E3 4 PDF - Central and peripheral tolerance to self antigens

Central and peripheral tolerance to self antigens  In central tolerance, immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs (referred to as central → 0 organs in...

Central and peripheral tolerance to self antigens  In central tolerance, immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs (referred to as central → 0 organs in the context of tolerance induction) and are deleted, change their specificity (B cells only), or (in the case of CD4+ T cells) develop into regulatory lymphocytes (Tregs).  In peripheral tolerance, some self-reactive lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by an encounter with self antigens in these tissues or are suppressed by the regulatory T cells (Tregs, peripheral tolerance). 3 Central T cell tolerance  Many immature T cells that recognize antigens with high avidity die, and some of the surviving cells in the CD4+ lineage develop into Tregs.  Death of immature T cells as a result of recognition of antigens in the thymus is known as deletion, or negative selection 4  The function of AIRE in deletion of T cells in the thymus  The antigens that are present in the thymus include many circulating and cell-associated proteins that are widely distributed in most tissues.  The thymus also has a special mechanism for expressing numerous protein antigens that are not ubiquitously expressed but rather are limited to certain peripheral 0 tissues, so that immature T cells specific for these antigens can be deleted from the developing T cell repertoire.  These peripheral tissue antigens are produced in medullary thymic epithelial cells (MTECs) under the control of the autoimmune regulator (AIRE) protein. 5 Mechanisms of peripheral T cell tolerance  The mechanisms of peripheral tolerance are anergy (functional unresponsiveness), suppression by Tregs, and deletion (cell death).  These mechanisms may be responsible for T cell tolerance to tissue-specific self antigens, especially those that are not abundant in the thymus.  The same mechanisms may also induce unresponsiveness to foreign antigens that are presented to the immune system under tolerogenic conditions. 6  Mechanisms of T cell anergy Several mechanisms may function to induce and maintain the anergic state:  TCR-induced signal transduction is blocked in anergic cells  Self antigen recognition without costimulation may activate cellular ubiquitin ligases, which ubiquitinate TCR-associated proteins and target them for proteolytic degradation in proteasomes or lysosomes.  When T cells recognize self antigens in the absence of innate immune responses, they may engage inhibitory receptors of the CD28 family, whose function is to terminate T cell responses 7  Mechanisms of action of CTLA-4  CTLA-4 functions as a competitive inhibitor of CD28 and reduces the availability of B7 for the CD28 receptor.  CTLA-4 has an unusual mechanism of action. It is expressed constitutively at high levels on Tregs and transiently on recently activated T cells, and it prevents the activation of responding T cells.  In other words, CTLA-4 on one T cell (a Treg) can inhibit responses of other T cells. Recall that CD28 and CTLA-4 recognize the same ligands, B7-1 (CD80) and B7-2 (CD86) 8 Mechanisms of action of CTLA-4 9 Actions and Functions of CTLA-4 and PD-1 10 Regulatory T cells 11 Role of interleukin-2 in the maintenance of regulatory T cells Tregs appear to suppress immune responses at multiple Steps:  Production of the immunosuppressive cytokines IL-10 and TGF-β.  Reduced ability of APCs to stimulate T cells.  Consumption of IL-2 12  Inhibitory Cytokines Produced by Regulatory T Cells Transforming Growth Factor-β.  TGF-β1 is produced by CD4+ Tregs, activated macrophages, and many other cell types.  TGF-β1 inhibits the proliferation and effector functions of T cells and the activation of macrophages.  TGF-β1 regulates the differentiation of functionally distinct subsets of T cells, FoxP3+ Tregs.  TGF-β1 stimulates production of immunoglobulin A (IgA) antibodies by inducing B cells to switch to this isotype.  TGF-β promotes tissue repair after local immune and inflammatory reactions subside. Interleukin-10  IL-10 is an inhibitor of activated macrophages and dendritic cells and is thus involved in the control of innate immune reactions and cell-mediated immunity.  IL-10 inhibits the production of IL-12 by activated dendritic cells and macrophages.  IL-10 inhibits the expression of co-stimulators and class II MHC molecules on dendritic cells and macrophages.  IL-10 inhibits T cell activation and terminates cell-mediated immune reactions. 13  When T cells avidly recognize self antigens Pathways of apoptosis Repeated stimulation of T cells 14 Factors That Determine the Immunogenicity and Tolerogenicity of Protein Antigens  Tolerogenic antigens are expressed in generative lymphoid organs, where they are recognized by immature lymphocytes. In peripheral tissues, self antigens engage antigen receptors of specific lymphocytes for prolonged periods and without inflammation or innate immunity.  The nature of the dendritic cell that displays antigens to T lymphocytes is an important determinant of the subsequent response. 15 Central tolerance in B cells  Immature B lymphocytes that recognize self antigens in the bone marrow with high affinity change their specificity or are deleted.  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. 16  Summary  Immunologic tolerance is unresponsiveness to an antigen induced by the exposure of specific lymphocytes to that antigen.  Tolerance to self antigens is a fundamental property of the normal immune system, and the failure of self-tolerance leads to autoimmune diseases.  Central tolerance is induced in the generative lymphoid organs (thymus and bone marrow) when immature lymphocytes encounter self antigens present in these organs.  Peripheral tolerance occurs when mature lymphocytes recognize self antigens in peripheral tissues under particular conditions.  Some immature T cells that encounter self antigens in the thymus die (negative selection), and others develop into FoxP3+regulatory T lymphocytes (Tregs) that function to control responses to self antigens in peripheral tissues.  Anergy is induced by antigen recognition without adequate costimulation or by engagement of inhibitory receptors such as CTLA-4 and PD-1.  In B lymphocytes, central tolerance is induced when immature B cells recognize multivalent self antigens in the bone marrow, resulting in the acquisition of a new specificity (receptor editing), or apoptotic death.  Mature B cells that recognize self antigens in the periphery in the absence of T cell help may be rendered anergic and ultimately die by apoptosis or become functionally unresponsive because of the engagement of inhibitory receptors. 17 Postulated mechanisms of autoimmunity  The 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 systemic or organ specific, depending on the distribution of the autoantigens that are recognized.  Various effector mechanisms are responsible for tissue injury in different autoimmune diseases including: immune complexes, circulating autoantibodies, and autoreactive T lymphocytes  Autoimmune diseases tend to be chronic, progressive, and self-perpetuating. 18  Immunologic Abnormalities Leading to Autoimmunity  Defective self-tolerance. Inadequate elimination or regulation of T or B cells, leading to an imbalance between lymphocyte activation and control, is the underlying cause of all autoimmune diseases.  Defects in deletion (negative selection) of T or B cells or receptor editing in B cells during the maturation of these cells in the generative lymphoid organs.  Defective numbers or functions of regulatory T lymphocytes.  Defective apoptosis of mature self-reactive lymphocytes.  Inadequate function of inhibitory receptors.  Abnormal display of self antigens. Abnormalities may include increased expression and persistence of self antigens that are normally cleared, or structural changes in these antigens resulting from enzymatic modifications or from cellular stress or injury, “neoantigens”.  Inflammation or an initial innate immune response may contribute to the development of autoimmune disease, perhaps by activating APCs, which overcome regulatory mechanisms and result in excessive T cell activation 19  Selected Non-HLA Genes Associated With Autoimmune Diseases Genetic Basis of Autoimmunity Association of HLA Alleles With Autoimmune Disease  Helper T cells are the key regulators of all immune responses to proteins, and most self antigens implicated in autoimmune diseases are proteins 20 Examples of Single-Gene Mutations That Cause Autoimmune Diseases Antiphospholipid syndrome (APS), Systemic lupus erythematosus (SLE), Autoimmune lymphoproliferative syndrome (ALPS), Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. 21 Role of infections in the development of autoimmunity 22