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Theories of Autoimmunity D. I. Stott Self/Non-self Discrimination Autoimmunity is a problem of self/nonself discrimination. 2 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 3 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 5 6 7 Molecular Mechanisms of Autoimmunity How is autoimmunity induced? What could go wrong here? 1-immunologic factor 2-genetic f. 3-inviroment f. 8 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 9 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 10 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. 11 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 12 3. Th By-pass Theory (a): Bcell response 13 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 14 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 15 Cross-Reactivity 16 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 17 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 18 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 19 Regulatory T-cells (b): SJL mice SJL mice have a Tr defect, immunisn. with rat RBC AIHA 20 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. 21 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. 22 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 23 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 24 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 26 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 27 (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 28 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 29 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 30 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) 31 Autoimmune disease • Dependent Ab 1-autoimmune hemolitic anemia 2-myasthenia gravis 3-graves 4-pemphigus vulgaris 5-goodpasture syndrome 6-rheumatic fever 32 • Dependent Tcell: 1-multiple sclerosis 2-type I insulin-dependent . diabetes mellitus(IDDM) 3- hashimotos thyroiditis 4-Ruemathoid Arthritis 33 • Dependent immune complex: syetemic lupus erythmatosus(SLE) Anti-DNA+DNA=IC 34 Rheumatoid Arthritis (RA) • • • • Cause (s) and Demographics Molecular Mechanism Mechanism of Tissue Damage Treatment Options 35 Cause and Demographics • Cause is unknown! • Affects 1-2% of worldwide population • Patients are 75% Women, between 40-60 years of age 36 Molecular Basis • Rheumatoid Factor (Rf): Antibodies to IgG • HLA-DR4 Antibody (MHC II!) 37 Mechanism of Tissue Damage 38 Treatment Options • • • • NSAIDs Cox-2 Inhibitors Methotrexate Herbal Remedies – Glucosamine – Chondroitin 39 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 40 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. 41 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 42 • 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 43 44 45