3 Immunopathology

Cells of the Immune System

Table 3-1. Types of Immune Cells

Cell Type Derivation Location Function
T cells CD4 (helper) Bone marrow Peripheral blood and CD4 cells: secrete cytokines
CD8 lymphocyte stem bone marrow, (IL-2 proliferation of
(cytotoxic/suppressor) cells mature in thymus, paracortex CD4/CD8 T cells; -interferon
thymus of lymph nodes, activation of macrophages);
Peyer's patches help B cells become antibody-
producing plasma cells
CD8 cells: kill virus-infected,
neoplastic, and donor graft
cells
B cells Bone marrow Peripheral blood and Differentiate into plasma cells
stem cells bone marrow, that produce immunoglobulins
germinal follicles in to kill encapsulated bacteria
lymph nodes, (e.g., Streptococcus
Peyer's patches pneumoniae)
Act as APCs that interact with
CD4 cells
Natural killer cells Bone marrow Peripheral blood Kill virus-infected and
stem cells (large granular neoplastic cells
lymphocytes)
Macrophages Conversion of Connective tissue; Involved in phagocytosis and
monocytes into organs (e.g., alveolar cytokine production
macrophages in macrophages, lymph Act as APCs
connective tissue node sinuses)
Dendritic cells Bone marrow Skin (Langerhans' Act as APCs
stem cells cells), germinal
follicles

Cells of the Immune System

Table 3-1. Types of Immune Cells

Cell Type Derivation Location Function
T cells CD4 (helper) Bone marrow Peripheral blood and CD4 cells: secrete cytokines
CD8 lymphocyte stem bone marrow, (IL-2 proliferation of
(cytotoxic/suppressor) cells mature in thymus, paracortex CD4/CD8 T cells; -interferon
thymus of lymph nodes, activation of macrophages);
Peyer's patches help B cells become antibody-
producing plasma cells
CD8 cells: kill virus-infected,
neoplastic, and donor graft
cells
B cells Bone marrow Peripheral blood and Differentiate into plasma cells
stem cells bone marrow, that produce immunoglobulins
germinal follicles in to kill encapsulated bacteria
lymph nodes, (e.g., Streptococcus
Peyer's patches pneumoniae)
Act as APCs that interact with
CD4 cells
Natural killer cells Bone marrow Peripheral blood Kill virus-infected and
stem cells (large granular neoplastic cells
lymphocytes)
Macrophages Conversion of Connective tissue; Involved in phagocytosis and
monocytes into organs (e.g., alveolar cytokine production
macrophages in macrophages, lymph Act as APCs
connective tissue node sinuses)
 Dendritic cells Bone marrow Skin (Langerhans' Act as APCs
stem cells cells), germinal
follicles

Innate (natural, nonspecific) immunity

1. Antigen-independent cells providing first defense against pathogens
2. Types of cells
a. Phagocytic cells (e.g., neutrophils, macrophages)

b. Natural killer cells

Acquired (specific) immunity

1. Antigen-dependent activation and expansion of lymphocytes
2. B lymphocytes produce antibodies (i.e., humoral immune response).
a. IgM synthesis begins at birth.
Presence of IgM at birth may indicate congenital infection
(e.g., cytomegalovirus).
b. IgG synthesis begins at 2 months.
Presence of IgG at birth is maternally derived IgG.

3. T cells are involved in cell-mediated immune responses.

Major Histocompatibility Complex (MHC)

Location
Short arm of chromosome 6

Location
Short arm of chromosome 6

Human leukocyte antigen (HLA) genes

Code for HLA proteins that are unique to each individual

Class I MHC molecules

1. Coded by HLA-A, -B, and -C genes
2. Present on the membranes of all nucleated cells
o Not present on mature RBCs; present on platelets

3. Recognized by CD8 T cells and natural killer cells

Class II MHC molecules

1. Coded by HLA-DP, -DQ, and -DR genes
2. Present on antigen-presenting cells (APCs)
o B cells, macrophages, dendritic cells

3. Recognized by CD4 T cells

HLA association with disease
1. HLA-B27 with ankylosing spondylitis
2. HLA-DR2 with multiple sclerosis

3. HLA-DR3 and -DR4 with type 1 diabetes mellitus

HLA testing
1. Transplantation workup
o Close matches of HLA-A, -B, and -D loci in both the donor and graft
recipient increase the chance of graft survival.
2. Determining disease risk

o Example-HLA-B27-positive individuals have an increased risk of

ankylosing spondylitis.

Hypersensitivity Reactions

Table 3-2. Hypersensitivity Reactions

Reaction Pathogenesis Examples
Type I IgE-dependent activation Atopic disorders: hay fever, eczema, hives, asthma,
of mast cells reaction to bee sting
Drug hypersensitivity: penicillin rash or anaphylaxis
Type II Antibody-dependent Complement-dependent reactions
reaction
Lysis: ABO mismatch, Goodpasture's syndrome,
hyperacute transplantation rejection
Phagocytosis: warm (IgG) autoimmune hemolytic
anemia, ABO and Rh hemolytic disease of newborn
Complement-independent reactions
Antibody (IgG, IgE)-dependent cell-mediated
cytotoxicity: natural killer cell destruction of neoplastic
and virus-infected cells; helminth destruction by
eosinophils
Antibodies directed against cell surface receptors:
myasthenia gravis, Graves' disease
Type III Deposition of antigen- Systemic lupus erythematosus (DNA-anti-DNA)
antibody complexes Rheumatoid arthritis (IgM-Fc receptor IgG)
Serum sickness (horse antithymocyte globulin-antibody)
Type IV Antibody-independent T Delayed type: contact dermatitis (e.g., poison ivy),
cell-mediated reactions tuberculous granuloma
Cell-mediated cytotoxicity: killing of tumor cells and virus-
infected cells

Type I (immediate) hypersensitivity

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Desensitization therapy involves repeated injections of increasingly
greater amounts of allergen, resulting in production of IgG
antibodies that attach to allergens and prevent them from binding to
mast cells.
 IgE antibody-mediated activation of mast cells (effector cells) produces an
inflammatory reaction.

1. IgE antibody production (sensitization)

a. Allergens (e.g., pollen, drugs) are first processed by APCs
(macrophages or dendritic cells).
b. APCs interact with CD4 TH2 cells, causing interleukins (ILs) to
stimulate B-cell maturation.
c. IL-4 causes plasma cells to switch from IgM to IgE synthesis.
d. IL-5 stimulates the production and activation of eosinophils.
2. Mast cell activation (reexposure)
a. Allergen-specific IgE antibodies are bound to mast cells.
b. Allergens cross-link IgE antibodies specific for the allergen on mast
cell membranes.
c. IgE triggering causes mast cell release of preformed mediators.
i. Early phase reaction with release of histamine, chemotactic
factors for eosinophils, proteases
ii. Produces tissue swelling and bronchoconstriction
d. Late-phase reaction
i. Mast cells synthesize and release prostaglandins and
leukotrienes.
ii. Enhances and prolongs acute inflammatory reaction
3. Tests used to evaluate type I hypersensitivity
a. Scratch test (best overall sensitivity)

Positive response is a histamine-mediated wheal-and-flare

reaction after introduction of an allergen into the skin.
b. Radioimmunosorbent test
Detects specific IgE antibodies in serum that are against
specific allergens

2. Clinical examples of type I hypersensitivity (see

Type II (cytotoxic) hypersensitivity

Antibody-dependent cytotoxic reactions

1. Complement-dependent reactions
a. Lysis
Antibody (IgG or IgM) directed against antigen on the cell
membrane activates the complement system, leading to lysis
by the membrane attack complex.
b. Phagocytosis
Fixed macrophages (e.g., in spleen) phagocytose
hematopoietic cells (e.g., RBCs) coated by IgG antibodies
and/or complement (C3b).
2. Complement-independent reactions
a. Antibody (IgG, IgE)-dependent cell-mediated cytotoxicity
Leukocytes with receptors for IgG or IgE lyse but do not
phagocytose cells coated by antibodies.
b. IgG autoantibodies directed against cell surface receptors
3. Tests used to evaluate type II hypersensitivity
a. Direct Coombs' test detects IgG and/or C3b attached to RBCs.
b. Indirect Coombs' test detects antibodies in serum (e.g., anti-D).

4. Clinical examples of type II hypersensitivity (see

Type III (immunocomplex) hypersensitivity
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Activation of the complement system by circulating antigen-antibody

complexes (e.g., DNA-anti-DNA complexes)

1. First exposure to antigen

o Synthesis of antibodies
2. Second exposure to antigen

a. Deposition of antigen-antibody complexes

b. Complement activation, producing C5a, which attracts neutrophils
that damage tissue
2. Arthus reaction
a. Localized immunocomplex reaction
b. Example-farmer's lung from exposure to thermophilic actinomycetes,
or antigens, in air
3. Test used to evaluate type III hypersensitivity
a. Immunofluorescent staining of tissue biopsies
b. Example-glomeruli in glomerulonephritis

4. Clinical examples of type III hypersensitivity (see

Type IV hypersensitivity
Antibody-independent T cell-mediated reactions (cellular immunity)

1. Delayed reaction hypersensitivity

o CD4 cells interact with macrophages (APCs with MHC class II
antigens), resulting in cytokine injury to tissue.
2. Cell-mediated cytotoxicity
o CD8 T cells interact with altered MHC class I antigens on neoplastic,
virus-infected, or donor graft cells, causing cell lysis.
3. Test used to evaluate type IV hypersensitivity

a. Patch test to confirm contact dermatitis

Example-suspected allergen (e.g., nickel) placed on an
adhesive patch is applied to the skin to see if a skin reaction
occurs.
b. Skin reaction to Candida

2. Clinical examples of type IV hypersensitivity (see

Transplantation Immunology
Factors enhancing graft viability
1. ABO blood group compatibility between recipients and donors
2. Absence of preformed anti-HLA cytotoxic antibodies in recipients
o People must have previous exposure to blood products to develop
 anti-HLA cytotoxic antibodies.

3. Close matches of HLA-A, -B, and -D loci between recipients and donors

Factors enhancing graft viability

1. ABO blood group compatibility between recipients and donors
2. Absence of preformed anti-HLA cytotoxic antibodies in recipients
o People must have previous exposure to blood products to develop
anti-HLA cytotoxic antibodies.

3. Close matches of HLA-A, -B, and -D loci between recipients and donors

Types of grafts
The fetus is an allograft that is not rejected by the mother.
Trophoblastic tissue may prevent maternal T cells from entering
fetus.

1. Autograft (i.e., self to self)

o Associated with the best survival rate
2. Syngeneic graft (isograft)
o Between identical twins
3. Allograft
o Between genetically different individuals of the same species
4. Xenograft

a. Between two species

b. Example-transplant of heart valve from pig to human

Types of rejection
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Acute rejection is potentially reversible with immunosuppressive
agents, such as cyclosporine (blocks CD4 T-cell release of IL-2),
OKT3 (monoclonal antibody against T-cell antigen recognition site),
and corticosteroids (lymphotoxic). Immunosuppressive therapy is
associated with an increased risk of cervical squamous cell cancer,
malignant lymphoma, and squamous cell carcinoma of the skin
(most common).

Transplantation rejection involves a humoral or cell-mediated host response

against MHC antigens in the donor graft.

1. Hyperacute rejection
a. Irreversible reaction occurs within minutes.
b. Pathogenesis
i. ABO incompatibility or action of preformed anti-HLA
antibodies in the recipient directed against donor antigens in
vascular endothelium
ii. Type II hypersensitivity reaction
 c. Pathologic finding

Vessel thrombosis
b. Example-blood group A person receives a blood group B heart.
2. Acute rejection
a. Most common transplant rejection
b. Reversible reaction that occurs within days to weeks

i. Type IV cell-mediated hypersensitivity

CD4 T cells release cytokines, resulting in activation
of host macrophages, proliferation of CD8 T cells,
and destruction of donor graft cells.
Extensive interstitial round cell lymphocytic infiltrate
in the graft, edema, and endothelial cell injury
ii. Antibody-mediated type II hypersensitivity reaction
Cytokines from CD4 T cells promote B-cell
differentiation into plasma cells, producing anti-HLA
antibodies that attack vessels in the donor graft.
Vasculitis with intravascular thrombosis in recent
grafts
Intimal thickening with obliteration of vessel lumens
in older grafts

2. Chronic rejection

b. Irreversible reaction that occurs over months to years

c. Pathogenesis
i. Not well characterized
ii. Involves continued vascular injury with ischemia to tissue

d. Blood vessel damage with intimal thickening and fibrosis

Graft-versus-host (GVH) reaction

1. Causes
a. Potential complication in bone marrow and liver transplants
b. Potential complication in blood transfusions given to patients with a T-
cell immunodeficiency and newborns.
2. Pathogenesis

o Donor T cells recognize host tissue as foreign and activate host CD4
and CD8 T cells.
2. Clinical findings

a. Bile duct necrosis (jaundice)

b. Gastrointestinal mucosa ulceration (bloody diarrhea)

c. Dermatitis

Types of transplants

Table 3-3. Some Types of Transplants

Type of Transplant Comments
Cornea Best allograft survival rate
 Danger of transmission of Creutzfeldt-Jakob disease
Kidney Better survival with kidney from living donor than from cadaver
Bone marrow Graft contains pluripotential cells that repopulate host stem cells
Host assumes donor ABO group
Danger of graft-versus-host reaction and cytomegalovirus infection

Autoimmune Diseases
Autoimmune dysfunction is associated with a loss of self-tolerance, resulting
in immune reactions directed against host tissue.

Mechanisms of autoimmunity
1. Release of normally sequestered antigens (e.g., sperm)
2. Sharing of antigens between host and pathogen
3. Defects in functions of helper or suppressor T cells
4. Persistence of autoreactive T and B cells

5. Presence of specific autoantibodies

Table 3-4. Autoantibodies in Autoimmune Disease

Test Sensitivity
Autoantibodies Disease (%)
Antiacetylcholine receptor Myasthenia gravis 90
Anti-basement membrane Goodpasture syndrome >90
Anticentromere CREST syndrome 30
Antiendomysial and antigliadin Celiac disease 95
Anti-insulin Type 1 diabetes 50
Anti-islet cell 75
Anti-intrinsic factor Pernicious anemia 60
Anti-parietal cell 90
Antimicrosomal Hashimoto's thyroiditis 97
Antithyroglobulin 85
Antimitochondrial Primary biliary cirrhosis 90-100
Antimyeloperoxidase Microscopic polyangiitis 80 (p-ANCA)
Antiproteinase 3 Wegener's granulomatosis >90 (c-ANCA)
Antiribonucleoprotein Mixed connective tissue 100
disease
Anti-thyroid-stimulating hormone Graves' disease 85
receptor

c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody; p-ANCA, perinuclear antineutrophilic cytoplasmic

antibody.

Systemic lupus erythematosus (SLE)

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Anticardiolipin antibodies may produce a false-positive syphilis
serologic test by cross-reacting with cardiolipin in the rapid plasma
reagin (RPR) and Venereal Disease Research Laboratory (VDRL)
tests.
 Connective tissue disease that mainly affects the blood, joints, skin, and
kidneys

1. Occurs predominantly in women of childbearing age

2. Pathogenesis
o Polyclonal B-cell activation, sustained estrogen activity,
environmental triggers (e.g., sun, procainamide)
3. Clinical findings

a. Hematologic
Autoimmune hemolytic anemia, thrombocytopenia,
leukopenia
b. Lymphatic

i. Generalized painful lymphadenopathy

ii. Splenomegaly
b. Musculoskeletal

Small-joint inflammation (e.g., hands) with absence of joint

deformity
b. Skin

i. Immunocomplex deposition along basement membrane

Produces liquefactive degeneration
ii. Malar butterfly rash
b. Renal

Diffuse proliferative glomerulonephritis (most common

glomerulonephritis)
c. Cardiovascular

i. Fibrinous pericarditis with or without effusion

ii. Libman-Sacks endocarditis (sterile vegetations on mitral
valve)
c. Respiratory
i. Interstitial fibrosis of lungs
ii. Pleural effusion with friction rub
d. Pregnancy-related
i. Complete heart block in newborns
Caused by IgG anti-SS-A (Ro) antibodies crossing
the placenta
ii. Recurrent spontaneous abortions
Caused by antiphospholipid antibodies
2. Drug-induced lupus erythematosus
a. Associated drugs

Procainamide, hydralazine
d. Features that distinguish drug-induced lupus from SLE

i. Antihistone antibodies
ii. Low incidence of renal and central nervous system (CNS)
involvement
iii. Disappearance of symptoms when the drug is discontinued
3. Laboratory findings in SLE
a. Positive serum antinuclear antibody (ANA) (almost all cases)
i. Anti-double-stranded DNA antibodies and anti-Sm antibodies
Used to confirm the diagnosis of SLE, because they
 are highly specific for the disease (i.e., few false-
positive results)
ii. Anti-Ro antibodies are positive in 25% to 50% of cases.
b. Antiphospholipid antibodies
i. Lupus anticoagulant and anticardiolipin antibodies
ii. Damage vessel endothelium, producing vessel thrombosis
iii. Increased incidence of strokes and recurrent spontaneous
abortions
c. Lupus erythematosus cell
i. Neutrophil containing phagocytosed altered DNA
ii. Not specific for SLE
d. Decreased serum complement

Used up with activation of complement system

e. Immunocomplexes at the dermal-epidermal junction in skin
biopsies

Immunofluorescent studies identify complexes in a band-like

distribution along the dermal-epidermal junction.

Systemic sclerosis (scleroderma)

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Excessive production of collagen that primarily targets the skin (scleroderma),

gastrointestinal tract, lungs, and kidneys

1. Occurs predominantly in women of childbearing age

2. Pathogenesis
a. Small-vessel endothelial cell damage produces blood vessel fibrosis
and ischemic injury.
b. T-cell release of cytokines results in excessive collagen synthesis.
3. Clinical findings
a. Raynaud's phenomenon
i. Sequential color changes (normal to blue to red) caused by
digital vessel vasculitis and fibrosis
ii. Digital infarcts
b. Skin
i. Skin atrophy and tissue swelling beginning in the fingers and
extending proximally
ii. Parchment-like appearance
iii. Extensive dystrophic calcification in subcutaneous tissue
iv. Tightened facial features (e.g., radial furrowing around the
lips)
c. Gastrointestinal
i. Dysphagia for solids and liquids
No peristalsis in the lower two thirds of the
esophagus (smooth muscle replaced by collagen)
Lower esophageal sphincter relaxation with reflux
ii. Small bowel
Loss of villi (malabsorption)
Wide-mouthed diverticula (bacterial overgrowth)
d. Respiratory
i. Interstitial fibrosis of lungs
ii. Respiratory failure (most common cause of death)
e. Renal
i. Vasculitis involving arterioles (i.e., hyperplastic
arteriolosclerosis) and glomeruli
 ii. Infarctions, malignant hypertension
4. Laboratory findings in systemic sclerosis
a. Serum ANA is positive in 70% to 90% of cases.
b. Antitopoisomerase antibody is positive in 15% to 40% of cases.
5. CREST syndrome

o Limited sclerosis

a. Clinical findings
i. C-calcification, centromere antibody
ii. R-Raynaud's phenomenon
iii. E-Esophageal dysmotility
iv. S-sclerodactyly (i.e., tapered, claw-like fingers)
v. T-telangiectasis (i.e., multiple punctate blood vessel dilations)
b. Laboratory findings

Anticentromere antibodies in 30% of cases

Dermatomyositis (DM; with skin involvement) and polymyositis (PM; no

skin involvement)
1. Occurs predominantly in women 40 to 60 years of age
2. Associated with risk of malignant neoplasms (15-20% of cases), particularly
lung cancer
3. Pathogenesis
a. DM is associated with antibody-mediated damage.
b. PM is associated with T cell-mediated damage.
4. Clinical findings
a. Muscle pain and atrophy
Shoulders are commonly involved.
b. Heliotrope eyelids or "raccoon eyes" (purple-red eyelid discoloration)
5. Laboratory findings
a. Serum ANA is positive in fewer than 30% of cases.
b. Increased serum creatine kinase

c. Muscle biopsy shows a lymphocytic infiltrate.

Mixed connective tissue disease (MCTD)

1. Signs and symptoms similar to SLE, systemic sclerosis, and PM
2. Renal disease is uncommon.

3. Antiribonucleoprotein antibodies are positive in almost 100% of cases.

Immunodeficiency Disorders
Defects in B cells, T cells, complement, or phagocytic cells

Risk factors for immune disorders

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1. Prematurity
2. Autoimmune diseases (e.g., systemic lupus erythematosus)
3. Lymphoproliferative disorders (e.g., malignant lymphoma)
 4. Infections (e.g., human immunodeficiency virus [HIV])

5. Immunosuppressive drugs (e.g., corticosteroids)

Congenital immunodeficiency disorders

Table 3-5. Congenital Immunodeficiency Disorders

Disease Defect(s) Clinical Features
B-Cell Disorders
Bruton's Failure of pre-B cells to become Sinopulmonary infections
agammaglobulinemia mature B cells Maternal antibodies protective
Mutated tyrosine kinase from birth to age 6 months
X-linked recessive disorder Immunoglobulins
IgA deficiency Failure of IgA B cells to mature into Sinopulmonary infections,
plasma cells giardiasis
Anaphylaxis if exposed to blood
products that contain IgA
IgA and secretory IgA
Common variable Defect in B-cell maturation to plasma Sinopulmonary infections, GI
immunodeficiency cells infections (e.g., Giardia),
Adult immunodeficiency disorder pneumonia, autoimmune disease
Immunoglobulins
T-Cell Disorder
DiGeorge syndrome Failure of third and fourth pharyngeal Hypoparathyroidism (tetany);
pouches to develop absent thymic shadow on
Thymus and parathyroids fail to radiograph; PCP
develop Danger of GVH reaction
Combined B- and T-
Cell Disorders
Severe combined Adenosine deaminase deficiency; Defective CMI
immunodeficiency adenine toxic to B and T cells, Immunoglobulins
(SCID) deoxynucleoside triphosphate Treatment: gene therapy, bone
precursors for DNA synthesis marrow transplant (patients with
Autosomal recessive disorder SCID do not reject allografts)
Wiskott-Aldrich Progressive deletion of B and T cells Symptom triad: eczema,
syndrome X-linked recessive disorder thrombocytopenia,
sinopulmonary infections
Associated risk of malignant
lymphoma
Defective CMI
IgM, normal IgG, IgA and IgE
Ataxia-telangiectasia Mutation in DNA repair enzymes Cerebellar ataxia, telangiectasias
Thymic hypoplasia of eyes and skin
Autosomal recessive disorder Risk of lymphoma and/or
leukemia
Serum -fetoprotein

CMI, cell-mediated immunity; GVH, graft-versus-host; PCP, Pneumocystis jiroveci pneumonia.

1. B-cell disorders
o Recurrent encapsulated bacterial infections (e.g., Streptococcus
pneumoniae)
2. T-cell disorders
o Recurrent infections caused by intracellular pathogens (fungi, viruses,
protozoa)

3. Combined B- and T-cell disorders

Acquired immunodeficiency syndrome (AIDS)

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Table 3-6. Laboratory Tests Used in HIV and AIDS

Test Use Comments
ELISA Screening test Detects anti-gp120 antibodies
Sensitivity 100%
Positive within 6-10 weeks
Western Confirmatory test Used if ELISA is positive or indeterminate
blot Positive test: presence of p24 antigen and gp41 antibodies
and either gp120 or gp160 antibodies
100% specificity
p24 Antigen Indicator of active viral Positive prior to seroconversion and when AIDS is
replication diagnosed (two distinct peaks)
Present before anti-
gp120 antibodies
CD4 T-cell Monitoring immune Useful in determining when to initiate HIV treatment and
count status when to administer prophylaxis against opportunistic
infections
HIV viral Detection of actively Most sensitive test for diagnosis of acute HIV before
load dividing virus seroconversion
Marker of disease
progression

AIDS, acquired immunodeficiency syndrome; ELISA, enzyme-linked immunoabsorbent assay; HIV, human
immunodeficiency virus.
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Table 3-7. Organ Systems Affected by AIDS

Organ System Condition Comments
Central nervous system AIDS-dementia complex Caused by HIV
(CNS) Multinucleated microglial cells reservoir of
virus
Primary CNS lymphoma Caused by EBV
Most common extranodal site for lymphoma
Cryptococcosis Cause of CNS fungal infection
Toxoplasmosis Cause of space-occupying lesions
CMV retinitis Cause of blindness
Gastrointestinal Esophagitis Caused by Candida, herpesvirus, CMV
Colitis Caused by Cryptosporidium, CMV
Hepatobiliary Biliary tract infection Caused by CMV
Renal Focal segmental Causes hypertension and nephrotic
glomerulosclerosis syndrome
Respiratory Pneumonia Caused by Pneumocystis jiroveci and
Streptococcus pneumoniae
Skin Kaposi sarcoma Caused by HHV-8
Bacillary angiomatosis Caused by Bartonella henselae

AIDS, acquired immunodeficiency syndrome; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV-8, human
herpes virus type 8; HIV, human immunodeficiency virus.

Complement system disorders

 Table 3-8. Complement Disorders
Disorder Comments
Hereditary angioedema Autosomal dominant disorder with deficiency of C1 esterase inhibitor
Continued C1 activation decreases C2 and C4 and increases their
cleavage products, which have anaphylatoxic activity
Normal C3
Swelling of face and oropharynx
C2 deficiency Most common complement deficiency
Association with septicemia (usually Streptococcus pneumoniae) and
lupus-like syndrome in children
C6-C9 deficiency Increased susceptibility to disseminated Neisseria gonorrhoeae or N.
meningitidis infections
Paroxysmal nocturnal Acquired stem cell disease
hemoglobinuria Defect in molecule anchoring decay accelerating factor (DAF), which
normally degrades C3 and C5 convertase on hematopoietic cell
membranes
Complement-mediated intravascular lysis of red blood cells
(hemoglobinuria), platelets, and neutrophils

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1. Complement pathways
a. Classic and alternative pathways
b. C1 esterase inhibitor inactivates the protease activity of C1 in the
classic pathway.
c. Membrane attack complex (C5-C9) is the final common pathway for
both the classic and alternative pathways.
2. Testing of the complement system
a. A decrease in C4 or C2 indicates activation of the classic pathway.
b. A decrease in factor B indicates activation of the alternative pathway.

c. A decrease in C3 indicates activation of either system.

Amyloidosis
Amyloid
1. Fibrillar protein that forms deposits in interstitial tissue, resulting in organ
dysfunction
2. Characteristics
a. Linear, nonbranching filaments in a -pleated sheet
b. Apple green-colored birefringence in polarized light with Congo red
stain of tissue
c. Eosinophilic staining with H[amp ]E (hematoxylin and eosin) stain
d. Derived from various proteins
3. Major types of amyloid proteins
a. Amyloid light chain (AL)
Derived from light chains (e.g., Bence Jones protein)
b. Amyloid-associated (AA)
Derived from serum associated amyloid (SAA), an acute
phase reactant (see
c. -Amyloid (A)

Derived from amyloid precursor protein (protein product of

chromosome 21)

Amyloid
1. Fibrillar protein that forms deposits in interstitial tissue, resulting in organ
 dysfunction
2. Characteristics
a. Linear, nonbranching filaments in a -pleated sheet
b. Apple green-colored birefringence in polarized light with Congo red
stain of tissue
c. Eosinophilic staining with H[amp ]E (hematoxylin and eosin) stain
d. Derived from various proteins
3. Major types of amyloid proteins
a. Amyloid light chain (AL)
Derived from light chains (e.g., Bence Jones protein)
b. Amyloid-associated (AA)
Derived from serum associated amyloid (SAA), an acute
phase reactant (see
c. -Amyloid (A)

Derived from amyloid precursor protein (protein product of

chromosome 21)

Types of amyloidosis

Table 3-9. Common Types of Amyloidosis and Associated Clinical

Findings
Type of Amyloidosis Clinical Findings
Primary and secondary Nephrotic syndrome, renal failure (common cause of death)
Arrhythmia, heart failure
Macroglossia, malabsorption
Hepatosplenomegaly
Carpal tunnel syndrome
Senile cerebral Dementia (Alzheimer's type) caused by toxic A deposits in neurons
Amyloid precursor protein coded by chromosome 21
Associated with Down syndrome

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1. Systemic
a. Similar tissue involvement in both primary and secondary types
b. Primary amyloidosis
i. AL amyloid disposition
ii. Associated with multiple myeloma (30% of cases)
c. Secondary (reactive)
i. AA amyloid
ii. Associated with chronic inflammation (e.g., rheumatoid
arthritis, tuberculosis)
2. Localized
a. Confined to a single organ (e.g., brain)
b. Alzheimer's disease
i. A
ii. Most common cause of dementia
3. Hereditary

o Autosomal recessive disorder involving AA amyloid (e.g., familial

Mediterranean fever)

Pathogenesis
 Abnormal folding of normal or mutant proteins

Techniques
used to
diagnose
amyloidosis
1. Immunoelectrophoresis (to detect light chains) in primary amyloidosis

2. Tissue biopsy (e.g., adipose, rectum)