Autoimmunity S22 Notes.pdf
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3/29/22 The Immune System Dr. Dalia Zakaria 1 Immunological Tolerance and Autoimmunity Textbook : Chapter 9 2 1 3/29/22 Objectives After completing this module, you should understand the following: The concept of immunological tolerance and the difference between central and peripheral tolerance The...
3/29/22 The Immune System Dr. Dalia Zakaria 1 Immunological Tolerance and Autoimmunity Textbook : Chapter 9 2 1 3/29/22 Objectives After completing this module, you should understand the following: The concept of immunological tolerance and the difference between central and peripheral tolerance The role of helper CD4+ in orchestrating the immune responses to protein antigens including cell mediated and humoral immunity tolerance against self antigens The mechanism of central tolerance The mechanism of peripheral tolerance and the role of costimulation and Treg cells in this process Mechanism of tolerance to commensal microbes and fetal antigens Factors that may trigger autoimmunity (genetic and environmental) 3 Immunological Tolerance The normal immune system is able to react to an enormous variety of microbes but not against self antigens Lymphocytes with the ability to recognize self antigens are constantly being generated during the normal process of lymphocyte maturation Certain mechanisms are responsible for the ability of the immune system to discriminate between self and nonself antigens. If these mechanisms fail, the immune system may attack the individual’s own cells and tissues (autoimmunity) In addition to tolerating the presence of self antigens, the immune system has to coexist with many commensal microbes that live within their human hosts The immune system of a pregnant female has to accept the presence of a fetus that expresses antigens derived from the father 4 2 3/29/22 Immunological Tolerance Self antigens normally induce tolerance, and failure of self-tolerance is the underlying cause of autoimmune diseases 5 Immunological Tolerance Central Tolerance (Bone Marrow and Thymus) Immunological tolerance to different self antigens may be induced when developing lymphocytes encounter these antigens in the generative (central) lymphoid organs a mechanism of tolerance only to self antigens that are present in the generative lymphoid organs—namely, the bone marrow and thymus Peripheral Tolerance (Secondary Lymphoid Organs and Peripheral Tissues) Tolerance to self antigens that are not present in the primary lymphoid organs must be induced and maintained by peripheral mechanisms 6 3 3/29/22 CD4+ helper T cells orchestrate virtually all immune responses to protein antigens, so tolerance in these cells may be enough to prevent both cellmediated and humoral immune responses against self proteins Self polysaccharides, lipids, and nucleic acids are T-independent antigens that are not recognized by T cells These antigens must induce tolerance in B lymphocytes to prevent autoantibody production 7 Maturation and Selection Maturation and Selection of T lymphocytes of T Lymphocytes (TCR) β chain is first expressed with pre-Tα protein Expand in number with the help of IL-7 Complete TCR 8 4 3/29/22 If Immature T Lymphocytes Recognize Self-Antigens with High Affinity in the Thymus Death of T cells (negative selection in the thymus) If an immature lymphocyte interacts strongly in the thymus with a self antigen, displayed as a peptide bound to a self MHC molecule, that lymphocyte receives signals that trigger apoptosis conversely, mature lymphocytes that get strong TCR signals in the periphery are activated The process of negative selection affects selfreactive CD4+ T cells and CD8+ T cells Generation of regulatory T cells (Treg) Play a role in Peripheral Tolerance (in the secondary lymphoid organs) 9 Central Tolerance of T Lymphocytes 10 5 3/29/22 Self Reactive Cells in the Thymus Undergo apoptosis Become T regulatory cells Play a role in peripheral tolerance 11 How do all of these antigens reach the thymus? 12 6 3/29/22 Autoimmune Regulator (AIRE) Antigens that induce negative selection may include proteins that are abundant throughout the body, such as plasma proteins and common cellular proteins Surprisingly, many self proteins that are normally present only in certain peripheral tissues are also expressed in some of the epithelial cells of the thymus A protein called AIRE (autoimmune regulator) is responsible for the thymic expression of these peripheral tissue antigens 13 Autoimmune Polyendocrine Syndrome (APS) Mutations in the AIRE gene are the cause of a rare disorder called autoimmune polyendocrine syndrome (APS) It is characterized by autoimmunity against more than one endocrine organ It is not clear why endocrine organs are the major targets of this autoimmune attack 14 7 3/29/22 Peripheral T Lymphocytes Tolerance Despite negative selection in the thymus, significant numbers of autoreactive T cells still escape to the periphery and cause autoimmune diseases Peripheral tolerance is induced when mature T cells recognize self antigens in peripheral tissues, leading to functional inactivation (anergy) or death, or when the self-reactive lymphocytes are suppressed by regulatory T cells Antigen recognition without adequate costimulation results in T cell anergy or death, or makes T cells sensitive to suppression by regulatory T cells Naive T lymphocytes need at least two signals to induce their proliferation and differentiation into effector and memory cells: Signal 1 is always antigen, and signal 2 is provided by costimulators that are expressed on APCs 15 Peripheral T Lymphocytes Tolerance It is believed that dendritic cells in normal uninfected tissues and peripheral lymphoid organs are in a resting (or immature) state, in which they express little or no costimulators, such as B7 proteins These dendritic cells may constantly process and display the self antigens that are present in the tissues T lymphocytes with receptors for the self antigens are able to recognize the antigens and thus receive signals from their antigen receptors (signal 1), but the T cells do not receive strong costimulation because there is no accompanying innate immune response (signal 2) The presence or absence of costimulation is a major factor determining whether T cells are activated or tolerized 16 8 3/29/22 Recognition of Self-Antigen (by T Cells) without Costimulation May Lead to: Death (Apoptosis) Suppression (Anergy) 1. TCR complex may lose its ability to transmit activating signals (in absence of B7) 2. T cells may preferentially engage one of the inhibitory receptors (CTLA-4, CD152 or PD-1) which are highly expressed in anergic cells (low expression of B7) 3. The Coexpression of the death receptors (Fas) and their ligands (FasL) which induces apoptosis Furthermore, T reg cells play a role in peripheral tolerance: When Treg cells bind to APC presenting their specific antigen, CTLA-4 (constitutively expressed by Treg) may block or remove B7 molecules made by APCs and make these APCs incapable of providing costimulation via CD28 and activating T cells Production of IL-10, TGF-β that inhibit the activation of lymphocytes and other innate immune cells 17 1 & 2. Anergy Due to No or Little B7 B7 CTLA-4, or PD-1 Reduce costimulation and deliver an inhibitory signal 18 9 3/29/22 2. Regulation of T Cell Responses by Inhibitory Receptors The concept that immune responses are influenced by a balance between activating and inhibitory receptors is established for all lymphocyte populations, including NK cells CTLA-4 is expressed transiently on activated CD4+ T cells and constitutively on regulatory T cells CTLA-4 works by blocking and removing B7 molecules from the surface of APCs, thus reducing costimulation and preventing the activation of T cells CTLA-4 might also deliver inhibitory signals to T cells 19 B7 Expressed by APC May Bind to: CD28 (activates T cell responses) OR CTLA-4 (Inhibits T cell responses) How do T cells choose CD28 or CTLA-4? CTLA-4 has a higher affinity for B7 molecules than does CD28 When B7 levels are low (when APCs are displaying self antigens), the high-affinity CTLA-4 will be preferentially engaged When B7 levels are high (as in infections), the low-affinity activating receptor CD28 is engaged to a greater extent 20 10 3/29/22 3. Death of T Lymphocytes (Apoptosis) Recognition of self antigens may lead to the coexpression of death receptors and their ligands which activates caspases and apoptosis The best-defined death receptor–ligand pair involved in self-tolerance is a protein called Fas (CD95), which is expressed on many cell types, and Fas ligand (FasL), which is expressed mainly on activated T cells 21 Suppression by Regulatory T Cells Production of IL-10, TGF-β that inhibit the activation of lymphocytes and other cells Expression of CTLA-4, which, may block or remove B7 on APCs 22 11 3/29/22 Function of Regulatory T Cells The majority of self-reactive regulatory T cells probably develop in the thymus but some develop in the secondary lymphoid organs Some regulatory cells produce cytokines (e.g., IL-10, TGF-β) that inhibit the activation of lymphocytes, dendritic cells, and macrophages Regulatory cells express CTLA-4, which, may block or remove B7 molecules made by APCs and make these APCs incapable of providing costimulation via CD28 and activating T cells Most regulatory T cells are CD4+ and express FoxP3, which is required for the development and function of the cells Mutations of the gene encoding FoxP3 in humans cause a systemic, multiorgan autoimmune disease called immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) 23 Immunological Tolerance of B Cells Peripheral tolerance In peripheral lymphoid tissues Central tolerance In the bone marrow Receptor Editing Anergy Deletion (apoptosis) Anergy Recognition of an antigen without T cell help Deletion (apoptosis) Recognition of an antigen without T cell help 24 12 3/29/22 Autoimmune Lymphoproliferative Syndrome (ALPS) Lymphoproliferative syndrome (ALPS) defective lymphocyte apoptosis secondary to mutations in the FAS gene http://www.bloodjournal.org/content/bloodjournal/89/4/1341/F1.large.jpg 25 Tolerance to Commensal Microbes The microbiome of healthy humans consists of about 1014 bacteria and viruses (which is 10 times the number of human cells, prompting microbiologists to point out that we are only 10% human and 90% microbial!) These microbes reside in the intestinal and respiratory tracts and on the skin, where they serve many essential functions Mature lymphocytes in these tissues are capable of recognizing the organisms but do not react against them In the gut, several mechanisms account for the inability of the healthy immune system to react against commensal microbes These mechanisms include an abundance of IL-10–producing regulatory T cells, an unusual property of dendritic cells such that signaling from some Toll-like receptors leads to inhibition rather than activation 26 13 3/29/22 Tolerance to Fetal Antigens Paternal antigens expressed in the fetus, have to be tolerated by the immune system of the pregnant mother One mechanism of this tolerance is the generation of peripheral FoxP3+ regulatory T cells specific for these paternal antigens It is unclear whether women who suffer recurrent pregnancy losses have a defect in the generation or maintenance of these regulatory T cells Other mechanisms of fetal tolerance include: 1. Exclusion of inflammatory cells from the pregnant uterus 2. Poor antigen presentation in the placenta 3. An inability to generate harmful Th1 responses in the healthy pregnant uterus 27 Autoimmunity Autoimmunity is defined as an immune response against self antigens The principal factors in the development of autoimmunity are the inheritance of susceptibility genes and environmental triggers, such as infections It is postulated that susceptibility genes interfere with pathways of self-tolerance and lead to the persistence of self-reactive T and B lymphocytes Environmental stimuli may cause cell and tissue injury and inflammation and activate these self-reactive lymphocytes, resulting in the generation of effector T cells and autoantibodies that are responsible for the autoimmune disease 28 14 3/29/22 Autoimmunity 29 Autoimmunity Genetic Factors Environmental Factors 30 15 3/29/22 Autoimmunity (Genetic Factors) Mutations in C1, C2, C4 complement proteins lead to defects in clearance of immune complexes and cause SLE 31 Role of Infections in Autoimmunity An infection of a tissue may induce a local innate immune response, which may lead to increased production of costimulators and cytokines by tissue APC which may be able to stimulate self-reactive T cells (Break T cell tolerance) Some infectious microbes may produce peptide antigens that are similar to, and crossreact with, self antigens. Such cross-reactions between microbial and self antigens are termed molecular mimicry. In rheumatic fever, antibodies against streptococci cross-react with a myocardial antigen and cause heart disease The innate response to infections may alter the chemical structure of self antigens. For example, some periodontal bacterial infections are associated with rheumatoid arthritis. It is postulated that the acute and chronic inflammatory responses to these bacteria lead to enzymatic conversion of arginines to citrullines in self proteins, which are recognized as nonself and elicit adaptive immune responses 32 16 3/29/22 Role of Infections in Autoimmunity 33 17
