Download Theories of Autoimmunity

Theories of Autoimmunity
D. I. Stott
Self/Non-self Discrimination
Autoimmunity is a
problem of self/nonself discrimination.
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Definition
• Breakdown of mechanisms responsible for
self tolerance and induction of an I.R. against
components of self
• Example:anti-idiotype Ab
anti-tumor
anti-RBC
anti-demage tissue
AUTO IMMUNE DISEASE
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Autoimmunity
“n. of, relating to, or caused by autoantibodies or
lymphocytes that attack molecules, cells, or
tissues of the organism producing them.”
(from Webster’s Online)
The Study of Autoimmunity
• Molecular Mechanisms of Autoimmunity
• Animal Models for Autoimmune
Dysfunction
• Treatments for Autoimmune Diseases
• Gender Differences in Autoimmunity
• Common Autoimmune Diseases
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Molecular Mechanisms of Autoimmunity
How is autoimmunity
induced?
What could go wrong
here?
1-immunologic factor
2-genetic f.
3-inviroment f.
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The Problem:• B &T-cell receptor specificities generated
randomly
• Anti-self lymphocytes are deleted or 
anergic
• Some escape: anti-self B (& T) L.s in healthy
individuals
• 1- in negative selection thymus
• 2- not all self Ag may be represent in thymus
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Evidence for anti-self lymphocytes in
healthy individuals:• L.s bind autoags., e.g. thyroglobulin, DNA
• Autoabs. in serum, e.g. RF  with age.
• L.s + mitogen or EBV  autoabs. in vitro
• Self-ags./FCA  autoimmune response, e.g.
 rats + thyroglobulin/FCA  autoimmune
thyroiditis
 MBP/FCA  EAE
 Collagen/FCA  RA
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Theories: 1. Cryptic Antigen
• Ag sequestered from immune system
• Damage & release of ag. (injury or
surgery)  AIR
e.g. Eye  sympathetic ophthalmia
Testes  anti-sperm & orchitis
Antibodies in blood can attack Myelin Basic Protein if
Blood-Brain barrier is breached.
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2. Somatic Mutation
Hypothesis
Mutation in V of -non-self  -self, e.g.
-Phosph. choline myeloma  -DNA
Mice/Ph-AsO3--pr.  B-Ls. with BCRs
-AsO3- + -DNA, latter normally 
anergic or die
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3. Th By-pass Theory (a): Bcell response
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Th By-pass Theory (b)
Foreign Th epitope/self B-cell epitope:• Ag modification (neo Ags), e.g. by
Drugs:
-Me-Dopa  altered synth. of Rh ag 
AIHA
Procainamide  nucleosomes  histone, - DNA  SLE
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Th By-pass Theory (c)
• Ag Mimicry: bact. & viruses X self ags.
 Strep. pyogenes  -M pr., X heart valves
 inflammn. of endocardium & damage to
valves rheumatic fever
 BK Polyoma virus/Rabs.  -DNA, histones
 SLE
 Rabies vaccine (brain tissue)  encephalitis
papilloma virus (HPV) and insulin receptor
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Cross-Reactivity
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4. Polyclonal Activation
Hypothesis
•
•
B-cell mitogens, e.g. LPS, EBV
Bact. Superag.  TCR (V)  -self or
Th
BUT
 Limited specificity, e.g. thyroiditis
 Clonally restricted e.g. -DNA in SLE
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5. Genetic Defects
• (a) Apoptosis: MRL-lpr/lpr & gld/gld
mice - Fas or FasL defect  SLE
• (b) Association with MHC Class II
 e.g. R.A. & DR4, SLE & DR3,
 IDDM & DQ - single  at posn. 56, Asp
protects, other s  IDDM
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6. Regulatory T-cells (a)
•
•
•
•
-self Ls. suppressed by Tr-cells
Is AIR result of defect in Tr?
Evidence: (a) Tx rats  -Tg & AIT
(b) Tx mice  AIR v. many organs &
tissues
 + adult T-L.s, suppress AIR
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Regulatory T-cells (b): SJL
mice
SJL mice have a Tr defect, immunisn. with rat RBC  AIHA
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7. Danger Theory
• Anti-self B & T-cells always present.
• AIR is due to release of “danger signals.”
• Response to tissue damage, necrosis or cell
distress, e.g. infection or injury.
• Inflammn. = response to danger signals
mediated by effector mols. inc. cytokines.
• BUT AIR can occur without tissue damage,
e.g. immunisn. with self-ag; Tx; genetic
defects.
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8. Theory
• Inappropriate MHC expression
Type I Diabetes: Pancreatic β cells express abnormally
high levels of MHC I and MHC II (?)
MHC II – APC only! This may hypersensitize TH cells to β
cell peptides.
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Summary
• Self reactive B-cells & T-cells are
normally present but anergic.
• Several factors can induce an AIR: Genetic
 Tissue damage & release of cryptic ag.
 Somatic mutation in Ig V-genes
 Ag mimicry
 Tr defects
 Danger signals
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How Are Autoimmune Diseases
Diagnosed?
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•
•
•
Symptoms
Detection auto-Abs and very rarely Tcells
BY I.F. AND ELISA OR RIA
in some case a biological / biochemical
assay
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Treatment of Autoimmune
Diseases
I.
Current Therapies
- aimed at reducing symptoms by
providing non-specific suppression of the
immune system
II. Experimental Therapeutic Approaches try to induce specific immunity
I. Current Therapies
• Immunosuppressive drugs
- corticosteroids, azathioprine
- slows the proliferation of lymphocytes
• Cyclosporin A
- blocks signal transduction mediated by the TCR
(inhibits only antigen-activated T cells while sparing
non-activated ones)
• Thymectomy
- removal of thymus from patients with myasthenia
gravis
• Plasmapheresis
- removes antigen-antibody complexes for a shortterm reduction in symptoms
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II. Experimental Therapeutic
Approaches
• T-cell Vaccination
- autoimmune T-cell clones elicit regulator T-cells
that
are specific for the TCR on the autoimmune Tcells
- results in suppression of the autoimmune cells
• Peptide Blockade of MHC molecules
- a synthetic peptide is used to bind in place of the
regular peptide on the MHC
- induces a state of clonal anergy in the autoimmune
T-cells
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(Experimental Therapies continued)
• Monoclonal-Antibody Treatment
- monoclonal antibody against the IL-2 receptor
blocks activated TH-cells
- blockage of preferred TCRs with monoclonal
antibodies
- monoclonal antibody against an MHC molecule
that is associated with autoimmunity while sparing
the others
• Oral antigens
- tend to induce tolerance
- still in early clinical trials
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Sex-based Differences in
Autoimmunity
• Differences can be traced to sex hormones
- hormones circulate throughout the body and alter
immune response by influencing gene expression
- (in general) estrogen can trigger autoimmunity and
testosterone can protect against it
• Difference in immune response
- ♀ produce a higher titer of antibodies and mount
more vigorous immune responses than ♂
- ♀ have a slightly higher cortisol secretion than ♂
- ♀ have higher levels or CD4+ T-cells and serum
IgM
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Sex-based Differences
• Estrogen
- causes autoimmunity (generally)
- stimulates prolactin secretion (helps regulate
immune response)
- stimulates the gene for CRH (corticotropinreleasing hormone) that promotes cortisol secretion
- causes more TH1-dominated immune responses
(promotes inflammation)
• Testosterone
- can cause autoimmunity or protect against it
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Sex-based Differences
• Pregnancy
- during this, ♀ mount more of a TH2-like response
- the change in hormones creates an antiinflammatory environment (high cortisol levels)
- diseases enhanced by TH2-like responses are
exaggerated and diseases that involve
inflammatory responses are suppressed
- fetal cells can persist in the mother’s blood or the
mother’s cells may appear in the fetus
(microchimerism)
- can result in autoimmunity if the fetal cells
mount an immune response in the mother’s
body (or vice versa)
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Autoimmune disease
• Dependent Ab 1-autoimmune hemolitic anemia
2-myasthenia gravis
3-graves
4-pemphigus vulgaris
5-goodpasture syndrome
6-rheumatic fever
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• Dependent Tcell: 1-multiple sclerosis
2-type I insulin-dependent
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diabetes mellitus(IDDM)
3- hashimotos thyroiditis
4-Ruemathoid Arthritis
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• Dependent immune complex:
syetemic lupus
erythmatosus(SLE)
Anti-DNA+DNA=IC
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Rheumatoid Arthritis (RA)
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Cause (s) and Demographics
Molecular Mechanism
Mechanism of Tissue Damage
Treatment Options
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Cause and Demographics
• Cause is unknown!
• Affects 1-2% of worldwide population
• Patients are 75% Women, between 40-60
years of age
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Molecular Basis
• Rheumatoid Factor (Rf): Antibodies to IgG
• HLA-DR4 Antibody (MHC II!)
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Mechanism of Tissue Damage
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Treatment Options
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NSAIDs
Cox-2 Inhibitors
Methotrexate
Herbal Remedies
– Glucosamine
– Chondroitin
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Grave’s Disease
•Production of thyroid hormones is
regulated by thyroid-stimulating
hormones (TSH)
•The binding of TSH to a receptor on
thyroid cells activates adenylate
cyclase and stimulates the synthesis
of two thyroid hormones: thyroxine
and triiodothyronine
•A person with Grave’s Disease
makes auto-antibodies to the
receptor for TSH. The binding of
these auto-antibodies to the receptor
mimics the normal action of TSH,
without the regulation, leading to
overstimulation of the thyroid
•The auto-antibodies are called longacting thyroid stimulating hormones
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Grave’s Disease
•Beta-blockers such as
propranolol are often used to
treat symptoms of rapid heart
rate, sweating, and anxiety until
the hyperthyroidism is
controlled.
•Hyperthyroidism is treated with
antithyroid medications,
radioactive iodine or surgery.
•Both radiation and surgery
result in the need for lifelong
use of replacement thyroid
hormones, because these
treatments destroy or remove
the gland.
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Autoimmune Anemias
• Pernicious Anemia
What is it?
- deficiency in vitamin B12
What causes it?
- auto-antibodies to intrinsic factor
What happens?
- B12 remains in the stomach and is excreted
Treatment
- treated with injections of B12
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• Hemolytic Anemia
- results from monoclonal antibodies to normal
RBC constituents
- antibodies coat the erythrocytes, causing clumping,
lysis, and premature clearance by the spleen
- can be induced by an “offending” agent (parasite,
drug, or toxin) that adheres to the RBC
- Drug-induced Hemolytic Anemia- drug binds
to RBC’s and causes them to become
antigenic
- antibodies that develop from the drug
recognize these cells and they are
lysed
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