Chapter 9 VTPB 409

Chapter 9: Immunological Tolerance and Autoimmunity o Immunological tolerance: unresponsiveness to self-antigens; lack of response to antigens that is induced by exposure of lymphocytes to these antigens - Immunogenic: when lymphocytes are activated to proliferate and to differentiate into effector and memory cells (productive immune response) – normally microbes - Tolerogenic: when lymphocytes are inactivated or killed, resulting in tolerance – normally self-antigens - Failure of self-tolerance is the underlying cause of autoimmune disease - Benefits of inducing tolerance: treat allergies and autoimmune diseases, prevent rejection of organ transplants, gene therapy, stem cell transplantation - Immunological Ignorance: antigen specific lymphocytes do not react, aka ignore presence of an antigen - Central tolerance: immature lymphocytes specific for self-antigens may encounter these antigens in generative lymphoid organs (bone marrow and thymus) and are deleted - Peripheral/secondary tolerance: mature lymphocytes encounter self-antigens in peripheral lymphoid organs/tissues - CD4+ T cells: mediator of virtually all immune responses to protein antigens; induced tolerance in which these cells may be enough to prevent both cell-mediated and humoral immune responses against self-proteins o Autoimmunity: when the immune system attacks the individual’s own cells and tissues o Central T Lymphocyte Tolerance: death of immature T cells and generation of CD4+ regulatory T cells - Negative selection: If an immature T lymphocyte interacts with a self-antigen, it triggers apoptosis and cannot become functionally competent (mature lymphocytes receive signals) - Some immature CD4+ T cells in the thymus don’t die but develops in to regulatory T cells and enter peripheral tissues - Immature lymphocytes may react strongly with an antigen if the antigen is present at high concentrations in the thymus - Self-proteins normally present in peripheral tissues and epithelial cells (thymus) - AIRE (autoimmune regulator): responsible for the thymic expression of peripheral tissue antigens  Mutations in AIRE caused by autoimmune polyendocrine syndrome where peripheral tissue antigens are not expressed in the thymus. Result = immature T cells specific for this antigen are not eliminated and are capable of harming self-antigens o Peripheral T Lymphocyte Tolerance: induced when mature T cells recognize self-antigens in peripheral tissues, leading to functional inactivation (anergy) or death, or when self-reactive lymphocytes are suppressed by regulatory cells (back up mechanism for autoimmunity) - Antigen recognition without costimulation results in T cell anergy or death, or makes T cells sensitive to suppression by regulatory T cells (signal 1 = antigen, signal 2 = expressed on APCs)  Major factor in determining whether T cells are activated or tolerized o Anergy (in T cells): long-lived functional unresponsiveness that is induced when T cells recognize self-antigens. Two mechanisms of anergy are: - 1) abnormal signaling by the TCR complex – TCR loses ability to transmit activating signals - 2) delivery of inhibitory signals from receptors other than the TCR complex – T cells may preferentially engage in the CD28 receptor, CTLA-4 or CD152, or PD-1 (death). Anergic T cells express higher levels of inhibitory receptors o Regulation of T Cell Responses by Inhibitory Receptors: CTLA-4 and PD-1 - CTLA-4: expressed on activated CD4+ T cells and regulatory T cells. Terminates activation of responding T cells and mediates suppressive function of regulatory T cells. Blocks and removes B7 from APCs to reduce costimulation and prevent T cell activation. CTLA-4 has high affinity for B7, meaning when B7 is low, more high-affinity CTLA-4. When B7 is high, more low-affinity CD28 - PD-1: expressed on both CD4+ and CD8+ after antigen stimulation. Has ITIM to deliver inhibitory signals that terminates responses of T cells to self-antigens and chronic infections (mostly virus) - Checkpoint blockade: using inhibitory receptors as a treatment for cancer patients with antibodies that block these receptors. If CTLA-4 or PD-1 are blocked, patients develop autoimmune responses against own tissues (kills tumor?) o Immune Suppression by Regulatory T cells: CD4+ that express CD25 and FoxP3 - Regulatory T cells are CD4+ that express CD25 (alpha chain of IL-2) - Develop in thymus or peripheral tissues after recognizing self-antigens and suppress activation of harmful lymphocytes specific for the self-antigens - FoxP3: transcription factor required for the development and function of regulatory T cells  Mutations: multiorgan autoimmune disease called IPEX - Survival and function of regulatory T cells are dependent on cytokine IL-2  Two opposite roles: promotes immune responses by stimulating T cell proliferation and inhibits immune response by maintaining functional regulatory T cells - TGF-beta: cytokine transforming growth factor that stimulates FoxP3 - Regulatory T cells may suppress immune responses by:  1) Some regulatory cells produce cytokines (IL-10 and TGF-beta) that inhibit activation of lymphocytes, dendritic cells, and macrophages  2) Regulatory cells express CTLA-4, which block/remove B7 on APCs, making APCs incapable of costimulation via CD28 and activating T cells  3) Regulatory T cells (by using IL-2) bind and consume T cell growth factor and reduce availability for responding T cells o Deletion: Apoptosis of Mature Lymphocytes: recognition of self-antigens may trigger apoptosis that results in elimination (deletion) of self-reactive lymphocytes. Two mechanisms: - 1) Antigen recognition induces production of pro-apoptotic proteins in T cells that induce cell death. This induces mitochondrial proteins to activate caspases, cytosolic enzymes that induce apoptosis - 2) Self-antigen recognition may lead to coexpression of death receptors and their ligands. Ligand-receptor interaction generates signals through death receptor that culminates in activation of caspases and apoptosis  Fas (CD95) and Fas ligand (FasL): death receptor-ligand pair involved in self-tolerance; mutation = develop autoimmune diseases with lymphocyte accumulation o Difference between self-antigens and foreign microbial antigens - Self-antigens:  present in thymus, where they induce deletion and generate regulatory T cells  displayed by resting APCs in absence of innate immunity and second signals (favor T cell anergy/death/suppression)  present throughout life and cause prolonged TCR engagement (development of regulatory T cells) - Microbial antigens:  not in thymus; captured from their site of entry and transported to the peripheral lymphoid organs  microbes elicit innate immunity, leading to expression of costimulators and cytokines that promote T cell proliferation and differentiation o B Lymphocyte Tolerance: prevent autoantibody production in self-polysaccharides, lipids, and nucleic acids (T-indie) o Central B Lymphocyte Tolerance: when immature B lymphocytes interact strongly with self-antigens in the bone marrow, the B cells either 1) change their receptor specificity (receptor editing) or 2) are killed (deletion) - Receptor editing: B cells after reacting with self-antigens will reexpress RAG genes, resume Ig light-chain gene recombination, and express new Ig light chain. This new light chain combines with unchanged Ig heavy chain to produce new antigen receptor that is no longer specific for self-antigen. This process reduces the chance of a potentially harmful self-reactive B cell - Deletion: happens when receptor editing fails. The immature B cells die after recognizing self-antigens (similar to negative selection of immature T cells) - Anergy (in immature B cells): B cells specific for antigens with low avidity become functionally unresponsive o Peripheral B Cell Tolerance: mature B lymphocytes that encounter self-antigens in peripheral lymphoid tissues become incapable of responding to that antigen. B cells that do not receive T cell help become anergic and die - During somatic hypermutation of Ig genes in germinal centers, some antigen receptors may be capable of recognizing self-antigens. B cells expressing these receptors die because no follicular T cell help or because they express high levels of Fas and are killed by FasL o Tolerance to Commensal Microbes and Fetal Antigens: products of commensal microbes that live in symbiosis with humans and paternally derived antigens in the fetus; coexistence needed to maintain peripheral tolerance to self-antigens o Tolerance to Commensal Microbes in the Intestines and Skin: microbes reside in intestinal and respiratory tracts and on skin (aid in digestion and absorption of foods, prevent overgrowth of harmful organisms). Mature cells recognize these organisms but do not react against them. This is a result of abundance of IL-10 producing regulatory T cells o Tolerance to Fetal Antigens: paternal antigens in placenta are foreign and must be tolerated by the mother - Peripheral FoxP3+ regulatory T cells: help with tolerance of paternal antigens - Other mechanisms: exclusion of inflammatory cells from the pregnant uterus, poor antigen recognition, and inability to generate harmful Th1 responses in healthy uterus o Autoimmunity: an immune response against self-antigens. Can be organ-specific or systemic. Tissue injury in autoimmune diseases caused by either antibodies against self-antigens or by T cells reacting with self-antigens o Pathogenesis of autoimmunity: developed by inheritance of susceptible genes and environment triggers (infections) o Genetic Factors: attributable to multiple gene loci, with most contribution by MHC genes. An autoimmune disease is more likely to develop in monozygotic (identical) twins - Polymorphisms: variations (basically mutations) in genes that contribute to autoimmune diseases. Same polymorphisms can be associated with different diseases. - Odds ratio or relative risk of HLA-disease association: autoimmune disease risk increases with individuals who inherit particular HLA alleles (though HLA is not the cause of the disease) - Non-HLA polymorphisms are associated with failure of self-tolerance or abnormal lymphocyte activation. This includes:  PTPN22: uncontrolled activation of B and T cells (arthritis, lupus, and T1DM)  NOD-2: causes reduced resistance to intestinal microbes (Crohn’s, IBD)  CD25: influences balance of effector and regulatory T cells  IL-23: promotes proinflammatory Th17  CTLA-4: inhibitory T cell receptor  Mendelian forms of autoimmunity: AIRE, FoxP3, Fas, and CTLA-4 o Role of Infections and other Environmental Influences: infections may activate self-reactive lymphocytes and trigger autoimmune diseases - Microbial nfection in tissue may induce innate immunity response  increased production of costimulators and cytokines by tissue APCs. These APCs may stimulate self-reactive T cells - Molecular mimicry: infectious microbes produce peptide antigens that are similar to and cross react with selfantigens. Immune responses to these peptide antigens may result in autoimmune disease (ex: rheumatic fever) - Innate response to infections can alter chemical structure of self-antigens, which are recognized as nonself and elicit adaptive immune responses - Infections may injure tissues and release antigens that are ignored by immune system  autoimmune reaction against tissues - Normal microbes in gut, skin, etc. may have an effect on health and maintenance of self-tolerance o Lupus (SLE): more common in women; triggered by sunlight in which antibodies are produced against self-nucleic acids and proteins