MED 210: Endocrine System and Mammary Gland -content– MED 210: Endocrine System and Mammary Gland ASSIGNMENT: Autoimmune Disorders of Endocrine System LEARNING OBJECTIVES: 1. Define autoimmunity A misdirected immune response that occurs when the immune system goes awry and attacks the body itself. Autoimmunity is present to some extent in everyone and is usually harmless. However, it can cause a broad range of human illnesses, known collectively as autoimmune diseases. Autoimmune diseases occur when there is progression from benign autoimmunity to pathogenic autoimmunity. This progression is determined by genetic influences as well as environmental triggers. Autoimmunity is evidenced by the presence of autoantibodies and T cells that are reactive with host antigens. 2. Explain the mechanisms of autoimmune diseases A common feature of all autoimmune diseases is the presence of autoantibodies, which are an important factor in the diagnosis or classification of the autoimmune disease. Due to the chronic nature of most autoimmune diseases, autoantibodies appear long before clinical symptoms, providing a good predictive marker for the potential to develop disease. Autoantibodies can induce damage to the body by binding to self-tissues, activating the complement cascade and inducing lysis and/or removal of cells by phagocytic immune cells. This occurs in certain forms of haemolytic anaemia when autoantibodies bind to red blood cell surface antigens inducing lysis of red blood cells. Autoantibodies can also interact with cell-surface receptors, altering their function. Autoantibodies to the acetylcholine receptor block transmission at the neuromuscular junction resulting in myasthenia gravis, while autoantibodies to the thyrotropin receptor block thyroid cell stimulation resulting in Graves’ disease. Self-antigen, autoantibodies and complement can combine to form injurious immune complexes that deposit in vessels or joints as is observed in lupus, inflammatory heart disease and arthritis. o CELL MEDIATED DAMAGE: Damage induced by cells of the immune system play a major pathogenic role in many autoimmune diseases. The predominant infiltrating cells include phagocytic macrophages, neutrophils, self-reactive CD4+ T helper cells and self-reactive CD8+ cytolytic T cells, with smaller numbers of natural killer cells, mast cells and dendritic cells. Immune cells damage tissues directly by killing cells or indirectly by releasing cytotoxic cytokines, prostaglandins, reactive nitrogen or oxygen intermediates. Tissue macrophages and monocytes can act as antigen-presenting cells to initiate an autoimmune response, or as effector cells once an immune response has been initiated. Macrophages act as killer cells through antibody-dependent cell-mediated cytotoxicity and by secreting cytokines, such as TNF or IL-1, which act as protein signals between cells. Macrophages and neutrophils damage tissues by releasing highly cytotoxic proteins like nitric oxide and hydrogen peroxide. Cytokines and other mediators released by macrophages recruit other inflammatory cells, like neutrophils and T cells, to the site of inflammation. CD4+ T cells have been classified as TH1 or TH2 cells depending on the release of the cytokines IFN-g or IL-4, respectively. IFN-g is a proinflammatory cytokine associated with many organ-specific autoimmune diseases like type I diabetes and thyroiditis, while IL-4 activates B cells to produce antibodies and is associated with autoantibody/immune complex-mediated autoimmune diseases like lupus and arthritis. Suppressor or regulatory T-cell populations, including activated CD25+CD4+ regulatory T cells, exist in peripheral tissues and are important in controlling inflammation and autoimmune responses by killing autoreactive cells. These regulatory cells also secrete anti-inflammatory cytokines like IL-10 and TGF-b that further inhibit TH1 immune responses, thereby reducing inflammation and autoimmune disease. If regulation of self-reactive T-cells and autoantibody production by regulatory T-cell populations is disrupted by environmental agents like infections or toxins, then chronic autoimmune disease may result o TOLERANCE Mechanisms of self-tolerance, defined as a state of non-responsiveness to self, can be divided into central and peripheral tolerance. In central tolerance, immature B cells and T cells that recognize self-antigens with high affinity die by apoptosis. In peripheral tolerance, mature self-reactive lymphocytes are inactivated, killed or turned off by regulatory mechanisms including functional anergy, ignorance and suppression by regulatory T cells. Defects in tolerance leading to autoimmune disease may occur in one or multiple tolerance mechanisms. For example, changes in the apoptotic cell death process, resulting in inappropriate cell death or survival or disturbances in clearing apoptotic cells, are thought to be involved in the pathogenesis of a number of autoimmune diseases such as rheumatoid arthritis, lupus and Hashimoto’s thyroiditis. o INNATE IMMUNITY Activation of the innate immune system is essential for the development of a protective adaptive immune response against infection and for the development of autoimmune disease. Innate immune cells produce responses to particular classes of pathogens via pattern recognition receptors (PRR), such as Toll-like receptors (TLR). Interaction of pathogen-associated molecular patterns (PAMP) on microorganisms with PRR on antigen-presenting cells (APC) like macrophages and dendritic cells results in the up-regulation of surface molecules essential for antigen presentation and the production of proinflammatory cytokines. Microbial components of adjuvants, like lipopolysaccharide (LPS) or the mycobacteria in complete Freund’s adjuvant, activate the innate immune response when administered with self-antigens resulting in autoimmune disease in animal models such as collagen-induced arthritis or cardiac myosin-induced myocarditis. Inoculation of adjuvants without self-antigen does not usually result in the development of autoimmune disease. Microorganisms not only stimulate the immune response by stimulating PRR like TLR2 and TLR4, but also provide self-antigens to the immune system by damaging tissues, both of which are necessary for the development of autoimmune disease in animal models. Recent studies in animal models have demonstrated that stimulating the innate immune response is critical for the later development of autoimmune disease. Thus, exposure to environmental agents that alter or influence the innate immune response may increase the risk of developing an autoimmune disease in genetically susceptible individuals o PROINFLAMMATORY CYTOKINES Another pathogenic mechanism common to autoimmune diseases is the increased production of the cytokines TNF and IL-1b. These proinflammatory cytokines are produced during the innate and adaptive immune response and act in a long-range endocrine manner, affecting immune cells far removed from the site of infection or inoculation. 3. List the different autoimmune diseases of endocrine system with examples 4. List the autoantibody responsible in each autoimmune disorder of endocrine system (refer to table above) Resources: 1. Warren Levinson, Review of Medical Microbiology and Immunology 13thed. McGrawHill 2014, ISBN-13: 978-0071818117, Chapter 66,P 550 – 559. 2. Ananthanarayan R, Jayaram Paniker, C.K. Ananthanarayan and Paniker’s Textbook of Microbiology 9th ed. Universities Press; 2010. ISBN-13: 978-8173716744, Chapter 18,P 178 – 183. 3. http://www.roitt.com/elspdf/autoimmune_disease_mechanisms.pdf 4. http://clinicalgate.com/endocrine-disease-2/

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