Autoimmunity by ashish

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AUTOIMMUNITYWhen the Good Turns Bad… : 

AUTOIMMUNITYWhen the Good Turns Bad… By Dr. Ashish J 2nd year PG Department of Microbiology NMC

History : 

History Controversial albeit intriguing Paul Ehlrich 1904- Julius Donath and Karl Landsteiner 1950’s Ernest Witebesky 1948 Hargraves

Tolerance and Autoimmunity : 

Tolerance and Autoimmunity The normal immune system must be able to distinguish between self and non-self Tolerance – mechanisms to prevent self reactivity Autoimmunity – a breakdown of tolerance

Slide 5: 

Self-nonself discrimination Self No response Strong response Non-self or foreign

During neonatal stage of life, or when immune system is developing, all Ags present are recognized as self. Tolerance Burnet’s Hypothesis:(1959)

Peripheral Tolerance : 

Peripheral Tolerance Once the cells have moved into the periphery, there are still more mechanisms in place to eliminate self-antigens Ignorance Anergy Phenotypic skewing Apoptosis Antigen sequestration Regulatory T cells

Autoimmunity : 

Autoimmunity Inappropriate response of immune system against self components is termed autoimmunity Autoimmune disease:

Slide 12: 

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

Features of Autoimmune disease : 

Features of Autoimmune disease Elevated level of immunoglobulins. Demonstrable autoantibodies Deposition of Ig at certain sites Lymphocytes and plasma cell accumulation at the sites of lesion. More than 1 type of leision.

Organ Specific autoimmune diseases : 

Organ Specific autoimmune diseases . Hashimoto’s thyroiditis Th1 cells and autoantibodies specific for thyroid Ag’s  infiltration of thyroid by L, M, and PC’s  hypothyroidism Chronic inflammation and enlargement

Normal thyroid gland : 

Normal thyroid gland

Gland in Hashimoto’s thyroiditis : 

Gland in Hashimoto’s thyroiditis

Autoimmune Anemia's : 

Autoimmune Anemia's Pernicious anemia. Auto antibodies to intrinsic factor. Hematopoiesis is affected. Treatment. Autoimmune hemolytic anemia. Auto antibody to red blood cell antigen triggering complement mediated lysis or antibody mediated opsonization and phagocytosis of red blood cells Drug induced anemia Diagnostic test.

Goodpasture syndrome : 

Goodpasture syndrome Antibodies to membrane antigens in kidney and alveoli in lungs Complement activation cell damage inflammation

Biopsy of kidney : 

Biopsy of kidney

Insulin Dependent Diabetes Melitus : 

Insulin Dependent Diabetes Melitus 0.2% of population. Beta cells of Islet of langerhans. Several factors. Activated TL migrate into islets and begin to attack insulin producing cells. Local cytokine production during this includes IFN-gamma, TNF-alpha and IL-1 Autoantibodies also part of process.

Pancreas with disease : 

Pancreas with disease

Antibodies to receptors : 

Antibodies to receptors

Myasthenia gravis : 

Myasthenia gravis Autoantibody blocks ACh receptor, eventually destroys it

Systemic Diseases : 

Systemic Diseases Rheumatoid Arthritis Auto-immune disorder which results in Chronic inflammation of the synovial lining of the joint and cartilage destruction. Rheumatoid Factor. HLA-DR1 and HLA-DR4 This result in loss of function. Affects 1% of adults.

Systemic lupus erythematosis : 

Systemic lupus erythematosis Autoantibodies to DNA, RNA, histones, leukocytes, RBC’s, platelets, clotting factors. Anti-nuclear antibodies (ANA) are diagnostic Type II, III and inflammatory damage; elevated C3a and C5a, vasculitis Immune complex of autoantibody with various nuclear antigens are deposited along wall of small blood vessel. 10:1 female to male ratio; 20-40 yr-old women

Butterfly rash : 

Butterfly rash

Multiple sclerosis : 

Multiple sclerosis T cell mediated Myelin sheath of nerves targeted CNS attacked by inflammatory lesions CSF. Starts in 20-40 yr. old people Infection by virus may predispose a person

Slide 36: 

Polyarteritis Nodosa: Necrotizing angitis. Autoantibody not yet identified. Sjogrens syndrome: Triad of Conjunctivitis sicca. Dryness of mouth with/without salivary gland enlargement. RA.

Mechanisms of inducing autoimmune response : 

Mechanisms of inducing autoimmune response

Slide 38: 

Ag released from hidden location. Antigen generated by molecular changes. Molecular mimicry. Alteration in Ag processing. Infection. Genetic factors. Lymphocytes abnormalities. Polyclonal lymphocytes activation. Mechanisms of autoimmunity

Ag released from hidden location : 

Ag released 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

Slide 40: 

Damage to immunologically privileged sites can lead to autoimmunity

Slide 41: 

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

Slide 42: 

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.

Slide 44: 

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 , diabetes. Alteration in Ag processing

Infection : 

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)

Slide 46: 

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 DLA-A3, A7, A10 and DLA-B4 SLE: DLA- A7 POLYARTHRITIS: DLA- A7

Lymphocytes abnormalities : 

Lymphocytes abnormalities Primary abnormalities either in B cell or T cell. 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.

Polyclonal B cell activation : 

Polyclonal B cell activation Polyclonal B cell activation by CMV, EBV, and some G-negative bacteria - T-cell-independent - Large amounts of IgM produced

Treatment of autoimmune disease : 

Treatment of autoimmune disease Reduce symptoms Immunosuppression Corticosteroids, azathioprine, cyclophosamide Removal of thymus (MG) Plasmapheresis Short-term relief (MG, Grave’s disease, RA, SLE)

Slide 50: 

Treatment of autoimmune disease (cont’d) Reduce inflammation TNF-alpha blockers (RA, Crohn’s dis., psoriasis) e.g., Enbrel, Remicade, Humira IL-1 receptor antagonist (RA) Ab’s against IL6R and IL-15R Statins, shown to lower CRP (RA, MS) Rituxin = monoclonal Ab = anti-CD20 Eliminates B cells in non-Hodgkins lymphoma (maybe also RA, and other Ab-mediated autoimmune diseases)

Slide 51: 

T cell vaccines (against activated Ag-specific TH cells) Interfere with antigen presentation (anti-MHC) Monoclonal antibodies against a variety of target antigens. Oral induction of tolerance (MS) So far, efforts have been more successful in mice than humans

Conclusion : 

Conclusion Major task of immune system is to distinguish self from non self. Mechanism to prevent self reactivity termed tolerance. Organ specific and systemic disease. Genetic defects. CD4 cells, Th1 and Th2 cells. Variety of mechanism for induction of autoimmunity. Current therapies include treatment with immunosuppresive drugs, thymectomy and plasmapheresis.

References : 

References Topley and Wilson textbook of immunology. Kuby Immunology kindt 6th edition. Lippincotts Illustrated review of Immunology Ananthnarayan textbook of microbiology 8th edition. C.P Baveja Textbook of microbiology. Autoimmunity by Dr. Anand Kumar &Dr. R.. A. Siddique N.D.R.I., Karnal Immunotolerance by Dr. Prakash Nagarkatti Harrison textbook of Medicine

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