Autoimmunity engl
- 2. Immune recognition and injury of self tissues (autoimmunity) results from a loss of self tolerance. Definition
- 6. Disruption of self or tissue barrier (Antibodies in blood can attack Myelin Basic Protein if Blood-Brain barrier is breached.) Infection of antigen presenting cell Binding of pathogen to self antigen Molecular mimicry Superantigen Superantigen 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 T H cells to β cell peptides.) Molecular Mechanisms of Autoimmunity
- 7. MOLECULAR MIMICRY Definition : D eterminants of infectious agent mimic a host antigen and trigger self-reactive T-cell clones to attack host tissues. Examples : S tromal keratitis due to herpes simplex virus type I R heumatic fever due to group A streptococc us SLE due Epstein-Barr virus cross reactive with nuclear Sm antigen Lyme a rt rhritis due B orrelia burgdorferi reactive with LFA- 1 (lymphocyte function antigen-1) Molecular Mechanisms of Autoimmunity
- 8. Molecular Mechanisms of Autoimmunity
- 9. Cross-Reactivity Molecular Mechanisms of Autoimmunity
- 11. Molecular mimicry- model in IDDM Molecular Mechanisms of Autoimmunity
- 12. Molecular Mechanisms of Autoimmunity Superantigen
- 13. EPITOPE SPREADING Definition : Initial response to one self determinant (one peptide) could expand to involve additional determinants on the same molecule as well as additional self-proteins. It explains how a response to one cryptic epitope can mature into a full-blown autoimmune response Examples : anti-Sm to U1RNP anti Ro/SS-A to anti-La/SS-B – lead to lupus-like disease Molecular Mechanisms of Autoimmunity
- 14. Molecular Mechanisms of Autoimmunity 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 T H cells to β cell peptides.
- 15. Inappropriate MHC Expression Normal Pancreas Pancreas with Insulitis Fig. 20-3
- 16. Molecular Mechanisms of Autoimmunity Polyclonal B Cell Activation by Viruses and Bacteria If B cells reactive to self-peptides are activated, autoimmunity can occur. Example: Epstein-Barr Virus, which is the cause of infectious mononucleosis.
- 17. Immune dysregulation A defect in any arm of the immune system can trigger autoimmunity Complement T cells B cells
- 18. The Complement See-Saw The complement system is a mediator in both the pathogenesis and prevention of immune complex diseases It has a protective effect when functioning in moderation against pathogens; at the same time, the inflammation promoted by complement activation can result in cellular damage when not kept in check.
- 19. Complement Deficiencies CD59 or CD55 – Paroxysmal nocturnal hemoglobinuria autoimmune hemolytic anemia autoimmune thrombocytopenia lupus lymphopenia Deficiencies in the classical complement pathway renders pts more likely to develop immune complex diseases SLE RA
- 20. OTHER FACTORS FAVORING AUTOIMMUNITY Overproduction and/or dysregulation of cytokines Disturbances of apoptosis Adjuvant effect of microorganisms Pre-existing defects in the target organ Direct stimulation of autoreactive cells by foreign antigen
- 22. Cytokine Dysregulation in Autoimmunity CD = Crohn’s Disease
- 23. Genes and Autoimmunity The concept that a single gene mutation leads to a single autoimmune disease is the EXCEPTION not the rule. Because of this autoimmune diseases are generally classified as complex diseases as there is not a single “pinpoint-able” gene
- 24. AD ARE COMPLEX GENETIC TRAITS Multiple genes determine susceptibility to AD No particular gene is necessary or sufficient for disease expression (relatively low gene penetrance) MHC and multiple non-MHC genes are involved Epistasis (interaction of susceptibility genes) Genetic alleles increasing susceptibility are relatively frequent in the general population
- 25. EXAMPLES OF GENE DEFECTS IN AUTOIMMUNITY Multiple sclerosis – particular alleles of HLA-DR ( DRB1*1501 , DRB5*0101 ) Systemic lupus – lack of C1q and C4 Genetically determined low expression of given self-antigen in the thymus Mutation (usually deletion) of autoimmune regulator-1 gene (AIRE-1)
- 28. H LA testing in diseases
- 29. HLA association with IDDM in Bulgarian population
- 30. HLA association with MS and JCA in Bulgarian population
- 31. Вероятен молекулен модел за автоимунна болест - верига - верига 57-58 3-ти HVR: 70-74
- 32. Exceptions to the Rule – Simple Genetic Autoimmune Illnesses Failure of apoptotic death of self reactive T or B cells FAS, FASL ALPS (autoimmune lymphoproliferative syndrome ) Decreased generation of Tregs FOXP3 IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, X-linked) Decreased expression of self-antigens in the thymus, resulting is a defect in negative selection AIRE APS-1 (Autoimmune polyglandular syndrome type 1) Mechanism Gene Disease
- 33. Environment in autoimmunity Pathogens, drugs, hormones, and toxins are just a few ways that the environment can trigger autoimmunity
- 34. Drugs and Toxins Drugs Examples: Procainamide (Pronestyl) Drug induced lupus Toxins Examples: Toxic Oil Syndrome Occurred in Spain in 1981 after people ate contaminated olive oil. People developed unique illness marked by lung disease, eosinophilia, and excessive IgE
- 35. 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
- 36. 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 T H 1-dominated immune responses (promotes inflammation) Testosterone - can cause autoimmunity or protect against it
- 37. Sex-based Differences Pregnancy - during this, ♀ mount more of a T H 2-like response - the change in hormones creates an anti- inflammatory environment (high cortisol levels) - diseases enhanced by T H 2-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)
- 39. Nature Immunology 2 , 777 - 780 (2001) Sex differences in autoimmunity
- 40. Pathogenetic mechanisms of Autoimmune diseases
- 43. Autoimmune diseases The immune response turns against the host Antibodies direct against cell-surface or extracellular-matrix molecules (Type II) Antibodies bound to molecules circulating in the plasma than deposit as immune complexes (Type III) T cells that are reactive with self antigens (Type IV)
- 52. Pathogenesis of SLE
- 58. Pick an organ, any organ . . . Autoimmunity can affect ANY organ/organ system in the human body Pemphigus Multiple Sclerosis Sjogren’s Syndrome Rheumatic Fever Autoimmune Hepatitis Ulcerative Colitis Goodpasture’s Syndrome Diabetes Autoimmune Uveitis Autoimmune hemolytic Anemia Addison’s Disease Rheumatoid Arthritis Autoimmune Oophoritis
- 59. Autoimmunity Classification Can be classified into clusters that are either organ-specific or systemic
- 60. Examples of Organ Specific Lungs of a patient with Goodpasture’s Vitiligo Hashimoto’s disease (thyroiditis)
- 61. Examples of Systemic Autoimmunity SLE
- 62. Examples of Systemic Autoimmunity Sjogren’s Syndrome
- 63. Putting it all together… Autoimmunity can be caused by immunological, genetic, viral, drug-induced, and hormonal factors. There are 4 immunological mechanisms of autoimmunity. All mechanisms cause abnormal B or T cell activation. Centrality of the Ternary Complex Most instances of autoimmune diseases occur with multiple mechanisms, which makes treatment difficult.
- 64. 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
- 65. 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
- 66. (Experimental Therapies continued) Monoclonal-Antibody Treatment - monoclonal antibody against the IL-2 receptor blocks activated T H -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
- 67. THERAPY OF AUTOIMMUNE DISEASES : I. SELF-ANTIGEN SPECIFIC Antibodies vs. autoreactive TCR Vaccine containing autoreactive TCR Administration of peptides – TCR antagonists Parenteral infusion of autoantigen or cDNA Oral administration of autoantigen Comment : all above are at the stage of experiment
- 68. THERAPY OF AUTOIMMUNE DISEASES: II. ANTIGEN NON-SPECIFIC Monoclonal antibodies vs.T cells -CD2, CD3, CD4 Antibodies vs. CD28, CD40L (modulation of T cell – APC interaction) Antibodies vs. cell adhesion molecules (VLA-4, ICAM-1) and chemokines Intravenous infusion of immunoglobulin (IVIG) Neutralization of proinflammatory cytokines Administration of anti-inflammatory cytokines