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‫بسم اللة الرحمن الرحيم‬


Tolerance And Autoimmune Diseases


Tolerence * It is a specific immunologic unresponsiveness

i.e. the absence of specific immunoresponses to a particular antigen in a fully immunocomptent person * Unresponsiveness to self antigens is known as auto tolerance * Both B-cells and T-cells participate in tolerence * But T-cells play the primary role


Central Tolerance Clonal窶電eletion: * The process by which T-cells acquire the ability to distinguish self from non self, in fetal thymus * This involves the killing of T-cells that react against antigens present in the fetus at that time


Peripheral Tolerance * T-cell tolerance (clonal anergy): * Some self-reactive T cells are not

killed in thymus

* Functional inactivation of surviving self-reactive T cells


Tolerance * B-cells become tolerant to self by two mechanisms: 1) Clonal deletion Probably while B-cell precursors are in bon marrow 2) Clonal anergy B cells in the periphery * Tolerance in B-cells is less complete than in T-cells * The most autoimmune diseases are mediated by antibodies


Factors Influencing The Induction Tolerance 1) Immunologic maturity of the host: Neonates are immunologically immature and well accept allograft that would be rejected by mature host 2) Structure and dose of antigen: a- Simple molecules induce tolerance more readily than complex ones b- Very high and very low doses of antigen may result in tolerance


Factors Influencing The Induction Tolerance 3) T-cells become tolerant more readily and remain tolerant longer than B-cells 4) The continuous presence of antigen helps to maintain tolerance 5) Administration of immunosuppressive drugs enhances tolerance as in transplantation


Clinical Importance of Tolerance 1) Organ transplantation: Introduction of tolerance may help in prevention of rejection 2) Tumor development: Tolerance to tumor antigen results in growth of the tumor without being detected by the immune mechanisms 3) Autoimmune disorders: Disturbance of self-tolerance results in autoimmune disease


Autoimmune Diseases


Autoimmune Diseases * Autoimmune diseases occur due to breakdown of the mechanisms that maintain auto tolerance * Auto-antibodies and self reactive T-cells are produced, resulting in tissue damage by several mechanisms


Etiology Of Autoimmune Diseases 1) Genetic predisposition: - Familial incidence of autoimmune diseases - Most of them appear to be associated with certain MHC genes, specially MHC II genes e.g. Rheumatoid arthritis is associated with DR4

Thyroditis with DR5 Multiple sclerosis with DR2 SLE with DR2/DR3 Type I diabetes with DR3/DR4 Ankylosing spondylitis with B27


Rheumatoid Arthritis


Etiology Of Autoimmune Diseases 2) Exposure to infectious antigens that cross react with self antigens - An immune response to these antigen will result in immune attack against self antigens e.g. Antibodies against M protein of Streptococcus pyogens may react with heart valves and cause

Rheumatic fever

3) Alteration of self antigens or the appearance of new antigens under the effect of drugs, chemicals, or viral infections 4) Hormonal influences play a role e.g. SLE affects women 10 times more than men


Mechanisms Of Disease Production * The disease may be organ specific e.g Hashimoto thyroditis * The disease may be systemic e.g. SLE or rheumatoid arthritis 1) Binding of an autoantibody to host cells result in complement fixation and tissue destruction e.g. Haemolytic anemia (Type II hypersensitivity)


Mechanisms Of Disease Production 2) Formation of immune complexes and their deposition in tissues, joints, kidney and skin The immune complexes fix complement resulting in tissue damage e.g. SLE and rheumatoid arthritis (Type III hyper.) 3) DTH reactions (Type IV)) due to auto reactive T-cells e.g. Ulcerative colitis, multiple sclerosis and type I diabetes


Laboratory Diagnosis 1- There is elevated serum immunoglobulins 2- Complement levels may be decreased 3- Immune complexe detected in serum or organ biopsy 4- Auto antibodies can be detected in serum e.g. anti-nuclear, anti-smooth muscles, Rh factor and anti-mitochondrial Ab 5- Testing for antibodies specific to particular Ag, involved in organ specific diseases (anti-thyroid Ab)


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Tolerence and autoimmun diseases