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

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Presentation on theme: "AUTOIMMUNITY. Self/Non-self Discrimination Autoimmunity is a problem of self/non-self discrimination."— Presentation transcript:

1 AUTOIMMUNITY

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

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

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

8 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 Effects of autoimmunity

9 Causes of autoimmunity 1) Release of sequestered Ag1) Release of sequestered Ag Smoking can trigger Goodpasture’s syndromeSmoking can trigger Goodpasture’s syndrome Alveolar basement membrane normally not exposed toAlveolar basement membrane normally not exposed to immune systemimmune system Smoking damages alveoli, exposes collagenSmoking damages alveoli, exposes collagen Anti-collagen Ag damages lung and kidneyAnti-collagen Ag damages lung and kidney Anti-sperm Ab produced in some men after vasectomyAnti-sperm Ab produced in some men after vasectomy Injection of myelin basic protein (MBP) produces MS- like EAEInjection of myelin basic protein (MBP) produces MS- like EAE in micein mice May be triggered by injury or infectionMay be triggered by injury or infection

10 Causes of autoimmunity 2) Immune stimulation2) Immune stimulation Microbial infection stimulates APCs carrying self AgMicrobial infection stimulates APCs carrying self Ag High level of APCs with “second signal” breaks anergyHigh level of APCs with “second signal” breaks anergy

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

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

14 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

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

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

17 Alteration in Ag processing A T cell may fail to develop tolerance to an self Ag simply because it is not efficiently procured.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.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. This usually happens at the site of inflamation resulting in modified Ab. Eg. Thyrotoxicosis, diabetese.Eg. Thyrotoxicosis, diabetese.

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

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

20 Lymphocytes abnormalities Lymphocytes abnormalities Primary abnormalities either in B cell or T cell. Primary abnormalities either in B cell or T cell. Since these cells are critical regulators of all IR.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.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.Abnormalities in lymphocytes could affect any one of the mechanism that normally maintains self tolerance.

21 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.

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

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28 Damage to immunologically privileged sites can lead to autoimmunity

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

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41 Treatment for autoimmunity Immunosuppression (e.g., prednisone, cyclosporin A)Immunosuppression (e.g., prednisone, cyclosporin A) Removal of thymus (some MG patients)Removal of thymus (some MG patients) Plasmapheresis (remove Ab-Ag complexes)Plasmapheresis (remove Ab-Ag complexes) T-cell vaccination (activate suppressing T cells??)T-cell vaccination (activate suppressing T cells??) Block MHC with similar peptideBlock MHC with similar peptide anti-CD4 monoclonal Abanti-CD4 monoclonal Ab anti-IL2R monoclonal Abanti-IL2R monoclonal Ab

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