YR1 Lecture 1H - Introduction to autoimmunity and hypersensitivity (2022) Western Sydney University PDF

Introduction to autoimmunity and hypersensitivity Dr Timothy West Clinical Immunologist and Allergist, Campbelltown Hospital [email protected] 4 May 2022 1 Learning objectives Understand the four main types of immunological hypersensitivity. Define what is meant by the term autoimmunity...

Introduction to autoimmunity and hypersensitivity Dr Timothy West Clinical Immunologist and Allergist, Campbelltown Hospital [email protected] 4 May 2022 1 Learning objectives Understand the four main types of immunological hypersensitivity. Define what is meant by the term autoimmunity. Understand the roles of genes, environment, and infection in the development of autoimmunity. Describe the possible mechanisms that can result in production of autoreactive lymphocyte clones. Describe the major ways in which self-tolerance is established and maintained. Understand the difference between central and peripheral tolerance. 2 Failures of the immune system 3 Failures of the immune system If the immune system is too weak… Reduced ability to fight off infection. – More frequent infections. E.g. recurrent sinopulmonary infections in antibody deficiency such as X-linked agammaglobulinaemia or common variable immunodeficiency. – Infections more severe than would be expected. E.g. CMV causing pneumonitis and hepatitis in a patient on chemotherapy for cancer. – Infections by pathogens which do not normally cause infection (i.e. opportunistic infections). E.g. PJP infection in a patient with AIDS. Reduced cancer surveillance. Caused by – Medications; primarily those used to used to treat cancer and autoimmune diseases. – Inherited problems of the immune system. 4 Failures of the immune system If the immune system reacts to our own tissue (to “self antigen”)… Immune-mediated damage to the tissue that is targeted: autoimmune disease. This is a “failure of tolerance”. Symptoms relate to the organ or tissue that is affected. – E.g. rheumatoid arthritis: joint pain and inflammation. – E.g. Hashimoto thyroiditis: symptoms of thyroid hormone deficiency. The body can potentially react to (almost) any protein in the body. – Autoimmune myositis, encephalitis, uveitis, etc etc… Caused by… see later this lecture 5 Failures of the immune system If the immune system reacts to a harmless foreign substance For example: peanut protein; grass pollen; penicillin. Hypersensitivity – most commonly allergy – occurs. Symptoms depend on the type of hypersensitivity – see future slides – but for allergy: – Hives, angioedema, anaphylaxis. 6 Failures of the immune system If the immune system reacts to a transplanted organ… For example: kidney transplant, liver transplant etc. Organ rejection occurs. Will occur in all individual with a transplanted organ unless immune suppressant drugs are given. 7 Janeway’s Immunobiology, 9e, page 32 8 Diseases related to the immune system occur through either: – A deficient response to an antigen that should be targeted (e.g. an invading microbe or cancer cell). – A normal response to an antigen that should be tolerated. This can cause allergy (reaction to an innocuous foreign substance), autoimmunity (reaction to self) or organ rejection (reaction to transplanted organ). That is: while the immune system can be “too weak” – causing immune deficiency with predisposition to infections – it is rarely “too strong”. Instead, in autoimmunity and hypersensitivity, it is misdirected. 9 Hypersensitivity 10 A little more about antibodies IgM: pentamer “Antibody” = “Immunoglobulin”. – “Immunoglobulin” is frequently shortened to “Ig”. Naïve B cells produce IgM, which circulates in blood as pentamers. After B cells are activated, they undergo two processes: – They switch from producing IgM to producing one of several kinds of antibody: IgG, IgA or IgE. This is known as class switching. – At the same time, their B cell receptor undergoes further changes to become better at binding to their target antigen. This is known as affinity maturation. IgG: the main antibody in blood and extracellular fluid; crucial for fighting off extracellular infections in these areas, and neutralises toxins. IgA: the main antibody in secretions, involved in immunity in the gastrointestinal and respiratory tracts. IgE: involved in fighting off parasitic worms, and binds tightly to mast cells where is central to the pathogenesis of allergy. (There is a fifth kind of immunoglobulin, IgD, which is the membrane-bound B cell antigen receptor, and is not released into plasma). https://en.wikipedia.org/wiki/Antibody IgG and IgE: monomer IgA: dimer 11 Definitions A hypersensitivity reaction is an inappropriate (i.e. pathological / nonbeneficial) immune response, provoked by either: – a usually benign environmental stimulus, e.g. penicillin, cat dander); or – a host antigen, e.g. RBC surface proteins in haemolytic anaemia; synovial antigens in rheumatoid arthritis. An allergic reaction is a specific form of hypersensitivity reaction (type I hypersensitivity) that is directed at harmless foreign substances (not to human tissues) and is mediated by IgE cross-linkage on mast cells. – Anaphylaxis is a severe allergic reaction with systemic features. Autoimmune disease is a hypersensitivity reaction targeted at the body’s own tissues (not a foreign antigen). In common medical discussion, the term “hypersensitivity” is often used as if it was the same as “allergy”. However, in immunological literature, hypersensitivity has four types which encompasses both allergy and all forms of autoimmune disease. Within these four types, allergy is “type 1 hypersensitivity”. Adverse reactions (to drugs / foreign substances) “Type A” reactions (“augmented”): dose dependent; predicted from the known pharmacology of the drug; occurs in everyone. – E.g. morphine causing drowsiness; alcohol causing hangover. “Type B” reactions (“bizarre”): unpredictable, dose-independent, does not occur in everyone. – Hypersensitivity reactions: a type B reaction that is mediated by the immune system. – There are other kinds: e.g. genetic variability: alcohol flushing syndrome, common in east Asians; G6PD deficiency causing oxidative crises. 13 Type I hypersensitivity (allergy) Key immune components Mast cells releasing histamine and other vasoactive cytokines. Angioedema of both eyes. This IgE-secreting B cells / plasma cells boy cannot open his eyes due to swelling. Example type I syndromes Food / drug allergy Anaphylaxis Hay fever Hives (urticaria) Clinical features Urticaria (hives) Angioedema Bronchospasm Hypotension Anaphylaxis https://en.wikipedia.org/wiki/Angioedema 14 Hives (urticaria) Type I hypersensitivity (allergy) Abbas’ Basic Immunology 6e 15 Example diseases mediated by type I hypersensitivity (allergy) You do not need to memorise this slide! However, you should have a general idea of the range of triggers of allergy, and the range of symptoms that can occur. 16 Type II hypersensitivity (Antibody-mediated) Key immune components/process IgM and IgG antibodies directed against cell surface antigens. In some cases: antibody dependent cytotoxicity (ADCC): complement activation, recruitment of neutrophils/macrophages. Example type II diseases Grave’s disease. Autoimmune haemolytic anaemia Clinical features Depends entirely upon tissue targeted and consequences of antibody binding. E.g. autoimmune haemolytic anaemia: signs of anaemia. E.g. Grave’s disease: signs of hyperthyroidism due to thyroid receptor activation by thyroid receptor antibodies. Abbas’ Basic Immunology 6e 17 Example diseases mediated by type II hypersensitivity You do not need to memorise this slide! I have included it to illustrate the range of diseases caused by type II hypersensitivity. You will learn about these diseases over the next few years. 18 Abbas’ Basic Immunology 6e Type III hypersensitivity (Immune complex mediated) Key immune components/steps IgM and IgG antibodies directed against soluble antigens. Immune complexes formed by these antibodies binding to antigens. Complexes deposit in small blood vessels, where they they can cause further immune damage e.g. by complement activation and/or recruitment of neutrophils. Example type II diseases Systemic lupus erythematosus. Post-streptococcal GN. Serum sickness. Clinical features Depends on nature of complexes and where they lodge. Often causes vasculitis in small blood vessels. Can cause renal impairment when complexes lodge in glomeruli. Abbas’ Basic Immunology 6e 19 Example diseases mediated by type III hypersensitivity You do not need to memorise this slide! I have included it to illustrate the range of diseases caused by type III hypersensitivity. You will learn about these diseases over the next few years. Abbas’ Basic Immunology 6e 20 Type IV hypersensitivity Key immune components T cells directed against either foreign or self antigen. Various mechanisms triggered by T cells e.g. cytokine-mediated inflammation; T-cell mediated destruction of host cells. [Subtypes of type IV hypersensitivity have been defined]. Example type II diseases Delayed-type drug reactions. Multiple sclerosis. Type I diabetes mellitus. Clinical features Depends entirely upon tissue targeted and consequences of antibody binding. E.g. in T1DM: immune destruction of insulinproducing cells leads to absence of insulin and its sequelae. E.g. in MS: immune damage of myelin sheaths around nerve leads to focal neurological symptoms. Abbas’ Basic Immunology 6e; https://en.wikipedia.org/wiki/Multiple_sclerosis Demyelinating lesion in MS 21 Example diseases mediated by type IV hypersensitivity You do not need to memorise this slide! I have included it to illustrate the range of diseases caused by type IV hypersensitivity. You will learn about these diseases over the next few years. 22 Abbas’ Basic Immunology 6e Types of hypersensitivity (Gell and Coombs classification) Type I – IgE-mediated; mast cell activation – Allergy; “immediate-type” reaction: within one hour. – Food/drug allergy; allergic asthma; hay fever; anaphylaxis. Type II – IgG antibody-mediated – Autoimmune haemolytic anaemia; Goodpasture’s syndrome; Grave’s disease; myasthenia gravis. Type III – immune complex-mediated – Systemic lupus erythematosus; post-streptococcal glomerulonephritis. Type IV – T cell-mediated – Rheumatoid arthritis; multiple sclerosis; type 1 diabetes mellitus; inflammatory bowel disease. 23 Mechanism Example diseases triggered by foreign antigen Example diseases triggered by self antigen Food allergy Drug allergy Hay fever Anaphylaxis N/A Type II IgM or IgG antibody mediated Drug-induced autoimmune haemolytic anaemia Autoimmune haemolytic anaemia Goodpasture’s syndrome Grave’s disease Myasthenia gravis Type III Immune complex mediated Serum sickness reaction Systemic lupus erythematosus Post-streptococcal GN Type IV T-cell mediated (Delayedtype) Coeliac disease Delayed type drug eruptions; druginduced hepatitis. Rheumatoid arthritis Multiple sclerosis Type 1 diabetes mellitus IgEType I mediated (Allergy) (Immediatetype) Type I = allergy. Reaction to foreign antigens only; no crossreactivity to self antigen. Types II to IV: typically cause autoimmune disease. Sometimes, these reactions are triggered by a foreign antigen, but the end result is usually host tissue damage. 24 Autoimmune disease 25 Autoimmune reactions reflect an imbalance between effector and regulatory immune responses, typically develop through stages of initiation and propagation, and often show phases of resolution (indicated by clinical remissions) and exacerbations (indicated by symptomatic flares). M. D. Rosenblum, K. A. Remedios, and A. K. Abbas, Mechanisms of human autoimmunity, Journal of Clinical Investigation, 2015. 26 The fundamental underlying mechanism of autoimmunity is defective elimination and/or control of self-reactive lymphocytes. B cell autoreactive clones produce autoreactive antibodies. T cell autoreactive clones may produce cellmediated cytotoxicity (CD8+ cytotoxic T cells) and activate autoreactive B cells (CD4+ helper T cells). M. D. Rosenblum, K. A. Remedios, and A. K. Abbas, Mechanisms of human autoimmunity, Journal of Clinical Investigation, 2015. 27 Terms: Subclinical disease: a disease process which has started in the body, but has not yet caused symptoms/signs that allow it to be recognised by the patient or their family/clinician. Teff: effector T cells, i.e. CD4+ helper and/or CD8+ cytotoxic T cells that are causing the autoimmune disease, i.e. recognise host antigens. Treg: regulatory T cells. M. D. Rosenblum, K. A. Remedios, and A. K. Abbas, Mechanisms of human autoimmunity, Journal of Clinical Investigation, 2015. 28 Autoimmune disease and genetics 29 Pathogenesis of autoimmune disease In the most general terms, autoimmune disease is thought to arise from a susceptible host who has a genetic susceptibility, who encounters an environmental stimulus that leads to production of self-reactive lymphocytes. Susceptible host: genetic risk is the best characterised; certain gene polymorphisms cause increased rates of autoimmune disease. Environmental stimulus: potential triggers include infection, tissue damage/trauma, or microbiome changes. Key concepts in pathogenesis of autoimmunity Genetic susceptibility Environmental factors leading to tissue injury 31 Autoimmunity and genetics Strong concordance in monozygotic twins. Genes confer vulnerability rather than being directly causative (importance of environmental factors). Most autoimmune diseases are polygenic. Susceptibility is frequently to several autoimmune conditions rather than just one. 32 Autoimmunity and genetics Recall the two key antigen presenting complexes (see previous lecture): – MHC class I is expressed on all nucleated cells, and presents intracellular antigens to CD8+ cytotoxic T cells. – MHC class II is expressed on professional APCs and presents extracellular antigens to CD4+ helper T cells. The genes for the MHC protein structures are called the HLA genes. – MHC Class I is coded for in the genes HLA-A, HLA-B and HLA-C. – MHC Class II is coded for in the genes HLA-DR, HLA-DP and HL-DQ. Why HLA and MHC? It would obviously be more sensible to say the MHC protein is coded in the MHC genes, but unfortunately history has not lead to this sensible approach. MHC stands for major histocompatibility complex. – So-called because of early mouse experiments in organ transplantation, in which it was found differences in MHC proteins between mice would cause rapid organ rejection. – “Histo” = “tissue” in Greek, hence “histocompatibility” = ”tissue compatibility”. In humans (but not mice), MHC is also termed human leukocyte antigen (HLA). – Because in organ transplantation, detection of foreign MHC molecules can cause organ rejection. So in the context of organ transplantation, the MHC molecule itself is an antigen which provokes an immune response. 33 Autoimmunity and genetics Particular HLA alleles confer risk factors for various autoimmune diseases. – HLA-B27 (one polymorphism of the HLA-B gene) is strongly associated with ankylosing spondylitis (200x risk). – HLA-DQ2 and HLA-DQ8 with coeliac disease. HLA-DQ2 homozygotes: around 30% will develop coeliac disease. – HLA risks for rheumatoid arthritis, type 1 diabetes, MS and other diseases are known (increased risk varies by gene and condition in range 2 – 30x increased risk). Exactly how these alleles increase the risk of autoimmune disease remains unknown. – It would be logical to think that they are “better” at presenting particular antigens, e.g. gluten in coeliac disease, but data have not supported this idea. – In fact the opposite could be true: it may be that they are inefficient at displaying self-antigens during T cell development, such that they selfreactive T cells are not killed during development. 34 Other genes that confer risk of autoimmune disease Genetic complement protein deficiencies (e.g. low C4) associated with development of systemic lupus erythematosus. Cytokine polymorphisms (e.g. IL-2 and IL-2 receptor polymorphisms) in several diseases. 35 Autoimmune disease and infection 36 Infection and autoimmunity Possible mechanisms of infection leading to autoimmunity: ”Bystander activation”: local tissue damage due to infection and subsequent inflammation results in self antigens being presented to lymphocytes in an environment of lymphocyte activation. – E.g. type I interferons produced by viral infections, associated with systemic lupus erythematosus. “Molecular mimicry”: Antigens on microbes cross-react with self antigens. – E.g. rheumatic fever: antibodies against streptococci cross-react with myocardial antigen and cause heart disease. Infection may change the shape of host proteins such that they are recognised as foreign. – E.g. periodontal infections association with rheumatoid arthritis. Tissue damage may release antigens that are normally hidden from the immune system. – E.g. sympathetic ophthalmia. 37 Other associations with autoimmunity Gender Obesity Microbiome Sunlight and cutaneous lupus 38 39 Abbas’ Basic Immunology 6e Tolerance What can happen when a lymphocyte meets its antigen? – Proliferation and activation (an “immunogenic response”). – Functional inactivation of lymphocyte, or destruction of lymphocyte (an “tolerogenic response”). The choice between lymphocyte activation and tolerance is determined largely by the nature of the antigen and the additional signals present when the antigen is displayed to the immune system. There are two key processes for self tolerance: – Central tolerance: a process of lymphocyte exposure to self antigen in the central lymphoid organs, during lymphocyte development. – Peripheral tolerance: when mature lymphocytes encounter self antigens in peripheral lymphoid tissues. 40 Tolerance 41 The principal mechanisms of central tolerance in T cells are death of immature T cells and the generation of CD4 + regulatory T cells. A protein called AIRE (autoimmune regulator) is heavily involved: it causes thymic expression of many peripheral tissue antigens. AIRE mutations cause autoimmune polyendocrine syndrome (APS). 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. 42 Abbas’ Basic Immunology 6e 43 Abbas’ Basic Immunology 6e Abbas’ Basic Immunology 6e Recap We have covered today The four types of hypersensitivity. The pathogenesis of autoimmune disease. The mechanisms of tolerance. We did not cover Systemic versus organ specific immune disease. The details of any of the diseases mentioned. … all of this and more is coming in future lectures! [email protected] 46