CHAPTER 299: AUTOIMMUNITY AND
sequestration of self-antigens, rendering
AUTOIMMUNE DISEASE
Immune system
- distinguish self from non-self
- normally does not mount immune
response to self-antigens
- recognition of self plays an
important role in shaping both T and B cell
repertoires of immune receptors
Autoimmunity
- the end result of the breakdown
of one or more of the basic
mechanisms regulating immune
tolerance
- presence of autoantibodies or T
lymphocytes that react with self
antigens does not necessarily
imply the development of self-
reactivity
- maybe seen in normal
individuals and higher
frequency in older people
- autoreactivity may develop
during infectious conditions
- may be self-limited or
persistent
- self-reactivity maybe the cause
or consequence of ongoing
pathologic process
Autoimmune disease
- essential feature is tissue injury
caused by immunologic
reaction of the organism
MECHANISMS OF AUTOIMMUNITY
Erlich
- first postulated the existence of
mechanisms to prevent the
generation of self-reactivity in
1900
Burnet
- clonal selection theory
- interaction of lymphoid cells
with their specific antigens
during fetal or postnatal life
would lead to elimination of
“forbidden clones”
- this became untenable when it
was shown that autoimmune
disease can be induced by
simple immunization
procedures
- mechanisms in addition to
clonal deletion were responsible
Table 299-1 Mechanisms Preventing
Autoimmunity
1.
them inaccessible to the immune sys
2. specific unresponsiveness (tolerance or
anergy) of relevant T or B cells
a. central deletion of autoreactive
lymphocytes
b. peripheral anergy of autoreactive
lymphocytes
c. receptor replacement by
autoreactive lyphocytes
3. limitation of potential reactivity by
regulatory mechanisms
- derangements may predispose
to development of
autoimmunity
Table 299-9 Mechanisms of
Autoimmunity
I. Exogenous Molecular mimicry
Superantigenic stimulation
Microbial adjuvanticity
II. Endogenous Altered antigen presentation
1. Loss of immunologic
privilege
2. Presentation of novel
or crytic epotopes
3. alteration of self-
antigen
4. enhance function of
antigen-presenting
cells
a. costimulatory
molecule expression
b. cytokine
production
Increased T cell help
1. cytokine production
2. costimulatory
molecules
Increase B cell function
Apoptopic defects
Cytokine imbalance
Altered immunoregulation
- in general these abnormal responses
relate to stimulation by exogenous
agents (bacterial or viral) or
endogenous abnormalities in the cells
of the immune sys
- microbial superantigens
(staphylococcal protein A,
staphylococcal enterotoxins) stimulate
a broad range of T and B cells
- Molecular mimicry
o Cross reactivity between
microbial product and self-
antigen
o Lead to autoreactive
lymphocytes
o Example Rheumatic fever
Antibodies to M protein
of strep cross-react with
myosin, laminin, matrix
prot
o DM type1, rheumatoid arthritis,
multiple sclerosis
- Microbial adjuvanticity
 o Autoantigens become more
immunogenic
o Infectious agents may be able
to overcome self-tolerance
because of bacterial endotoxin
- Immunologically privileged sites
o Brain, ant chamber of eye
o Inability of engrafted tissue to
elicit immune responses
 Limited entry of proteins
from lymphatic
 Local production of
immunosuppressive
cytokines (TGF β)
 Local expression of
molecules (Fas ligand)
that can induce
apoptosis of activated T
cells
o Lymphoid cells remain in a
state of immunologic ignorance
o If site is damaged by trauma or
inflammation or if T cells are
activated elsewhere it can
become the sites of
immunologic assault
o MS, sympathetic opthalmia
- Alteration in antigen presentation
o Epitope spreading not routinely
by lymphocytes (cryptic
epitopes)
- Chemical Alteration in proteins
o Inflammation, drug exposure,
normal senescene
- intense stimulation of T
lymphocytes
o bypass the need for
antigen-specific helper T
cells and lead to
polyclonal B cell
activation
o Graft versus host rxn,
autoimmune hemolytic
anemia, immune
complex mediated
glomerulonephritis
- Nonspecific stimulation of B
lymphocytes
o Production of
autoantibodies
o polyclonal B cell
activators like bacterial
endotoxin
- Primary alterations in the activity of T
and or B cells, cytokine imbalances or
defective immunoregulatory circuits
o Defects in Fas (CD95) or
Fas ligand
o Decrease in TNF and IL-
10
o Defects in expression of
regulatory T cell activity
- No single mechanism can explain all
the varied manifestations
- A number of factors need to converge
- Additional factors
o Age, sex (F>M) genetic
background, exposure to
infectious agents and
environmental contacts
GENETIC CONSIDERATIONS
- Certain susceptibility genes
o Alleles of major
histocompatibility
complex
 Shape Tcell
receptor
repertoire
 Cross reactivity
might lead to
molecular
mimicry
 MHC genotype
alone does not
determine the
development of
autoimmunity
 Several
independently
segregating
disease
susceptibility loci
o Homozygous deficiency
of the classic pathway of
complement (C1, C4 or
C2) associated with SLE
o Abnormalities in coding
proteins involved in the
regulation of apoptosis
Fas (CD95) and Fas
ligand
o Inherited variation in the
expression of cytokines
(TNF-a or IL 10)
IMMUNOPATHOGENIC MECHANISMS IN
AUTOIMMUNE DISEASES
- antibody mediated and cell-
mediated process
- pathogenicity of autoantibodies
can be mediated through
o Opsonization of soluble
factors or cells
o Activation of
inflammatory cascade
o Interference with the
physiological function of
soluble molecules or
cells
- In autoimmune
thrombocytopenic purpura
o Opsonization of platelets
targets them for
elimination for
phagocytosis
- Autoimmune hemolytic anemia
o Binding of Ig to RBC
membranes leads to
phagocytosis and lysis
- Goodpasture’s syndrome
 o Activation of
complement and
neutriophils
- SLE
o Activation of the
complement cascade at
sites or immunoglobulin
deposition in renal
glomeruli
- Autoantibodies
o Can interfere with
normal physiologic
functions of cells or
soluble factors
o Stimulateof cells
o Inhibit cell function
through interference of
cell signaling
- Anti-phiospholipid antibodies
o Antibody is directed to
the phospholipids-β2-
glycoprotein I
- Pemphigus vulgaris
o Auto-Ab bind to a
component of epidermal
cell desmosome,
desmoglein 3
o Disrupt cell-cell
junctions
- Wegener’s granulomatosis
o c-ANCA causes cell
activation and
granulation of
neutrophils
- Auto-Ab may cause disease
only in genetically susceptible
hosts
- Auto-Ab seem to be markers for
disease
AUTOIMMUNE DISEASE
- to classify a diease as auto-
immune
o immune response to a
self-antigen causes the
observed pathology
o demonstrate the
autoimmunity is
pathogenic
- mechanistic understanding of
pathogenic potential of auto-Ab
has not been established
o cytokine production of T
helper cells
table 299-4 Human Autoimmune
Disease: Presumptive Evidence for an
Immunologic Pathogenisis
Major Criteria
1. presence of autp-Ab or evidence of
cellular reactivity to self
2. documentation of relevant auto-ab
or lymphocytic infiltrate in the
pathologic lesion
3. demonstration that the relevant
auto-ab or T cells can cause tissue
pathology
a. transplacental transmission
b. adaptive transfer into animals
c. in vitro impact on cellular
function
Supportive evidence
1. reasonable animal evidence
2. beneficial effect from
immunosuppressive agents
3. association with other eveidence of
autoimmunity
4. no evidence of infection or other
obvious cause
ORGAN-SPECIFIC VERSUS SYSTEMIC
AUTOIMMUNIE DISORDERS
- autoimmune diseases form a
spectrum from a single organ to
systemic disorders
(please see table 299-5)
- there is tendency for overlap, if
the person has one syndrome
more likely to develop a second
syndrome
- those with an organ-specific
autoimmune disease to develop
multiple other manifestations of
autoimmunity w/o the
development of associated
organ pathology
o may relate to the
genetic elements of the
individual
- SLE
o Pathologic lesions found
in multiple diverse
organs and tissues
o Protean manifestation:
kidneys, joints, skin,
serosal surfaces, blood
vessels and CNS
o Generalized
hyperreactivity of the
humoral immune system
o Generalized B cell
hyperresponisveness
o Polyclonal
hypergammaglobulinemi
a
o Increased titers of auto-
ab
TREATMENT
- suppressing induction of
autoimmunity
- restoring normal regulatory
mechanisms
- inhibiting the effector
mechanisms
- eliminate autoreactive cells
o immunosuppressive or
ablative therapy
- cytokine blockade
o limit organ damage
- eliminating effector T or B cells
- auto-antigen to induce
tolerance