AUTOIMMUNITY AND AUTOIMMUNE DISEASE Dr. Mayssaa Essam

immunological tolerance Immunological tolerance is a state of unresponsiveness to a particular antigen to which a person has been exposed earlier. The important aspect of tolerance is the self-tolerance, which prevents the body to mount immune response against self-antigens. the immune cells (lymphocytes) possess vast diversities of antigen receptors, it is possible that some receptors may be self-reactive.

immunological tolerance classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). Central tolerance is the main way the immune system learns to discriminate self from non-self. Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities (allergens, gut microbes, etc.

Central tolerance is established by deletion of lymphocytes in primary lymphoid organs (thymus for T cells and bone marrow for B cells) if they possess receptors that can react with self antigens or by the emergence of regulatory T cells that can inhibit self-reactive cells.

AUTOIMMUNITY The term autoimmunity refers to a failure of the body’s immune system to recognize its own cells and tissues as “self”. Instead, immune responses are launched against these cells and tissues as if they were foreign or invading bodies.

AUTOIMMUNE DISEASE Autoimmune disease is caused by failure of the tolerance processes described above to protect the host from the action of self-reactive lymphocytes. These diseases result from the destruction of self proteins, cells, and organs by auto-antibodies or self-reactive T cells,or disease in which the pathology is caused by immune responses to self antigens of normal cells and organs.

ORGAN-SPECIFIC AND NON ORGAN-SPECIFIC (SYSTEMIC) AUTOIMMUNE DISEASES *Autoimmune attack vs. self-antigens of given organ *It results in a damage of organ structure and function *Treatment is focused on the replacement of organ function. Non organ- specific (systemic) *Widespread self-anti-gens are targets for autoimmune attack *Damage affects such structures as blood vessels, cell nuclei etc. *Treatment is aimed to inhibit excessive activation of the immune system

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

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

Ag related from hidden location Many self Ag are found in hidden location eg. TESTES ,EYE (CORNEA) organ damage 1. Hidden Ag released 2. Reaches blood stream 3 . Encounter Ag sensitive cells 4. Stimulate autoimmunity

Antigen generated by molecular changes Development of completely new epitopes on normal protein. eg RF immuno conglutinine. 1. Ab + Ag 2. new epitopes exposed on Fc region of Ab 3.Stimulate the formation of Rf 4. Establishment of disease like rheumatiod artheritis.

Molecular mimicry 1.Sharing of epitopes between an infectious agent and its host. 2.Antibodies directed against the infectious 3.agents starts reacting with normal self Ag. 4.Triggers autoimmunity.

Alteration in Ag processing 1.T cell may fail to develop tolerance to an self Ag simply because it is not efficiently procured. 2.If something happens to improve the processing, an autoimmune disease may be triggered. 3.This usually happens at the site of inflamation resulting in modified Ab. eg. Thyrotoxicosis , diabetese.

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).

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 . *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

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. Failure of central tolerance starts AU diseases.

Intracellular dna rna autoantigens *The increased prevalence of the disease in women may be traced to the fact that estrogen enhance B cell activity *Estrogen also suppresses regulator activities of T cells as a result, there is a decrease in the absolute number of T cells *Complement is activated which results in decrease in the serum level of complement components *At the same time there is an increase in the level of breakdown products of complements such as C3d and C3a *IgG is most pathogenic and it forms complexes that are deposited in the glomerular basement membrane

Graves’ Disease (cell receptors) *Graves’ disease is another autoimmune disease that affects the thyroid gland *Graves’ disease produces hyperthyroidism *It the most common cause of hyperthyroidism and affects about 0.5% of the population *Women are more susceptible than men by a margin of 7:1 and usually present between the ages of 30 and 40. *In whites, the disease is associated with the HLA antigen DR3 while in Asians HLA Bw35 and Bw36 occur more frequently

Proteins(Rheumatoid Arthritis) *Rheumatoid arthritis is a systemic autoimmune disorder *It involves the synovial membrane of multiple joints *Women are more likely to be affected than men and usually strikes between the ages of 20 and 40 *RA has been associated with certain of the HLA class II molecules.

Proteins(Rheumatoid Arthritis *Symptoms include morning stiffness around the joints lasting at least 1 hour, swelling of the soft tissue around three or more joints *Others include swelling of the proximal interphalangeal, metacarpophalangeal, or wrist joints, symetric arthritis, subcutaneous nodules, a positive RF test *Also included is a radiographic evidence of erosion of the joints of the hands, the wrist, or both

Rheumatoid Arthritis The main immunologic finding is the presence of RF. RF is a 19S Ab directed against the Fc portion of IgG. The Ab is not specific for RA as it is found in other diseases such as SLE, scleroderma, Sjögren’s syndrome and B cell lymphoproliferative disorders, It has been suggested that RF may be anti-idiotypic antibodies involved in the regulation of immune response. In RA, polyclonal activation of B cells may occur resulting in overwhelming amount of antibody to IgG.

Rheumatoid Arthritis *Other auto Abs associated with RA include ANA, anti-collagen Abs, Abs against cytoskeleton filamentous proteins etc. *These Abs may cause immune complex formation with the activation of complement which contribute to pathogenesis *Joint damage is due to invasion of inflammatory cells such as neutrophils, and macrophages *Proliferation of fibroblast, macrophages, mast cells, and stellar cells result in the formation of a pannus, an organized mass of cells that grow into the joint space

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,

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