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

Theme 5b Tolerance, Hypersensitivity, and Mucosal Immunity 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...

Theme 5b Tolerance, Hypersensitivity, and Mucosal Immunity 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 Hypersensitivity Reactions Gell and Coombes classification: Types I-IV I, II and III: Antibody mediated, IV: cell-mediated and ‘delayed’ Are normal mechanisms that are not controlled or occur at the wrong time (&V) (Type II) (Type V) Tolerance, Hypersensitivity, and Mucosal Immunity 3 Type I: Antibody (IgE) & Mast cell mediated Mediated by antibodies of the IgE isotype following sensitization Following FIRST exposure (sensitisation) to Ag, IgE remains bound by Fcε receptors on mast cells On subsequent exposures, Fcε receptor cross-linking triggers immediately resulting in mast cell degranulation Granules contain potent inflammatory mediators (eg. histamine, prostaglandins and leukotrienes) Requires priming by Th2 cells to cause B cells to switch to IgE production (due to IL-4 and IL-5) This reaction is the basis of atopic (allergic) responses to environmental antigens Tissue location governs disease symptoms Tolerance, Hypersensitivity, and Mucosal Immunity 4 Type I: Allergic rhinitis Dendritic cell (APC) Antigen or ‘allergen’ Th2 & IL-13 Tolerance, Hypersensitivity, and Mucosal Immunity 5 Type I: Asthma DC (APC) IL-4, IL-5, IL-9, IL-13 Mast cell Th2 Allergen-specific Th2 cells in the lung promote release of IgE and activation of mast cells Th2 cytokines, such as IL-5 and eotaxin, recruit eosinophils to the lung Release of mediators such as histamine trigger bronchial constriction and mucus production While some asthma-related allergens have been identified the underlying cause is unclear Treatments Tolerance, Hypersensitivity, and Mucosal Immunity 6 Type II: Antibody (IgG/M)-mediated Antibodies (IgG or IgM isotype) can be directed against antigen on an individual's own cells (target cell) following Th1 activation of B cells Antibody targets extracellular matrix proteins and connective tissues Can also be triggered by innocuous (normally harmless) foreign antigens, such as antigens on transfused red blood cells or platelets or even drugs (penicillin) IgG binding to antigen triggers opsonisation and complement fixation leading to recruitment of neutrophils and macrophages and eventual destruction of cell or tissue by antibody dependent cellular cytotoxicity ADCC OR IgG antibodies bind to signalling molecules or cell receptors, disrupting normal cell function (sometimes called Type V) Tolerance, Hypersensitivity, and Mucosal Immunity 7 Type II : Antibody (IgG)-mediated Pathology: (3) Fc receptors on Neutrophils, NK cells induce release of mediators onto cell surface (ADCC) (2) Autoreactive Abs bind (1) Self antigens on cells and/or (4) 8 Tolerance, Hypersensitivity, and Mucosal Immunity Goodpasture's syndrome Autoimmune haemolytic anaemia Linked to viral infections Abs target basement membrane collagenase IV in lung or kidney (glomerulonephritis) Can be visualised by immunofluorescence Antibodies target own RBCs via blood group Ags (ABO, Rhesus) Cause of transfusion reactions and hemolytic disease of newborn (reactive IgG crosses the placental barrier) Abs opsonize & fix complement, MAC lyses RBCs Diagnosed using Coomb‘s test Type II/V : Antibody (IgG)-mediated Graves' disease Caused by ‘auto’antibodies targeting the thymic stimulating hormone receptor Abs trigger receptor activation stimulating thyroid hormone synthesis, secretion, and thyroid growth (goitre) 50% of patients show opthalmopathy as Abs also target eye muscles Causes unknown (genetic/environment) Myasthenia gravis Antibodies block nicotinic acetylcholine receptors at the postsynaptic neuromuscular junction Causes muscle weakness and fatigue Weak genetic link to HLA-DR3 (MHCII gene) Often presents with other autoimmune disease eg. Diabetes type I and Rheumatoid Tolerance, Hypersensitivity, and Mucosal Immunity Arthritis 10 Type III: Immune complex-mediated Soluble antigens processed, presented and Th1 cells induce IgG production by B cells. Soluble IgG complex with soluble antigens leading to ‘immune complex’ formation which occurs during all immune responses and are normally removed by the mononuclear-phagocyte system Small complexes preferentially deposit within vessels; large complexes accumulate in liver, spleen, and kidneys Immune complex deposition activates innate immune cells (macrophages & neutrophils) via activation of Fc receptors and activation of complement which initially helps solubilise immune complexes by disrupting antigen-antibody bonds. Disease symptoms depend on site of complex deposition, which depends on complex size Complement deficiencies are associated with insoluble immune complexes and deposition in tissues Tolerance, Hypersensitivity, and Mucosal Immunity 11 Type III: Immune complex-mediated Pathology: Serum sickness Sensitisation results in deposition of antigen:antibody complexes in blood vessel walls triggering neutrophil degranulation and vasculitis Triggered by injection of poorly catabolised foreign Ag (eg.anti-snake venom serum) Arthus reaction When symptoms are seen on the skin Triggered occasionally after some diptheria vaccine or in autoimmune diseases Systemic lupus erythematosus “the great imitator” Abs target cytoplasmic antigens eg. DNA, histones, RNA binding proteins (LSm proteins) Complexes can accumulate in the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system Hallmark of SLE is glomerulonephritis due to immune complex deposition at glomerular basement membrane in kidneys Other symptoms - skin rash, arthritis SLE has a genetic component – runs in families, but is also linked to infectious agents 12 Type IV: Delayed-type (DTH) – T cell-mediated T cell mediated and delayed due to sensitisation taking 1-2 weeks – mainly of TH1 helper cell subset Antigen-sensitised T cells release inflammatory cytokines following a secondary contact with the same antigen that induce inflammatory reactions and activate and attract macrophages Sometimes TH2, TH17 and CTL(CD8+) mediated with eosinophil and mast cell activation Activated Macrophages much better at Ag presentation, thereby perpetuating the response, particularly if the antigen is not cleared Tolerance, Hypersensitivity, and Mucosal Immunity 13 Type IV: Contact dermatitis Haptens = small molecules which can only elicit an immune response when bound to a large molecule (carrier) Sensitizing agents (haptens) eg. Poison ivy, latex, nickel, gold, chromium, solvents Pentadecacatechol in poison ivy leaf is lipid soluble - can cross cell membranes and modify intracellular proteins and are picked up by APCs Modified self-proteins are presented on MHC class I (intracellular Ags) to CD8+ CTLs and MHC class II (extracellular Ags) to CD4+ Th1 CD8+ CTLs kill Ag-expressing cells and Th1 cells activate inflammatory macrophages mainly via release of IFNg Tolerance, Hypersensitivity, and Mucosal Immunity 14 Type IV: Granulomatous DTH Granulomatous hypersensitivity is clinically the most important form of type IV hypersensitivity Granulomas form in response to persistent antigen (eg. M.tuberculosis) to wall off threat Formed from a combination of fused macrophages (giant cells), surrounded by epithelioid cells driven by IFNγ released by Th1 cells Granuloma formation appears to require Th1 and Th2 cytokines but is dependent on TNFα (often produced by macrophages at site) Chronic diseases showing granuloma formation – tuberculosis, leprosy, schistosomiasis, sarcoidosis, and Crohn‘s disease Tolerance, Hypersensitivity, and Mucosal Immunity 15 Hypersensitivity: Summary Inappropriately vigorous immune responses and breakdown of immuno-regulatory mechanisms can result in a variety of hypersensitivity reactions defined by their principle mechanism of action Type I: IgE / mast cell-mediated eg. allergic rhinitis, asthma Type II: IgG/IgM-mediated triggering complement fixation and neutrophil activation eg. Rheumatic fever, Goodpasture’s syndrome Type II/V: IgG-mediated causing functional responses in the tissues eg. Graves’ disease (thyroid) and myasthenia gravis (neuromuscular) Type III: Immune complex mediated eg. SLE Type IV: Cell mediated DTH eg. contact dermatitis, granulomatous diseases, multiple sclerosis, diabetes mellitus, rheumatoid arthritis, Crohn’s disease Tolerance, Hypersensitivity, and Mucosal Immunity 16