24.09.06 Tolerance and Autoimmunity Handout Mather.pdf

IMS-I SFM 2024: Immunology/Mather Tolerance and Autoimmunity September 6, 2024 Thais Salazar Mather, Ph.D. [email protected] Key Objectives: § List...

IMS-I SFM 2024: Immunology/Mather Tolerance and Autoimmunity September 6, 2024 Thais Salazar Mather, Ph.D. [email protected] Key Objectives: § List and describe the major central and peripheral tolerance mechanisms in B and T cells. § Define autoimmunity and list the principal factors that may contribute to its development. OVERVIEW A major task of the immune system is to distinguish self from non-self antigens. Failure to do so results in autoimmunity or immune responses against self (autologous) antigens, with the possible onset of autoimmune disease. The immune system has evolved several mechanisms to restrain its potentially “self-reactive” cells and antibodies. This process is called self-tolerance. “Self” tolerance: Þ Prevents an active and specific immune response against self-antigens Þ Primarily established in T and B lymphocytes Þ Provides protection against the development of autoimmunity without inhibiting effective immune responses against pathogens Why is immunological tolerance needed? § The antigen-specific binding sites in T and B cell receptors are produced by random selection of the variable-region gene segments V(D)J in the heavy and light chains of BCR or a- and b-chains of TCR [Remember somatic rearrangement?] § Due to the random recombination of V(D)J antigen receptor genes: useful, useless and harmful receptors will be produced. § Selection processes are therefore required to sort out dangerous receptors that could recognize and destroy self-tissues. Tolerance is established at two levels: § Central tolerance: induced before lymphocytes mature. o Takes place in primary lymphoid organs (bone marrow and thymus). o Important mechanism of inducing self-tolerance in lymphocytes developing in the thymus and bone marrow. § Peripheral tolerance: induced after lymphocytes mature and enter peripheral tissues. o Takes place outside the bone marrow and thymus (e.g., secondary lymphoid organs) o Important mechanism of inducing self-tolerance in mature lymphocytes once cells have left the primary lymphoid organs. T CELL TOLERANCE Central Tolerance Removal of strongly autoreactive immature lymphocytes (first checkpoint in tolerance!). 1 IMS-I SFM 2024: Immunology/Mather § High affinity for self-antigen results in induction of apoptosis in immature T cells – this process is called negative selection (deletion). § The T cells that survive negative selection (low affinity for self-antigen) will mature, leave the thymus and migrate throughout the immune system (lymph nodes, spleen, etc.). § In the CD4+ T-cell lineage, some of the cells that see self-antigens in the thymus are not deleted but instead differentiate into regulatory T cells (Tregs) that are specific for these self-antigens. o Most Tregs are generated in the thymus (called thymic or natural - nTregs), but may also develop after induction in the periphery during inflammation (inducible - iTregs). (see below) o CD4+ Tregs express high levels of the interleukin-2 (IL-2) receptor α chain (CD25) and the transcription factor called FoxP3. o Development and function is dependent on the intracellular expression of FoxP3 and they also require IL-2. o They are phenotyped as CD4+ FoxP3+ CD25+ cells. How is central tolerance to tissue-restricted protein antigens achieved in the thymus? Selected tissue antigens are expressed in thymic medullary epithelial cells under the control of the autoimmune regulator (AIRE) gene product – a transcription factor that facilitates the expression in the thymus of tissue-specific genes encoding proteins normally found outside the thymus. No AIRE = No negative selection = Autoreactive T cells escaping thymic deletion = Autoimmune disease § AIRE gene is defective in patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease in which children suffer from a number of autoimmune symptoms including hypoparathyroidism, adrenal insufficiency, thyroiditis, type I diabetes mellitus, and ovarian failure. Peripheral Tolerance § Safety net to catch autoreactive lymphocytes that escape to or arise in the periphery (second checkpoint in tolerance!). § Peripheral tolerance also prevents us from responding to every foreign antigen we encounter, such as those in our food. § There are several mechanisms for maintaining tolerance throughout the body: Anergy, Suppression, Deletion. 2 IMS-I SFM 2024: Immunology/Mather Anergy Self-antigen recognition in the absence of costimulation = T-cell anergy (unresponsive or anergic T cell) § Naïve T cell activation requires two signals: o Antigen recognition: TCR binding to the epitope (MHC-peptide) o Co-stimulation: binding of CD28 on the T cell to B7 on the APC (no co-stimulation = anergy) Mechanisms of T-cell anergy: o Block in signal transduction from the TCR complex o Engagement of inhibitory receptors such as CTLA-4 and PD-1 CTLA-4 and PD-1 are inhibitory receptors of the CD28 family § CTLA-4 o Expressed in responding T cells upon activation by nonself antigens, shutting off further activation and thus terminating the response. o Expressed in Tregs, and use it to prevent the activation of T cells responding to self antigens (see below). § CTLA-4 has a much higher affinity for B7 than CD28 and thus functions as a competitive inhibitor of CD28 and thereby prevents CD28-mediated T cell costimulation. The net effect = termination or suppression of T cell responses in secondary lymphoid organs (anergy!). o Functions via receptor-mediated endocytosis Note: (1) Mutations or blocks in CTLA-4 = severely dysregulated immune responses with enlarged lymph nodes; lymphoproliferation; multiorgan inflammation. (2) Blocking of CTLA-4 with antibodies as part of cancer immunotherapy often results in various autoimmune and inflammatory disorders. § PD-1 delivers inhibitory signals that block signaling from the TCR and by CD28. It is most important for terminating the responses of effector T cells, especially CD8+ cells, in peripheral tissues. It recognizes two ligands PD-L1 and PD-L2. o Expressed on antigen-activated T cells. o PD-1 binds to two ligands PD-L1 and PD-L2 expressed on APCs and other tissue cells (also tumors). 3 IMS-I SFM 2024: Immunology/Mather Suppression by Tregs § Tregs are generated mainly by self antigen recognition in the thymus (nTregs) and they can be induced in peripheral tissues (eg. lymph nodes) by the recognition of antigen by naïve CD4+ T cells in the absence of strong innate immune responses (iTregs). The generation of nTregs or populations of iTregs requires the cytokines IL-2 or TGF-b, respectively. § Tregs inhibit T cell activation in lymphoid organs and at the effector phase of these responses in tissues. § Tregs have also been shown to suppress B cells, dendritic cells, and NK cells. Note: A rare autoimmune disease in humans called IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) is caused by mutations in the FOXP3 gene and is associated with deficiency of regulatory T cells. Patients can present early in life with diarrhea, diabetes and eczema. Mechanisms of Treg cell activity: 1. Cytokine deprivation: Tregs consume IL-2 and compete for the cytokine that activated T cells need to survive and proliferate. 2. Production of inhibitory cytokines: IL-10 and TGF-b inhibit surrounding autoreactive T cells. 3. Inhibition of APCs: CTLA-4 on Tregs or responding T cell binds B7 on APC or removes this molecule from the APC surface, blocking B7 and therefore T cell activation. 4. Cytotoxicity: Tregs can directly kill T cells. Deletion by apoptotic cell death T lymphocytes that recognize self-antigens with high affinity or are repeatedly stimulated by antigens may die by apoptosis. Two major pathways of apoptosis have been implicated in peripheral deletion of mature T cells: 1. Mitochondrial apoptotic pathway § Death caused by deficiency of survival signals. § Mediates negative selection in the thymus and deletion of T cells that recognize self-antigens in absence of costimulation in the periphery. § Triggered by loss of survival signals; associated with leakage of pro-apoptotic proteins from mitochondrial membrane into the cytoplasm, where they activate caspases. 2. Death receptor pathway § Mediates the deletion of mature auto-reactive T cells (and B cells) in the periphery. 4 IMS-I SFM 2024: Immunology/Mather § Initiated by engagement of death receptor Fas (CD95) by Fas ligand (FasL) on adjacent cells. § The ligation of Fas initiates apoptosis in the cell expressing Fas, by activating a “death” domain in Fas. Note: Patients with mutations in the Fas gene can develop a severe autoimmune lymphoproliferative syndrome (ALPS) caused by abnormal lymphocyte survival. Lymphocytes accumulate in the lymph nodes, liver, and spleen and can lead to enlargement of these organs. B CELL TOLERANCE Central Tolerance § Immature B cells in the bone marrow that produce a high affinity receptor for self-antigen undergo a process of receptor editing. § If receptor editing is not successful, the autoreactive B cells die by apoptosis (negative selection). Peripheral tolerance in B cells Anergy § Self-antigen recognition in the absence of costimulation from the T helper cell = B-cell anergy § Anergic B cells do not migrate to germinal centers. Instead they are arrested in development at the T cell–B cell border and die by apoptosis. 5 IMS-I SFM 2024: Immunology/Mather Recap: Central Tolerance § Deletion (negative selection) § Receptor editing (B cells) Peripheral Tolerance § Anergy § Suppression § Deletion AUTOIMMUNITY § Autoimmunity refers to an adaptive immune response against self-antigens. It is caused by failure of tolerance mechanisms. § Autoimmune disease occurs when autoreactive T cells or autoantibodies cause causes clinical damage or destruction of self proteins, cells, and organs through hypersensitivity reactions. § May be organ specific or systemic. Mechanisms breaking T cell tolerance 6 IMS-I SFM 2024: Immunology/Mather Contributing factors in the development of autoimmunity are the inheritance of susceptibility genes and environmental triggers, such as infections and other inflammatory stimuli. Immune privilege There are several sites in the body where immune responses are not readily initiated. These sites, known as immune privileged sites, include the eye, testis, brain, ovary, and placenta. Immune protection in privileged sites include: § Exclusion of naïve lymphocytes and inflammatory cells due to lack of lymphatic drainage. § Blood-tissue barriers. § Expression of immunosuppressive cytokines IL-10 and TGF-b. § Expression in privileged site of FasL. Sequestration allows tissue-specific privileged antigens to avoid encounter with self-reactive lymphocytes under normal circumstances. Physical damage to privileged sites can release “hidden” antigens that are normally not seen by T cells and trigger an autoimmune attack. Genetic factors in susceptibility to autoimmunity § Certain MHC (HLA) genes associated with specific autoimmune disorders. § May contribute to the development of autoimmunity because they are inefficient at displaying self-antigens, leading to defective negative selection of T cells, or because peptide antigens presented by these MHC alleles may fail to stimulate regulatory T cells. § Autoimmunity is multifactorial!!!! Not every person who has a particular predisposing allele experiences autoimmune disease. 7 IMS-I SFM 2024: Immunology/Mather § Numerous non-HLA genes also are associated with various autoimmune diseases. Most tend to play prominent roles in immune regulation. § Some rare autoimmune diseases are caused by mutations in single genes and lead to autoimmunity in most or all individuals who inherit these mutations. In someone genetically prone to autoimmunity, the balance may be tipped toward autoimmune disease by external triggers: Infection in autoimmunity Infections may activate self-reactive lymphocytes, thereby triggering the development of autoimmune diseases. Mechanisms by which pathogens may promote autoimmunity include inflammation and molecular mimicry. 8 IMS-I SFM 2024: Immunology/Mather § Inflammation o Inflammation associated with infection may lead to increased production of costimulators and cytokines by APCs (e.g., dendritic cells) in tissues. o These activated tissue APCs stimulate self-reactive T cells that encounter self-antigens in the tissues, promoting activation of self-reactive lymphocytes. § Molecular mimicry by pathogen antigens o Process in which infection by particular microbes is associated with the subsequent development of a specific autoimmune disease. o Occurs when components of a pathogen bears an epitope that resembles an epitope from a self-antigen. This can result in an immune attack against self-antigens by self-reactive T or B cells. 9