Hypersensitivity S23 Notes PDF

4/3/23 The Immune System Dr. Dalia Zakaria 1 Hypersensitivity Textbook : Chapter 11 2 1 4/3/23 Hypersensitivity and Autoimmunity Both hypersensitivity and autoimmunity are examples of overly aggressive immune system and can overlap However, hypersensitivity generally refers to when the immune system...

4/3/23 The Immune System Dr. Dalia Zakaria 1 Hypersensitivity Textbook : Chapter 11 2 1 4/3/23 Hypersensitivity and Autoimmunity Both hypersensitivity and autoimmunity are examples of overly aggressive immune system and can overlap However, hypersensitivity generally refers to when the immune system responds aggressively to a normally harmless antigen Autoimmunity generally refers to the immune response against self antigens 3 Types of Hypersensitivity Type I Immediate hypersensitivity (IgE) Type II Antibody against cell or tissue fixed antigen Type III Antibody against soluble antigen complex production of IgE antibody against environmental antigens and the binding of IgE to mast cells in various tissues followed by release of inflammatory mediators (classical allergy) Antibodies against cell or tissue antigens (not soluble immune complexes) can cause damage and activate the complement and ADCC Antibodies against soluble antigens may form immune complexes which may deposit in blood vessels in various tissues, causing inflammation and tissue injury Type IV T Cell Mediated Some diseases result from the reactions of T cells, often against self antigens in tissues 4 2 4/3/23 Immediate Hypersensitivity (Type I) Immediate hypersensitivity is an IgE antibody– and mast cell–mediated reaction to certain antigens that causes rapid vascular leakage and mucosal secretions, often followed by inflammation Such disorders are also called allergy, or atopy, and individuals with a propensity to develop these reactions are said to be atopic Common types of allergies include hay fever, food allergies, bronchial asthma, and anaphylaxis 5 Steps of Immediate Hypersensitivity (Type I) Activation of Th2 cell and production of IgE antibody Immediate hypersensitivity develops as a consequence of the activation of Th2 cells in response to protein antigens or chemicals that bind to proteins. Two of the cytokines secreted by Th2 cells or by Tfh cells activated by the same antigen are IL-4 and IL-13 which stimulate B lymphocytes to switch to IgE-producing plasma cells. Therefore, atopic individuals produce large amounts of IgE antibody in response to antigens that do not elicit IgE responses in other people Activation of mast cells and secretion of mediators Thus, in an atopic individual, mast cells are coated with IgE antibody specific for the antigen(s) to which the individual is allergic. This process of coating mast cells with IgE is called sensitization, because coating with IgE specific for an antigen makes the mast cells sensitive to activation by subsequent encounter with that antigen. In normal individuals, by contrast, mast cells may carry IgE molecules of many different specificities 6 3 4/3/23 Steps of Immediate Hypersensitivity (Type I) Mast cell activation results from binding of the allergen to two or more IgE antibodies on the cell. FcεRI molecules that are carrying the IgE are cross-linked, triggering biochemical signals which lead to: 1. Rapid release of granule contents (degranulation) 2. Synthesis and secretion of lipid mediators 3. Synthesis and secretion of cytokines 7 How are mast cells activated by the allergen? 8 4 4/3/23 Role of Innate Immunity in Type I Hypersensitivity The innate immune system consists of multiple cell types that express PRRs Allergens are frequently found in forms and mixtures that contain PAMPs and DAMPs The innate immune system is interposed between the external environment and the internal acquired immune system. It is also an integral part of the airways, gut, and skin. These tissues face continuous exposure to allergens, PAMPs, and DAMPs Interaction of allergens with the innate immune system normally results in immune tolerance but, in the case of allergic disease, this interaction induces recurring and/or chronic inflammation as well as the loss of immunologic tolerance 9 Type I Hypersensitivity Exposure to the allergen and activation of Th2 cells and stimulation of IgE class switching IgE antibodies (specific to the allergen) bind to the high affinity FcεR1 on mast cells Cytokines produced by mast cells and by epithelial cells in the tissues also contribute to leukocyte recruitment Eosinophils and neutrophils liberate proteases, which cause tissue damage, and Th2 cells may exacerbate the reaction by producing more cytokines 10 5 4/3/23 Immediate Hypersensitivity (Type I) The sequence of events in the development of immediate hypersensitivity reactions begins with the activation of Th2 and IL-4–secreting follicular helper T (Tfh) cells, which stimulate the production of IgE antibodies in response to an antigen, binding of the IgE to specific Fc receptors of mast cells, then on subsequent exposure to the antigen, cross-linking of the bound IgE by the antigen, and release of mast cell mediators Some mast cell mediators cause a rapid increase in vascular permeability and smooth muscle contraction, which may occur within minutes of reintroduction of antigen into a previously sensitized individual, hence the name immediate hypersensitivity Other mast cell mediators are cytokines that recruit neutrophils and eosinophils to the site of the reaction over several hours. This inflammatory component is called the late-phase reaction, and it is mainly responsible for the tissue injury that results from repeated bouts of immediate hypersensitivity 11 Late Hypersensitivity (type I) Eosinophils and neutrophils liberate proteases, which cause tissue damage Eosinophils are prominent components of many allergic reactions and are an important cause of tissue injury in these reactions These cells are activated by the cytokine IL-5, which is produced by Th2 cells, innate lymphoid cells, and mast cells Although basophils present in blood circulation can contribute to type I hypersensitivity, by far the most implicated cell type is the tissue mast cell Both mast cells and basophils possess the high affinity IgE receptor FcεR1 Binding to these receptors greatly increases the half-life of the IgE from 2 days to approximately 2 weeks when attached to these cells 12 6 4/3/23 Steps of Type I Hypersensitivity Interaction of allergens with the innate immune system (PAMP/PRR binding) Activation of Th2 and IL-4–secreting follicular helper T (Tfh) cells Production of IgE antibodies specific for the allergen IgE bind to high affinity FcεR1 of mast cells which prolong the life span of IgE to weeks (Sensitization) On subsequent exposure to the antigen, cross-linking of the bound IgE by the antigen Release of mast cell mediators (primary inflammatory mediators) (Immediate Response) Recruitment and activation of Th2 response and recruitment of more eosinophils and neutrophils which release tissue damaging chemicals (Late Response) 13 Clinical Syndromes Hay Fever Food allergies Bronchial asthma Anaphylaxis 14 7 4/3/23 Clinical Syndromes 15 Hay Fever Inhaled allergens such as a protein of ragweed pollen causes rhinitis and sinusitis Mast cells in the nasal mucosa produce histamine, and Th2 cells produce IL-13, and these two mediators cause increased production of mucus Late-phase reactions may lead to more prolonged inflammation 16 8 4/3/23 Food Allergy Food allergy is defined as an immune-mediated adverse reaction to food. This definition includes IgE-mediated immediate hypersensitivity reactions, delayed non-IgE-mediated reactions, and disorders with contributions from both IgE-mediated and non-IgE-mediated immune pathways 17 Bronchial Asthma Inhaled allergens (often undefined) stimulate bronchial mast cells to release mediators, including leukotrienes, which cause repeated bouts of bronchial constriction and airway obstruction In chronic asthma, large numbers of eosinophils accumulate in the bronchial mucosa, excessive secretion of mucus occurs in the airways, and the bronchial smooth muscle becomes hypertrophied and hyperreactive to various stimuli 18 9 4/3/23 Anaphylaxis A systemic reaction characterized by edema in many tissues, including the larynx, accompanied by a fall in blood pressure and bronchoconstriction It is the most severe form of immediate hypersensitivity Some of the most frequent inducers of anaphylaxis include bee stings, injected or ingested penicillin-family antibiotics, and ingested nuts or shellfish The reaction is caused by widespread mast cell degranulation in response to the systemic distribution of the antigen It is life threatening because of the sudden fall in blood pressure and airway obstruction 19 Therapy 20 10 4/3/23 What is the difference between type II and type III hypersensitivity? Type II = Antibody-cell or tissue attached antigen complex Antibodies are specific for tissue or cell antigens which activates an immune response against tissue/cells Type III = Soluble (circulating immune complexes) Antibodies could be specific for foreign antigens making circulating immune complexes. If the immune complexes for any reason are not efficiently cleared, they may deposit in blood vessels or other tissues leading to tissue damage and release of autoantigens followed by the generation of autoantibodies 21 Diseases Caused by Antibodies and Antigen-Antibody Complexes Type II Antibody-cell or tissue fixed antigen Triggered by chemical modification of cell surface antigens generating foreign epitopes Antibodies against cells or extracellular matrix components may deposit in any tissue that expresses the relevant target antigen Diseases caused by such antibodies usually are specific for a particular tissue Type III Antibody- soluble antigen complex (immune complex) Immune complexes often deposit in blood vessels, including vessels through which plasma is filtered at high pressure (e.g., in renal glomeruli and joint synovium) Therefore, immune complex diseases tend to be systemic and often manifest as widespread vasculitis, arthritis, and nephritis 22 11 4/3/23 Antibody-Antigen (Cell Attached) Mediated Hypersensitivity (Type II) 23 Mechanism of Tissue Injury and Disease in Type II Hypersensitivity Inflammation complement activation Opsonization and phagocytosis Antibody Dependent Cytotoxicity (ADCC) Abnormal cellular responses 24 12 4/3/23 Inflammation Antibodies against tissue antigens induce inflammation by attracting and activating leukocytes. IgG antibodies bind to neutrophil and macrophage Fc receptors and activate them causing inflammation IgG and IgM, activate the complement system by the classical pathway and induce inflammation. When leukocytes are activated at sites of antibody deposition, these cells release ROS and lysosomal enzymes that damage the adjacent tissues 25 Inflammation and Complement Activation 26 13 4/3/23 Opsonization and Phagocytosis If antibodies bind to cells, such as erythrocytes and platelets, the cells are opsonized and may be ingested and destroyed by host phagocytes In addition to Antibody Dependent Cytotoxicity (ADCC) 27 Abnormal Cellular Responses Some antibodies may cause disease without directly inducing tissue injury For example, antibodies against hormone receptors may inhibit receptor function In some cases of myasthenia gravis, antibodies against the acetylcholine receptor inhibit neuromuscular transmission, causing paralysis Other antibodies may directly activate receptors, mimicking their physiologic ligands In a form of hyperthyroidism called Graves disease, antibodies against the receptor for thyroid-stimulating hormone stimulate thyroid cells even in the absence of the hormone 28 14 4/3/23 Abnormal Cellular Responses Graves disease Myasthenia Graves 29 Good Pasture Syndrome Goodpasture syndrome (GPS) is a rare autoimmune disease in which antibodies attack the basement membrane in lungs and kidneys, leading to bleeding from the lungs and kidney failure The bright green colour shows the location of anti glomerular basement membrane (GBM) antibodies bound to the GBM of a glomerulous 30 15 4/3/23 Hemolysis and Type II Hypersensitivity Hemolytic reactions against ABO blood groups and Rhesus (Rh) factor incompatibility could be also classified as Type II Hypersensitivity (will be discussed later) Hypersensitivity to penicillin (type II) may lead to hemolysis 31 Penicillin Type II Hypersensitivity Penicillin may modify proteins on red blood cells Activation of immune responses against the modified antigen including complement activation and production of IgG antibodies Hemolysis 32 16 4/3/23 Type II 33 Antibody-Antigen (Soluble Immune Complex) Mediated Hypersensitivity (Type III) 34 17 4/3/23 Mechanism of Tissue Injury and Disease in Type III Hypersensitivity Antibodies against immune complexes deposited in vessels induce inflammation by attracting and activating leukocytes. IgG antibodies bind to neutrophil and macrophage Fc receptors and activate them causing inflammation IgG and IgM, activate the complement system by the classical pathway and induce inflammation. When leukocytes are activated at sites of antibody deposition, these cells release ROS and lysosomal enzymes that damage the adjacent tissues 35 Type III 36 18 4/3/23 Intermolecular Epitope Spreading Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by IgG antibodies specific for a wide range of self antigens present in numerous cells of the body. These include constituents of cell surfaces, cytoplasm and nucleus including nucleic acids and nucleoprotein particles This broad and destructive antibody response develops gradually by a general process of epitope spreading due to the expansion of the cellular constituents that become autoantigens Exposure to sunlight is a trigger for the development of SLE in which autoantibodies are produced against self nucleic acids and nucleoproteins. It is postulated that these nuclear antigens may be released from cells that die by apoptosis as a consequence of exposure to ultraviolet radiation in sunlight 37 Systemic Lupus Erythematosus (SLE) SLE is a complex disease in which genetic and environmental factors contribute to a breakdown of tolerance in self-reactive B and T lymphocytes. Among the genetic factors is the inheritance of particular HLA alleles Genetic deficiencies of classical pathway complement proteins, especially C1q, C2, or C4, are seen in about 5% of patients with SLE The complement deficiencies may result in defective clearance of immune complexes and apoptotic cells and the failure of B cell tolerance Studies including animal models have shown that UV irradiation and other environmental insults lead to the apoptosis of cells and release of nuclear antigens Inadequate clearance of the nuclei of these cells, in part because of defects in clearance mechanisms such as complement protein, results in a large burden of nuclear antigens Polymorphisms in various susceptibility genes for lupus lead to defective ability to maintain self-tolerance in B and T lymphocytes, because of which self-reactive lymphocytes remain functional Failure of B cell tolerance may be due to defects in receptor editing or in deletion of immature B cells in the bone marrow or in peripheral tolerance Self-reactive B cells that are not rendered tolerant are stimulated by the self nuclear antigens, and antibodies are produced against the antigens 38 19 4/3/23 Serum Sickness vs Arthus Reaction (Type III Hypersensitivity) Systemic reaction sickness) Localized reaction (Arthus reaction) (Serum Serum sickness, seen in subjects who repeatedly received animal serum for the treatment of infections. Serum sickness is induced by systemic administration of a protein antigen, which elicits an antibody response and leads to the formation of circulating immune complexes Arthus reaction is induced by subcutaneous administration of a protein antigen to a previously immunized animal; it results in the formation of immune complexes at the site of antigen injection and a local vasculitis In a small percentage of vaccine recipients who have previously been vaccinated or already have antibodies against the vaccine antigen, a painful swelling that develops at the injection site represents a clinically relevant Arthus reaction 39 Etiology of Antibody Mediated Diseases (Type II and Type III) Two of the best-described diseases caused by antibodies produced against microbial antigens are rare, late consequences of streptococcal infections After such infections, some individuals produce antistreptococcal antibodies that cross-react with an antigen in heart tissues Deposition of these antibodies in the heart triggers an inflammatory disease called rheumatic fever, which can lead to acute heart failure or slow scarring of valves and lateonset heart failure Other individuals make antistreptococcal antibodies that deposit in kidney glomeruli, causing an inflammatory process called poststreptococcal glomerulonephritis that can lead to renal failure 40 20 4/3/23 Streptococcal Infection May Lead to Type II or Type III Hypersensitivity Rheumatic fever(Type II) Vasculitis, arthritis, or nephritis (Type III) Antistreptococcal antibodies that cross-react with an antigen in heart tissues Deposition of these antibodies in the heart triggers an inflammatory disease called rheumatic fever, which can lead to acute heart failure or slow scarring of valves and late-onset heart failure Immune complexes may deposit in blood vessels, including vessels through which plasma is filtered at high pressure (e.g., in renal glomeruli and joint synovium) Therefore, immune complex diseases tend to be systemic and often manifest as widespread vasculitis, arthritis, and nephritis 41 Therapy Therapy for antibody-mediated diseases is intended mainly to limit inflammation using corticosteroids Some of these diseases respond well to treatment with intravenous IgG (IVIG) pooled from healthy donors How IVIG works is not known It may induce the expression of and bind to the inhibitory Fc receptor on myeloid cells and B cells or It may reduce the half-life of pathogenic antibodies by competing for binding to the neonatal Fc receptor in endothelial and other cells 42 21 4/3/23 Therapy One approach is the production of autoantibodies include treating patients with antibodies that block CD40 or its ligand and thus inhibit helper T cell–dependent B cell activation and antibodies to block cytokines that promote the survival of B cells and plasma cells 43 T Cell Mediated Hypersensitivity (Type IV) The major causes of T cell–mediated hypersensitivity reactions are autoimmunity and exaggerated or persistent responses to environmental antigens T cell–mediated autoimmune diseases are limited to a few organs and usually are not systemic Examples of T cell–mediated hypersensitivity reactions against environmental antigens include contact sensitivity to chemicals In tuberculosis, a T cell–mediated immune response develops against protein antigens of Mycobacterium tuberculosis, and the response becomes chronic because the infection is difficult to eradicate. The resultant granulomatous inflammation causes injury to normal tissues at the site of infection 44 22 4/3/23 Mechanisms of Tissue Injuries by T Lymphocytes Inflammation induced by cytokines that are produced mainly by CD4+ T cells CD4+ T cells may react against cell or tissue antigens and secrete cytokines that induce local inflammation and activate macrophages Different diseases may be associated with activation of Th1 (source of IFN-γ) and Th17 cells (recruit neutrophils) The actual tissue injury in these diseases is caused mainly by the macrophages and neutrophils Killing of host cells by CD8+ CTLs OR CD8+ T cells specific for antigens on host cells may directly kill these cells CD8+ T cells also produce cytokines that induce inflammation In many T cell–mediated autoimmune diseases, both CD4+ T cells and CD8+ T cells specific for self antigens are present, and both contribute to tissue injury 45 Mechanisms of Tissue Injuries by T Lymphocytes 46 23 4/3/23 Delayed Type Hypersensitivity (DTH) It occurs 24 to 48 hours after an individual previously exposed to a protein antigen is challenged with the antigen The delay occurs because it takes several hours for circulating effector T lymphocytes to home to the site of antigen challenge and secrete cytokines that induce a detectable reaction DTH reactions are manifested by infiltrates of T cells in the tissues, edema caused by increased vascular permeability in response to cytokines produced by CD4+ T cells DTH reactions are used to determine if people have been previously exposed to and have responded to an antigen. For example, a DTH reaction to a mycobacterial antigen, PPD (purified protein derivative), is an indicator of a T cell response to the mycobacteria 47 Clinical Syndromes Many organ-specific autoimmune diseases in humans are believed to be caused by T cells These disorders typically are chronic and progressive Tissue injury causes release and alteration of self proteins, which may result in reactions against these newly encountered proteins (epitope spreading) The initial immune response against one or a few self antigen epitopes may expand to include responses against many more self antigens 48 24 4/3/23 Clinical Syndromes 49 Super Antigens (Type IV Hypersensitivity) Excessive polyclonal T cell activation by certain microbial toxins (superantigens) can lead to production of large amounts of inflammatory cytokines, causing a syndrome similar to septic shock Superantigens bind to invariant parts of T cell receptors on many different clones of T cells, regardless of antigen specificity, thereby activating these cells Normal Antigen Super Antigen 50 25 4/3/23 Therapy Anti-inflammatory steroids are efficient, but these drugs have significant side effects Antagonists of TNF-α have proved to be beneficial in patients with rheumatoid arthritis and inflammatory bowel disease by reducing inflammation Newer agents developed to inhibit T cell responses include drugs that block costimulators such as B7, and antagonists against cytokines or their receptors such as IL-1, IL-6, and IL-17 51 Summary 52 26