Immunological Tolerance and Autoimmunity PDF

Chapter 4: IMMUNOLOGICAL TOLERANCE AND AUTOIMMUNITY DEFINITION OF TOLERENCE  Immune Tolerance: The failure of the immune system to respond to an epitope in an aggressive way.  Immune Self-tolerance: results from the inactivation or destruction of lymphocytes bearing BCRs...

Chapter 4: IMMUNOLOGICAL TOLERANCE AND AUTOIMMUNITY DEFINITION OF TOLERENCE  Immune Tolerance: The failure of the immune system to respond to an epitope in an aggressive way.  Immune Self-tolerance: results from the inactivation or destruction of lymphocytes bearing BCRs and TCRs that recognize and binds self antigens GENERAL FEATURES OF IMMUNOLOGIC TOLERANCE  Normal individuals are tolerant of their own (self) antigens because the lymphocytes that recognize self antigens are killed or inactivated or the specificity of these lymphocytes is changed  Self-tolerance may be induced in immature self-reactive lymphocytes in the generative lymphoid organs (central tolerance) or in mature lymphocytes in peripheral sites (peripheral tolerance)  Central tolerance occurs during the maturation of lymphocytes in the central (generative) lymphoid organs  Peripheral tolerance occurs when, as a consequence of recognizing self antigens, mature lymphocytes become incapable of responding to that antigen, or are induced to die by apoptosis, or mature T cells are actively suppressed by regulatory T cells.  Immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs and:  Deleted  Change their specificity (B cells only)  In the case of CD4+ T cells develop into regulatory lymphocytes  Some self-reactive lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by encounter with self antigens. T LYMPHOCYTE TOLERANCE Central Tolerance in T Cells  During their maturation in the thymus, many immature T cells that recognize antigens with high avidity are deleted.  Some self-reactive CD4+ T cells that see self antigens in the thymus are not deleted but instead differentiate into regulatory T cells specific for these antigens. T LYMPHOCYTE TOLERANCE Peripheral Tolerance in T Cells  Peripheral tolerance is the mechanism by which mature T cells that recognize self antigens in peripheral tissues are rendered incapable of subsequently responding to these antigens  Exposure of mature CD4+ T cells to an antigen in the absence of costimulation or innate immunity may make the cells incapable of responding to that antigen in a state called anergy (Functional Unresponsiveness)  Another regulatory mechanism is the engagement of regulatory T cells. T LYMPHOCYTE TOLERANCE Peripheral Tolerance in T Cells  When T cells recognize self antigens, they may engage inhibitory receptors of the CD28 family, whose function is to terminate T cell responses:  CTLA-4: binds to B7 molecules with higher affinity than CD28 for B7 molecules and thus prevents B7 costimulators on APCs from engaging CD28  PD-1: recognizes two ligands, PD-L1 which is expressed on APCs and many other tissue cells and PD-L2 mainly on APCs. Engagement of PD-1 by either ligand leads to inactivation of the T cells Mechanisms of action of CTLA-4:  delivery of inhibitory signals that block TCR- and CD28-mediated signals  engagement of B7 molecules on APCs so they are inaccessible to CD28 Suppression of Self-Reactive Lymphocytes by Regulatory T Cells  Regulatory T cells produce IL-10 and TGF-β both of which inhibit immune responses.  Transforming Growth Factor-β (TGF-β) : inhibits the proliferation and effector functions of T cells and the activation of macrophages. Suppresses the activation of other cells, such as neutrophils  Interleukin-10 (IL-10): inhibits the production of IL-12 by activated dendritic cells and macrophages>>> inhibition of IFN- γ. Also it inhibits the expression of costimulators and class II MHC molecules on dendritic cells and macrophages B LYMPHOCYTE TOLERANCE Central Tolerance in B Cells  Immature B lymphocytes that recognize self antigens in the bone marrow with high affinity either change their specificity or are deleted.  Receptor editing: in the process by which the genes in the self-reactive B cell which are responsible for BCR expression are rearranged to produce a modified receptor.  Deletion: If editing fails, the immature B cells may be deleted  Anergy: If developing B cells recognize self antigens weakly (with low affinity), the cells become functionally unresponsive (anergic) and exit the bone marrow in this unresponsive state B LYMPHOCYTE TOLERANCE Peripheral Tolerance in B Cells  Mature B lymphocytes that recognize self antigens in peripheral tissues in the absence of specific helper T cells may be rendered functionally unresponsive or die by apoptosis  Inhibitory receptors function to set a threshold for B cell activation PATHOGENESIS OF AUTOIMMUNITY  Autoimmunity results from a failure of the mechanisms of self- tolerance in T or B cells, which may lead to an imbalance between lymphocyte activation and control mechanisms.  Some of the general mechanisms that are associated with autoimmune reactions are the following:  Defects in deletion (negative selection) of T or B cells or receptor editing in B cells during the maturation in the generative organs  Defective numbers and functions of regulatory T lymphocytes  Defective apoptosis of mature self-reactive lymphocytes  Inadequate function of inhibitory receptors PATHOGENESIS OF AUTOIMMUNITY  The major factors that contribute to the development of autoimmunity are genetic susceptibility and environmental triggers, such as infections and local tissue injury.  Autoimmune diseases may be either systemic or organ specific, depending on the distribution of the autoantigens that are recognized.  Autoimmune diseases tend to be chronic, progressive, and self- perpetuating  a response initiated against one self antigen that injures tissues may result in the release and alterations of other tissue antigens, activation of lymphocytes specific for these other antigens, and exacerbation of the disease in a phenomenon is called epitope spreading. PATHOGENESIS OF AUTOIMMUNITY  Most autoimmune diseases are complex polygenic traits, in which affected individuals inherit multiple genetic polymorphisms that contribute to disease susceptibility and these genes act with environmental factors to cause the diseases.  Viral and bacterial infections may contribute to the development and exacerbation of autoimmunity.  Microbes may activate the APCs to express costimulators, and when these APCs present self antigens, the self-reactive T cells are activated rather than rendered tolerant.  Some microbial antigens may cross-react with self antigens (molecular mimicry). Therefore, immune responses initiated by the microbes may activate T cells specific for self antigens. Systemic lupus erythematosus (SLE)  is an autoimmune disease. In this disease, the immune system of the body mistakenly attacks healthy tissue. It can affect the skin, joints, kidneys, brain, and other organs.  Causes The cause of SLE is not clearly known. It may be linked to the following factors:  Genetic  Environmental  Hormonal  Certain medicines IMMUNE PRIVILEGED TISSUES  Body sites that do not develop immune response to pathogens, tumor cells or tissue transplant.  Foreign antigens that would evoke an immune response in most tissues are often tolerated in these immune privileged sites.  The mechanisms underlying immune privilege vary between these tissues and are not fully understood  Eye, Testis, brain, placenta, fetus  How:  Lack of lymphatic drainage  Blood barriers  Immunosuppressive cytokines  FasL or PD-L1 expression APOPTOSIS  What is apoptosis?  apoptosis is involved in many physiological (e.g., death of inflammatory cells after inflammatory response, removal of self-reactive lymphocytes…) and pathological conditions (e.g. virally infected cells).  Two pathways: extrinsic or intrinsic by which apoptosis is initiated and all will lead to the activation of proteins called Caspases.  The activation of caspases will lead to the fragmentation of the nucleus and breakdown of the cytoskeleton.