Autoimmunity

   
 Autoimmunity
• Definition: A breakdown in tolerance
in which the body’s immune system
begins to recognize self-antigens as
foreign.
• Problems:
– Failure to identify target antigens,
heterogeneous disease
manifestations, disease usually
presents long after initiation

   
 General principles

1
• Autoimmunity results from a failure
or breakdown of the mechanisms
normally responsible for maintaining
self—tolerance in B cells, T cells, or
both.

   
   
 AIRE
• AIRE (autoimmune regulator)
– Transcription factor that induces the ectopic
transcription of proteins normally expressed in
a tissue specific manner in the thymus.
– Encoded by the APECED (autoimmune-
polyendocrinopathy-candidiasis-ectodermal
dystrophy) gene.
– AIRE enhances the clonal deletion of self-
reactive T cells in the thymus.

   
 AIRE
• AIRE controls the ectopic expression
of a subset of peripheral-tissue
antigens genes in the thymus.
– One such gene is preproinsulin II.

   
   
   
   
 General principles

• The major factors that contribute to

the development of autoimmunity are
genetic susceptibility and
environmental triggers, such as
infections, tissue immunity etc.

   
   
 Genetic basis of autoimmunity
• Genetic predisposition of autoimmune diseases
– Increased incidence in twins
– Identification of disease-associated genes by breeding and
genomic approaches

• Multiple genes are associated with autoimmunity

– No single mutation causes autoimmunity

• MHC genes
– Major genetic association with autoimmune diseases (relative
risk)
– Disease-associated alleles may be found in normal individuals

• Non-MHC genes
– Many loci identified by genomic methods, animal studies
–  Mutations in complement genes
  predispose to lupus
 Figure 13-3
Recent work in this model suggests
Th17 cells are important!

   
 Environment

• Environmental factors also play a role

in autoimmune disease. infectious
organisms are the most significant
environmental factor.
In a few cases we have evidence for a
direct link between a specific infection
and an autoimmune disease.

   
   
   
   
 Molecular Mimicry Hypothesis

   
 Mechanism of Rheumatic Fever

   
 Endocrine factors
• Most autoimmune disease do not
occur with equal frequency in males
and females.
• For example Graves' and Hashimoto's
are 4-5 times, and SLE 10 times,
more common in females while
Ankylosing Spondylitis is 3-4 × more
frequent in males. These differences
are believed to be the result of
hormonal influences
   
• A second well documented hormonal
effect is the marked reduction in
disease severity seen in many
autoimmune conditions during
pregnancy. Rheumatoid arthritis is
perhaps the classic example of this
effect. In some cases there is also a
rapid exacerbation (rebound) after
giving birth.

   
 General principles

• Autoimmune diseases may be

either systemic or organ specific.

   
   
 General principles

4
• Epitope spreading: Autoimmune
reactions initiated against one self
antigen may injure tissues, resulting
in the release and alteration of other
tissue antigen, activation of
lymphocytes specific for these other
antigens , and exacerbation of the
disease.
   
 General principles

• Various effector mechanisms are

responsible for tissue injury in
different autoimmune diseases.

   
 General principles
6
• Anatomic alterations in tissues, such
as inflammation (possibly secondary
to infection), ischemic injury, or
trauma, may lead to the exposure of
self antigens that are normally
concealed from the immune system.
• Eg. Intraocular protein.

   
 CLASSIFICATION OF
AUTOIMMUNE DISEASES
• MHC CLASS II-ASSOCIATED
• Organ specific (autoantibody directed against a
single organ or closely related organs)
• Systemic (systemic lupus erythematosis-variety
of autoantibodies to DNA, cytoplasmic antigens,
etc.)
• MHC CLASS I-ASSOCIATED
• Hla-b27-related spondyloarthropathies
(ankylosing spondylitis, reiter’s syndrome)
• Psoriasis vulgaris (associated with hla-b13, b16,
b17)
   
 Classification of Autoimmune
Diseases
• Broadly separated by the type of effector
mechanism (similar to hypersensitivity
classification scheme)
• Three classes:
– Type II: Antibody against cell-
surface antigen or matrix antigens
– Type III: Immune-complex disease
– Type IV: T cell-mediated disease

   
 Type II: Antibody-mediated diseases

   
 Graves’ disease

   
 Graves’ disease:
Proof that it’s antibody
mediated

   
 Myasthenia Gravis
In this disease, autoantibodies to
the Acetylcholine receptor block
neuromuscular transmission from
cholinergic neurons by blocking the
binding of acetylcholine and by
causing downregulation
(degradation) of its' receptor.

   
   
 Type III: Immune-complex
mediated diseases

   
Systemic Lupus Erythematosus (SLE)
• Systemic diseases such as SLE and vasculitis almost
certainly result from autoantibody-antigen complexes
and their consequences. Circulating antibodies to
constituents of the cell surface, cytoplasm, and nucleus
– Anti-DNA, anti-histone, anti-sRNP
• Certain organs are especially sensitive to immune
complex deposition particularly the kidney. SLE
patients possess a wide variety of autoantibodies to
both cytoplasmic and nuclear antigens.
• The presence of IgG anti double- stranded DNA is
characteristic of this condition (Note: IgM anti-ds DNA
is NOT pathogenic).
   
• Two significant facts point to the
role of immune complexes in SLE.
– First, patients demonstrate
significant depletion of
complement (C3) and
neutrophils resulting from
activation by the complexes.
– Second, complement
deficiencies which impair IC
clearance (C1,C2 or C4) are very
strong predisposing factors for
SLE.
• Symptoms include rash, arthritis,
glomerulonephritis,
 
vasculitis.
 
 SLE: Immune complexes in
the kidney

   
 Type IV: T cell-mediated
Figure 11-1 part
diseases
3 of 3

   
T cell mediated effects (cellular
immune)
– Direct T cell cytotoxicity via CD8+ CTL
– Self-destruction of tissue cells induced
by cytokines, eg, TNFa
– Recruitment and activation of
macrophages leading to bystander tissue
destruction
– Induction of target tissue apoptosis by
the T cell membrane protein FasL
   
 Type I Diabetes
• T cell response to antigens expressed in the
β-cells of the islets
– Proinsulin/Insulin, GAD, I-A2
– T cell response is Th1 “like”, makes γ-IFN and
helps recruit a tissue/cell destruction response
• >90% islet destruction needed for the
disease to be expressed
• Patients also have autoantibodies to islet
antigens
   
   
 Overview of Autoimmunity

Failure of central
or peripheral Environmental
Genetic Predisposition
tolerance Factors

CD4+ T Cell
Driving Force
Autoreactive
Specialized cells B Cells
present self­tissue
proteins IFN­gamma Autoantibodies
IL­2, etc.
Tissue injury;
release of self antigens;
activation of self­reactive
CD8+ T Cell lymphocytes
Driving Force
   
 ALLOIMMUNITY
The immune system acts against antigens on the tissues
of other members of the same species.

A) Transient neonatal diseases:

• Graves Disease – Antibody Against Receptor For Thyroid-
stimulating Hormone, Neonatal Hyperthyroidism
• Myasthenia Gravis – Antibody Binds With Receptors For
Neural Transmitters On Muscle Cells
• Immune Thrombocytopenic Purpura – Antiplatelet Antibody,
Destroys Fetal Cells
• Alloimmune Neutropenia – Antibody Against Neutrophils,
Destroys Neutrophils In Fetus
• Systemic Lupus Erythromatosus (Sle) –Autoantibodies Cause
Abnormalities In Fetus
• Rh And ABO Alloimmunization - Erythroblastosis Fetalis
   
B) TRANSPLANT REJECTION – Typically A
Type IV Cell-mediated Reaction.
•Hyperacute - Immediate, Usually Occurs In
The Presence Of Pre-existing Antibody To
Antigens In The Graft.
•Acute - Occurs 2 Weeks After Transplant,
Immune Response Is Mounted Against
Unmatched Hla Antigens.
•Chronic – May Occur Months Or Years
After Transplant, Characterized By Slow
Progressive Organ Failure.