BMS2045 5a Tolerance, Hypersensitivity & Mucosal Immunity 2024.pdf

Theme 5a Tolerance, Hypersensitivity, and Mucosal Immunity part 1 Tolerance, Hypersensitivity, and Mucosal Immunity 1 Theme 5 learning outcomes Explain the difference between central and peripheral tolerance and the different mechanisms involved in its maintenance Describe how a breakdown in toleran...

Theme 5a Tolerance, Hypersensitivity, and Mucosal Immunity part 1 Tolerance, Hypersensitivity, and Mucosal Immunity 1 Theme 5 learning outcomes Explain the difference between central and peripheral tolerance and the different mechanisms involved in its maintenance Describe how a breakdown in tolerance can cause autoimmune disease Distinguish between different types of hypersensitivity responses, identify the underlying mechanisms and the diseases they can cause Describe the specialised structural and cellular features of mucosa that contribute to mucosal immunity Tolerance, Hypersensitivity, and Mucosal Immunity 2 The Need for Tolerance Random gene rearrangements required to generate T cell receptors (TCR) and B cell receptors (BCR) have the potential to produce selfreactive immune cells Self-reactive immune cells have the potential to trigger "horror autotoxicus” (Paul Ehrlich, ~1900) or autoimmunity The body maintains a state of ‘immunological tolerance’ - a state of unresponsiveness to particular antigens Central tolerance T cells are ‘educated’ in the THYMUS B cells are ‘educated’ in the BONE MARROW Peripheral tolerance Many mechanisms for B and T cells Tolerance, Hypersensitivity, and Mucosal Immunity 3 Central Tolerance: T cells in the thymus Thymocytes develop in the bone marrow before migrating to the thymus Thymocytes POSITIVE SELECTION in the thymic cortex – T cells are tested for MHC binding – nonbinding cells undergo apoptosis Thymic capsule Thymic nurse cells CORTEX Blood vessels Subcapsular epithelium POSITIVE SELECTION Cortical epithelial cells Medullar epithelial cells Dendritic cells MEDULLA Hassall‘s corpuscle NEGATIVE SELECTION NEGATIVE SELECTION in the thymic medulla – specialised epithelial cells (TMEC) and some dendritic cells present self-antigen/MHC complexes – T cells with high affinity for self Ag/MHC undergo apoptosis LIMITATIONS? Not all self-Ag/MHC can be expressed in the thymus Macrophage High affinity for self antigens apoptosis Low affinity for self antigens CD8+ CD4+ Deleting all self-reactive cells would severely limit the repertoire Cannot account for innocuous environmental antigens Tolerance, Hypersensitivity, and Mucosal Immunity 4 Central Tolerance: B cells in the bone marrow Self reactive B cells undergo a form of selection that can lead to 3 possible fates within bone marrow: BCR with high affinity for self-antigen undergo Receptor editing (variable genes of light chains) expression of new antigen receptor (BCR) can lead to (1) survival or (2) deletion by an unknown mechanism (if the process fails and the BCR still recognises self antigens present in the bone marrow) (2) ? (1) or circulation (3) Where there is weak recognition/binding of antigen, the B cells can undergo receptor editing OR become ‘anergic’ (unresponsive) and are released into the circulation Tolerance, Hypersensitivity, and Mucosal Immunity 5 Peripheral Tolerance The diversity of the host immune response is maintained at the risk of generating specificity for self antigens Some self-reactive immune cells may be a requirement of a healthy immune system eg. mediating tumour surveillance, regulating inflammatory immune responses If auto-reactive immune cells do escape central tolerance, how are they regulated in the periphery? CENTRAL TOLERANCE PERIPHERAL TOLERANCE Thymus Bone Marrow Self-reactive T or B cell Naϊve B cells Naϊve CD4+ / CD8+ T cells Tolerance, Hypersensitivity, and Mucosal Immunity 4 mechanisms for T cells & 3 mechanisms for B cells 6 Peripheral Tolerance: T cells (1) Ignorance Some self antigens are only expressed at certain times (eg. some hormones during puberty; during inflammatory responses) so not present during early +/- selection in thymus Some self antigens remain sequestered (‘hidden’) in immunologically privileged sites (eg. anterior chamber of eye, behind blood/brain barrier) which are not normally accessible Some self antigens are not present in sufficient quantities (low dose) to reach threshold of activation for TCR As long as remain hidden/not expressed, tolerance is maintained ! Tolerance, Hypersensitivity, and Mucosal Immunity 7 (2) Anergy - TCR activation with lack of co-stimulation (CD80/86 : CD28) Co-stimulator deficient APCs (including tolerogenic or immature DCs) the action of negative co-stimulatory pathways eg. CTLA-4 that inhibits CD28 binding to CD80/86 CTLA-4 expression is induced upon TCR stimulation and has high affinity for CD80/86 (B7.1/7.2) on APCs CTLA-4 engagement sends an inhibitory signal to block further TCR signalling – so works as a regulatory function to dampen Anergic cells are unresponsive to down T cell responses – binding to subsequent stimulation CD80/86 and also supresses APCs (Mutations in CTLA-4 gene are associated with some autoimmune diseases) Tolerance, Hypersensitivity, and Mucosal Immunity 8 (3) Deletion via apoptosis – through Activation-Induced Cell Death (AICD) Self-reactive T cells can be deleted in periphery by activation–induced cell death (AICD) Repeated activation of the TCR induces expression of death receptors such as Fas and FasL; and pro-apoptotic proteins such as Bax, Bad, and Bim (Bcl-2 proteins) Tolerance, Hypersensitivity, and Mucosal Immunity 9 (4) Effects of regulatory T cells Types: Natural or Inducible CD4 or CD8 Some express internal marker FoxP3 Action: Cell : Cell contact dependent: – T-regs have fully functional TCR and also express high levels of CTLA-4 so when in contact with APCs CTLA-4 binds to CD80/86 (B7.1/7.2) making the APCs tolerogenic – Can directly kill APCs and other T cells via perforin and granzyme secretion (lysis) Soluble (cell contact independent): – Secretion of cytokines such as IL-10 and TGF-b – Mopping up of IL-2 – they possess low affinity IL-2R so act as sponge depriving other T cells of IL-2 Tolerance, Hypersensitivity, and Mucosal Immunity 10 Peripheral Tolerance: B cells A high proportion of short-lived, low-avidity, auto-reactive B cells are present in peripheral lymphoid organs – 3 mechanisms for maintaining peripheral tolerance: B cell activation depends on adequate co-stimulation (CD40L, TLR etc) (1) Chronic, low level of Ag, BCR cross-linkage and lack of sufficient co-stimulation results in B cell anergy – seen in chronic infections and sometimes referred to as B cell ‘exhaustion’ (2) Acute, high level of Ag, BCR cross-linkage and lack of co-stimulation results in B cell deletion via apoptosis Chronic low level Ag (1) (2) Acute high level Ag Tolerance, Hypersensitivity, and Mucosal Immunity Apoptosis 11 (3) Partially activated B cells do not express the right chemokine receptors and are excluded from the lymphoid follicles – cannot develop into mature plasma B cells (3) Other considerations include FcgR2b (ITIM in cytoplasmic tail) when crosslinked by Ab/Ag complexes leads to –ve signal into B cell, availability of BAFF (survival factor) Tolerance, Hypersensitivity, and Mucosal Immunity 12 Tolerance: Summary Random rearrangements of TCR and BCR genes can produce receptors which react to self-antigens Central tolerance mechanisms remove most self-reactive T and B cells in the thymus and bone marrow (deletion via apoptosis) Self-reactive immune cells that escape central tolerance are controlled by peripheral tolerance mechanisms T cell peripheral tolerance mechanisms include ignorance, anergy, deletion and the effects of regulatory T cells B cell peripheral tolerance mechanisms include anergy, deletion and exclusion Breaking tolerance can lead to autoimmune disease Tolerance, Hypersensitivity, and Mucosal Immunity 13 Uncontrolled immune responses cause disease Inflammatory responses towards self-antigens triggers autoimmune disorders (which are mediated by hypersensitivity mechanisms II, III and IV) Inappropriate or uncontrolled responses towards environmental antigens causes allergy (atopy) and hypersensitivity diseases Unwanted immunity can also arise in response to transplantation Tolerance, Hypersensitivity, and Mucosal Immunity 14 Autoimmune Disorders Over 50 diseases/syndromes recognised as being autoimmune Range from organ specific to systemic: www-immuno.path.cam.ac.uk/.../lec12_97.html Most autoimmune diseases thought to have a genetic component + environmental trigger: Caused by vitamin D deficiency & disrupted by leaky gut HLA-DQ, DR & other genes Gluten, grains, nutritional deficiencies, virus, bacteria etc Usually affect women > men: Tolerance, Hypersensitivity, and Mucosal Immunity 16 Tolerance, Hypersensitivity, and Mucosal Immunity 17