Theories of Autoimmunity

D. I. Stott

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Self/Non-self Discrimination

Autoimmunity is a problem of self/non-self 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

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)

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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

What could go wrong here?

1-immunologic factor

2-genetic f.

3-inviroment f.

How is autoimmunity induced?

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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 ophthalmiaTestes 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 -DNAMice/Ph-AsO3

--pr. B-Ls. with BCRs -

AsO3- + -DNA, latter normally

anergic or die

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3. Th By-pass Theory (a): B-cell 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?

• Symptoms

• Detection auto-Abs and very rarely Tcells

• BY I.F. AND ELISA OR RIA

• in some case a biological / biochemical assay

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

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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 short- term 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 T- cells

- 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 (corticotropin- releasing 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 anti- inflammatory 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 . 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)

• 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

• 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 long-acting 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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