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AUTOIMMUNITY

AUTOIMMUNITY. Dr. Anand Kumar & Dr. R.. A. Siddique N.D.R.I., Karnal (Haryana) India, 132001 Email-riazndri@gmail.com. Self/Non-self Discrimination. Autoimmunity is a problem of self/non-self discrimination. Autoimmunity.

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AUTOIMMUNITY

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  1. AUTOIMMUNITY Dr. Anand Kumar & Dr. R.. A. Siddique N.D.R.I., Karnal (Haryana) India, 132001 Email-riazndri@gmail.com

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

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

  4. AUTOIMMUNITY & LEFT-HANDEDNESS • LEFT handed individuals more affected. • 11% of left handed & 4% of right handed. • Reasons for this are obscure. • left-handedness & immune malfunction may both result from abnormal endocrine function in fetal life.

  5. Effects of autoimmunity 1) Tissue destruction Diabetes: CTLs destroy insulin-producing b-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

  6. Causes of autoimmunity • 1) Release of sequestered Ag • Smoking can trigger Goodpasture’s syndrome • Alveolar basement membrane normally not exposed to • immune 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 MS-like EAE • in mice • May be triggered by injury or infection

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

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

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

  10. Ag related from hidden location Many self Ag are found in hidden location eg. C N S ,TESTES ,EYE (CORNEA) organ damage Hidden Ag released Reaches blood stream Encounter Ag sensitive cells Stimulate autoimmunity

  11. Antigen generated by molecular changes • Development of completely new epitopes on normal protein. eg RF immuno conglutinine. Mech of formation of RF : Ab + Ag new epitopes exposed on Fc region of Ab Stimulate the formation of Rf Establishment of disease like rheumatiod artheritis and SLE

  12. 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.

  13. Alteration in Ag processing • A T cell may fail to develop tolerance to an self Ag simply because it is not efficiently procured. • If something happens to improve the processing, an autoimmune disease may be triggered. • This usually happens at the site of inflamation resulting in modified Ab. • Eg. Thyrotoxicosis , diabetese.

  14. 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. • inhanced stimulation of co stimulator. • Alteration of self Ag(cross reactive neo-Ag)

  15. GENETIC FACTORS • The important genes that regulate the development of autoimmunity are located within MHC. • MHC have got critical role in maturation of T cell & induction of IR . • MHC ll genes are directly responsible for auto antigen processing and presentation. • The structure of Ag binding groove will determine , if specific Ag will trigger an AU response. • Eg. Diabetes mellitus in dog: DLA-A3, A7, A10 and DLA-B4 SLE: DLA- A7 POLYARTHRITIS: DLA- A7

  16. Lymphocytes abnormalities • Primary abnormalities either in B cell or T cell. • Since these cells are critical regulators of all IR. • MHC 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.

  17. Failure of central tolerence Inside primary lymphoid organ; • positive selection • negative selection (Deletion of self reacting T cells in thymus apoptosis). • Failure of central tolerance starts AU diseases.

  18. 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

  19. Damage to immunologicallyprivileged sites can lead to autoimmunity

  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 MG patients) • Plasmapheresis (remove Ab-Ag complexes) • T-cell vaccination (activate suppressing T cells??) • Block MHC with similar peptide • anti-CD4 monoclonal Ab • anti-IL2R monoclonal Ab

  22. THANKS

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