of phylaxis is indicated whenever a patient is to undergo a
C1-INH are less than 30% of normal. Patients with type procedure (e.g., invasive dental work or surgery) that has
II HAE have normal levels of a mutated (nonfunctional) the potential to precipitate an attack. Long-term prophy-
protein. There is at least one additional form of HAE laxis is used to reduce the frequency of spontaneous
with autosomal dominant inheritance and completely attacks. Impeded androgens such as danazol, stanozolol,
normal C1-INH function. It is designated HAE type III and oxandrolone are useful for short- and long-term
and arises from mutations in the gene encoding coagula- prophylaxis.585-588 These hormones act to increase expres-
tion factor XII.575 The mechanism of angioedema is not sion of the normal SERPING1 gene. Pediatric use is
known. In HAE I and II the unopposed activities of C1r, limited by the tendency of these hormones to promote
C1s, and kallikrein lead to consumption of C2, C4, and epiphyseal closure; use in female subjects is limited by
kininogen.572,573 Diminished levels of these proteins are their undesirable virilizing effects. Tranexamic acid is also
highly characteristic of HAE. Peptides derived from C2 useful as long-term prophylaxis. Recently, another puri-
and especially bradykinin cause the increase in vascular fied human plasma–derived C1 inhibitor product
permeability and edema. (Cinryze) has been FDA approved for prophylactic
The SERPING1 gene is located on chromosome 11. therapy.599-601 Rituximab has been used with mixed
A variety of genetic lesions have been identified in patients success in a small cohort of patients with AAE resulting
with HAE.575 Despite having one normal copy of the from autoantibodies to C1-INH.602

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920 SECTION VII  IMMUNE SYSTEM

impact: an updated report from the Jeffrey Modell Foundation.


Factor I Deficiency Immunol Res 51:61–70, 2011.
A unique report with global scope using the resources of the
Also known as C3 inactivator, the disulfide-linked het- Jeffrey Modell Foundation international network of clinical
erodimeric complement regulatory molecule factor I centers caring for patients with immunodeficiency to provide a
cleaves C3b. Deficiency of factor I leads to increased worldwide assessment of the current status of diagnosis and treat-
degradation of C3 (and factor B), principally because of ment of PIDD.
2. Zebracki K, Palermo TM, Hostoffer R, et al: Health-related quality
the inability to control constitutive low-level activity of of life of children with primary immunodeficiency disease: a com-
the alternative pathway of activation. These patients have parison study. Ann Allergy Asthma Immunol 93:557–561, 2004.
manifestations of C3 deficiency such as recurrent infec- One of the earliest wide-ranging quality of life studies in PIDD.
tions, urticaria, and immune complex disease.603-607 Factor 3. Al-Herz W, Bousfiha A, Casanova JL, et al: Primary immunode-
I deficiency is also associated with atypical hemolytic ficiency diseases: an update on the classification from the interna-
tional union of immunological societies expert committee for
uremic syndrome. primary immunodeficiency. Front Immunol 2:54, 2011.
This is the most recent report of an international committee
Factor H Deficiency charged with the classification of immunodeficiency disorders and
Factor H cooperates with factor I in the inactivation of is a standard reference in the field. The report is updated
biennially.
C3b; its absence leads to reduced C3 and factor B and a 4. Bonilla FA, Bernstein IL, Khan DA, et al: Practice parameter for
syndrome of recurrent infections with Neisseria meningiti- the diagnosis and management of primary immunodeficiency. Ann
dis and membranoproliferative glomerulonephritis.608-614 Allergy Asthma Immunol 94:S1–S63, 2005.
Both familial and sporadic relapsing hemolytic-uremic syn- A set of guidelines developed under the auspices of a task force
dromes have also been associated with mutations in factor of the Joint Council of Allergy, Asthma, and Immunology for the
diagnosis and management of all forms of PIDD.
H. Similar clinical complications result from autoantibody- 27. Hassan A, Booth C, Brightwell A, et al: Outcome of hematopoi-
mediated depletion of factor H.615-617 etic stem cell transplantation for adenosine deaminase-deficient
severe combined immunodeficiency. Blood 120:3615–3624, 2012.
Diagnosis and Management of Complement Disorders ADA deficiency is one of the more common forms of SCID. This
is an excellent recent review of the outcome of HSCT for this
Clinical tests are available to assess the function of each disorder.
of the three major pathways of complement activa- 32. Candotti F, Shaw KL, Muul L, et al: Gene therapy for adenosine
tion.4,487,488,516,618-620 The lectin pathway is not as frequently deaminase-deficient severe combined immune deficiency: clinical
evaluated because the definition of clinically significant comparison of retroviral vectors and treatment plans. Blood
deficiency is controversial. Activation of the classical 120:3635–3646, 2012.
Gene therapy is one of the most important recent advances in
pathway is measured by the CH50 assay (total classical immunology and medicine in general. This is an excellent review
pathway hemolytic assay), which can be performed by a of the state of the art in the context of ADA SCID.
variety of methods. The alternative pathway is assessed by 39. Alt FW, Zhang Y, Meng FL, et al: Mechanisms of programmed
a similar test called the AH50. If the CH50 is low and the DNA lesions and genomic instability in the immune system. Cell
152:417–429, 2013.
AH50 is normal, then there is likely to be a defect in C1, B and T lymphocytes are the only cells in the body that somati-
C2, or C4. If the AH50 is low and the CH50 is normal, cally rearrange their genomes. Study of this process has led to
there is likely to be a defect in properdin, or factor D. If important knowledge regarding mechanisms that maintain
both are low, it is likely that there is a defect in any of the genome integrity and how they fail and lead to mutation and
terminal pathway components (C3-C9). Complement malignancy, as discussed in this paper.
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The same situation is seen in regulatory component defects in SCID, variant SCID, and other PIDDs with prominent T-cell
(factor H and factor I) because of consumption of C3. deficiency and relation to limits of detection in newborn screening
assays based on TRECs.
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ciated with complement deficiency. Eculizumab is an tive molecular diagnosis in a patient with PIDD.
anti-C5 monoclonal antibody that inhibits the terminal 116. Puck JM: Laboratory technology for population-based screening
pathway and is approved for the management of atypical for severe combined immunodeficiency in neonates: the winner is
hemolytic-uremic syndrome.621 T-cell receptor excision circles. J Allergy Clin Immunol 129:607–
616, 2012.
Newborn screening for SCID represents a very important
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24  Primary Immunodeficiency Diseases 921

Most states that are conducting SCID newborn screening use a This study culminates 40 years of searching for the molecular
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outcome of patients with severe combined immunodeficiency who nance of tolerance and how it is broken in autoimmune disease.
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162. Markert ML, Devlin BH, Alexieff MJ, et al: Review of 54 patients This study highlights the complex nature of genetic aberrations
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likely have increasing application in other situations as the tech- ogy. J Allergy Clin Immunol 130:S1–S24, 2012.
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24  Primary Immunodeficiency Diseases  921.e1

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