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AUTOIMMUNITY

AUTOIMMUNITY. Self/Non-self Discrimination. Autoimmunity is a problem of self/non-self discrimination. Frequence of AI. 5 % to 7% adult affected. Two third women. More than 40 human diseases autoimmune in origin. Mechanisms of AI. 1 ) Tissue destruction

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AUTOIMMUNITY

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  1. AUTOIMMUNITY

  2. Self/Non-self Discrimination Autoimmunity is a problem of self/non-self discrimination.

  3. Frequence of AI • 5 % to 7% adult affected. • Two third women. • More than 40 human diseases autoimmune in origin.

  4. Mechanisms of AI 1) Tissue destruction Diabetes: CTLs destroy insulin-producing beta-cells in pancreas 2) Antibodies block normal function Myasthenia gravis: Ab binds acetylcholine receptors 3) Antibodies stimulate inappropriate function Graves’ disease: Ab binds TSH receptor Mimics thyroid-stimulating hormone Activates unregulated thyroid hormone production 4) Antigen-antibody complexes affect function Rheumatoid arthritis: IgM specific for Fc portion of IgG IgM-IgG complexes deposited in joints inflammation

  5. Onset of autoimmunity • Release of sequestered Ag - Smoking can trigger Goodpasture’s syndrome Alveolar basement membrane normally not exposed system Smoking damages alveoli, exposes collagen Anti-collagen Ag damages lung and kidney - Anti-sperm Ab produced in some men after vasectomy - Injection of myelin basic protein (MBP) produces multiple sclerosis –like disease in mice - May be triggered by injury or infection

  6. Onset of autoimmunity 2) Immune stimulation • Microbial infection stimulates APCs carrying self Ag • High level of APCs with “second signal” breaks anergy

  7. Mechanisms of autoimmunity • Ag released from hidden location • Antigen generated by molecular changes • Molecular mimicry • Alteration in Ag processing • Infection • Genetic factors

  8. Mechanisms of autoimmunity • Lymphocytes abnormalities • Failure of central tolerance • Overcome of peripheral tolerance • Polyclonal lymphocytes activation

  9. Ag released from hidden location Many self Ag are found in hidden location eg. bone joints CNS,testes, eye. Damage of tissue Hidden Ag released Reaches blood stream Encounter Ag sensitive cells Stimulate autoimmunity

  10. Antigen generated by molecular changes RFs are immunoglobulins of any isotype with antibody activity directed against antigenic sites on the Fcportion of IgG molecules

  11. Molecular mimicry • Sharing of epitopes between an infectious agent and its host. • Antibodies directed against the infectious agents starts reacting with normal self Ag. • Triggers autoimmunity.

  12. Alteration in Ag processing • A T cell may fail to develop tolerance to an self Ag in the thymus. • Stimulation of Ag processing can stimulate autoimmune T cells and trigger autoimmune disease. • This usually happens at the site of inflammation. • Examples: Thyrotoxicosis , diabetes.

  13. Infection • Here autoimmunity is not due to infectious agent itself ,but results from dis-regulation of host immune response by the microbes. This may be due to : • Polyclonal lymphocyte activation. • Enhanced stimulation of co stimulator. • Alteration of self Ag(cross reactive neo-Ag).

  14. GENETIC FACTORS • HLA genes are directly responsible for auto antigen processing and presentation. Example: HLA B27 morbus Bechterew spondylarthritis

  15. Lymphocytes abnormalities • Primary abnormalities either in B cell or T cell. • Since these cells are critical regulators of immune system • HLA presentation of all antigenic peptide to these cells will be defective, in case the cells are abnormal. • Abnormalities in lymphocytes could affect any one of the mechanism that normally maintains self tolerance.

  16. Failure of central tolerence Inside primary lymphoid organs - positive selection - negative selection -> Deletion of self reacting T cells in thymus Failure of central tolerance starts autoimmune diseases.

  17. POLYCLONAL LYMPHOCYTE ACTIVATION • Stimulation of non deleted self reacting lymphocytes. • These are activated by some activators- • LPS- POLYCLONAL B CELL ACTIVATOR • BACTERIAL SUPER ANTIGEN- POLYCLONAL T CELL ACTIVATOR

  18. Damage to immunologicallyprivileged sites can lead to autoimmunity

  19. Graves` disease

  20. Rheumatiod Arthritis • Auto-immune disorder which results in inflammation of the synovial lining of the joint and cartilage destruction. • This result in loss of function. • Affects 1% of adults.

  21. Treatment for autoimmunity • Immunosuppression (e.g., prednisone, cyclosporin A) • Removal of thymus (some myasthenia gravis patients) • Plasmapheresis (remove Ab-Ag complexes) • T-cell vaccination (irradiated autologous autoreactive T-cell lines or clones >>activate suppressing T cells??) • Block MHC with similar peptide • anti-CD4 monoclonal Ab • anti-IL2R monoclonal Ab

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