Hypersensitivity Reactions Notes (VETS2007) PDF

HYPERSENSITIVITY REACTIONS VETS2007 Chiara Palmieri ([email protected]) A hypersensitivity reaction is defined as the altered reactivity to a specific antigen that results in pathological reactions upon the exposure of a sensitised host to that specific antigen. The designation of these immune r...

HYPERSENSITIVITY REACTIONS VETS2007 Chiara Palmieri ([email protected]) A hypersensitivity reaction is defined as the altered reactivity to a specific antigen that results in pathological reactions upon the exposure of a sensitised host to that specific antigen. The designation of these immune responses as “hyper” is somewhat of a misnomer because the reactions elicited are better characterised as inappropriate or misdirected responses. It should be emphasised that the mechanisms underlying hypersensitivity reactions are the same as those normally employed by the body in combating infections, the problem if that they are occurring with much too high an intensity, are directed against antigens that pose no threat and/or are taking place at locations in the body that are inappropriate. Therefore, if the immune response is beneficial, it is immunity; if it is harmful, it is hypersensitivity. All hypersensitivity reactions are characterised by sensitisation and effector phases. The sensitisation phase requires that the host must have had either a previous exposure or a prolonged exposure to the antigen so that he or she can develop an immune response to the inciting agent. The pathology associated with hypersensitivity occurs in the effector phase and is most commonly manifested as an inflammatory reaction or as cell lysis. Hypersensitivity reactions have historically been classified (Gell and Coombs classification) on the basis of the immunological mechanisms that mediate the disease in: 1) Type I (immediate): result of an IgE response directed against an environmental or exogenous antigen (also known as allergen). The result is the release of vasoactive mediators from IgE-sensitised mast cells, and these mediators produce an acute inflammatory response. Can be systemic (e.g. anaphylaxis) or localised (e.g. allergic dermatitis). 2) Type 2 (cytotoxic): occurs when IgG or IgM is directed against either an altered self-protein or a foreign antigen bound to a tissue or a cell. The results can lead to either destruction of the tissue or cell by ADCC, complement-mediated lysis, or altered cellular function without evidence of tissue or cell damage. 3) Type 3 (immune complex): due to the formation of insoluble antibody-antigen complexes. This results in activation of the complement system and the development of an inflammatory reaction at the sites of immune complex deposition. 4) Type 4 (delayed-type): result of activation of sensitised T lymphocytes to a specific antigen. The resulting immune response is either mediated by direct cytotoxicity or by the release of cytokines that act primarily through macrophages to produce chronic inflammation. Few prototype disorders of each type of hypersensitivity reaction in the table below: Type Type I Type II Type III Type IV Prototype disorder Anaphylaxis, allergies Autoimmune haemolytic anaemia; neonatal isoerythrolysis; transfusion reactions; drug reactions; pemphigus Systemic lupus erythematosus; some forms of glomerulonephritis; Arthus reaction Contact dermatitis; transplant rejection; tuberculosis; chronic allergic diseases TYPE I HYPERSENSITIVITY Type I reactions are most commonly the results of an IgE-mediated immune response directed against environmental antigens (e.g. allergens). It occurs in a previously sensitised host and is initially manifested as acute inflammatory process that occurs within minutes of exposure. The basic pathogenesis involves: 1) a sensitisation phase: occurs during the initial exposure to an antigen when the host develops an antigen-specific IgE response, which results in sensitisation of the host by the binding of the antigen-specific IgE to FCε receptors on the surface of mast cells 2) an effector phase: either through a second exposure or prolonged initial exposure to the IgEspecific antigen, there is cross-linking of 2 or more IgE molecules on the surface of the mast cells. This results in their activation and release of preformed and newly synthesised mediators. This phase can be limited to an acute inflammatory reaction (over a period of hours; characterised by responses associated with release of preformed vasoactive amines from mast cell and includes increased vascular permeability, smooth muscle contraction and influx of inflammatory cells) or can progress to a late-phase reaction (over a period of hours), or to a chronic reaction (persisting for days to years), both resulting from a more intense inflammatory cell infiltration (eosinophils, neutrophils, macrophages, T lymphocytes) and tissue damage. MAST CELLS and EOSINOPHILS Mast cells are a heterogeneous population of bone-marrow granulated cells. They can be divided into mucosal and connective tissue subpopulations and are primarily found adjacent to blood vessels and nerves where their mediators have their greatest influence. Mast cell activation can occur through a number of IgE-mediated and non-IgE-mediated mechanisms: a. IgE-Mediated (type I hypersensitivity)= cross-linking of membrane-bound IgE by antigen b. Non-IgE-mediated (anaphylactoid reaction): cytokines (IL8), complement products (C3a, C5a), drugs (codein, morphine), physical stimuli (heat, cold, trauma). Mediators released by mast cells are broadly classified as:   Preformed (primary): - stored in cytoplasmic granules - vasoactive amines (histamine, serotonin, adenosine); chemotactic factors for eosinophils and neutrophils; enzymes; proteoglycans (heparin, chondroitin sulfates) Newly synthesised (secondary): - arachidonic acid metabolites, especially PGD2 and LTC4, D4, E4 - cytokines: IL4 (B lymphocyte activation and IgE synthesis), IL5 (chemotactic for eosinophils), IL6, TNFα (pathogenesis of shock during a systemic anaphylactic reaction) - platelet-activating factor (PAF) (increased vasodilation and vascular permeability, recruitment and activation of inflammatory cells) The immediate response is characterised by increased blood flow, increased vascular permeability and smooth muscle spasm. As the reaction progresses, additional leukocytes are recruited and they sustain the inflammatory response and cause cell damage. One of these leukocytes, eosinophil, is particularly important. Eosinophils are recruited to the sites of type I hypersensitivity reactions by chemokines, such as eotaxin and IL5. They release: - - components of their granules (e.g. eosinophilic major basic protein, that is toxic not only to parasites but also normal cells and therefore contribute to the epithelial cells damage associated with chronic type I reactions) lipid mediators (e.g. PAF, leukotrienes) cytokines The factors that determine whether a host will develop a type I hypersensitivity reaction are complex. The genetic makeup of the host and the dose and route of antigen exposure are most important. These factors influence whether the individual will have Th1 or Th2 response. The development of an IgE-secreting B lymphocyte from an immature B lymphocyte depends on activated CD4+ lymphocytes of the Th2 type. The cytokines that define a Th2-lymphocyte response have important roles in regulating the cells involved in a type 1 hypersensitivity reaction: IL3, IL4 and IL10 influence mast cell production; IL4 is involved in isotype switching to IgE; IL3 and IL5 influence eosinophil maturation and activation. The major cytokine that defines a Th1 response, IFNγ, inhibits the Th2 response. Thus an animal that develops predominantly a Th2 response to a particular antigen would be more likely to develop a type I hypersensitivity reaction as compared with one that develops predominantly a Th1 response. In humans, additional genetic influences can be linked to the human leukocyte antigen (HLA)-linked immune response genes. These genes appear to control allergen-specific IgE responses. The association of specific class I MHC molecules with an increased susceptibility to atopy (genetic predisposition to develop localised type I hypersensitivity reactions to innocuous antigens) in the dog has been proposed. Systemic type I hypersensitivity (anaphylaxis) This refers to an acute systemic hypersensitivity reaction to an antigen that is mediated by IgE and involved mast cells activation, resulting in a shock-like state often involving multiple organ systems. The clinical signs and pathology vary by species and often correlate to the primary shock organ in its most severe manifestation – death. The primary target tissues are blood vessels and smooth muscle. Fatal anaphylaxis may occur as a result of asphyxiation secondary to oedema of the upper airway, circulatory failure as a result of dilation of the splanchnic vascular bed or hypoxaemia as a result of sever bronchospasm. The specie most sensitive to the development of anaphylaxis is the guinea pig. The most common pathologic findings in most species are pulmonary oedema and emphysema, except for dogs, for which the major shock organ is the liver, and severe hepatic congestion and visceral haemorrhage are the most common finding. The types of antigens that can elicit a systemic anaphylactic reaction are diverse, but most commonly include drugs (especially penicillin-based antibiotics), vaccines, venom of stinging insects, and heterologous sera. Localised type I hypersensitivity In this case, the clinical signs and pathological findings are restricted to a specific tissue or organ. Localised reactions most commonly occur at epithelial surfaces such as skin, respiratory tract and gastrointestinal tract. Few examples: - allergic dermatitis, mostly in small animals (e.g. food allergy, flea bites…) allergic rhinitis, mostly in ruminants (e.g. grass and weed pollens, mold spores) TYPE II HYPERSENSITIVITY (cytotoxic hypersensitivity) This type of hypersensitivity most often occurs as the result of the development of antibodies directed against antigens on the surface of a cell or in a tissue, with the result that the cell or tissue is destroyed. Antigen may be either endogenous (normal cell or tissue protein) or exogenous (e.g. a drug or microbial protein adsorbed to the cell). In some instances, the antigen may be a cell surface receptor and the antibody may activate or block the activation of the cell rather than cause the cytotoxicity (this is the pathogenesis of many immune-mediated and autoimmune diseases). The largest group of cytotoxic hypersensitivity reactions involves the haematologic disorders with antibodies directed against antigens present on the surface of red blood cells or platelets. Type II hypersensitivity reactions most frequently involve IgM and IgG and occur within hours after exposure in a sensitised host. There are three basic antibody-mediated mechanisms that result in type II hypersensitivity: 1) opsonisation and phagocytosis: phagocytosis is largely responsible for depletion of cells coated with antibodies. Cells opsonised by IgG antibodies are recognised by phagocyte Fc receptors. In addition, when IgM or IgG antibodies are deposited on the surfaces of cells, they may activate the complement system by the classical pathway. Complement activation generates by-products, mainly C3b and C4b, which are deposited on the surfaces of the cells and recognised by phagocytes that express receptors for these proteins. The net result is phagocytosis of the opsonised cells and their destruction. Complement activation on cells also leads to the formation of the membrane attack complex, which disrupts membrane integrity and cause osmotic lysis of the cells. 2) complement and Fc receptor-mediated inflammation: when antibodies deposit in fixed tissues, such as basement membranes and extracellular matrix, the resultant injury is due to inflammation. The deposited antibodies activate complement, generating by-products, including chemotactic agents, which direct the migration of polymorphonuclear leukocytes and monocytes, and anaphylotoxins which increase vascular permeability. This results in the production of other substances that damage tissues. Antibody-mediated inflammation is the mechanism responsible for tissue injury in some forms of glomerulonephritis or pemphigus disease. 3) antibody-mediated cellular dysfunction: antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation. For example, in myasthenia gravis, antibodies reactive with acetylcholine receptors in the motor end plates of skeletal muscle block neuromuscular transmission and therefore cause muscle weakness. Examples of diseases with a primary type II hypersensitivity pathogenesis: Disease Target Antigen Mechanisms of Disease Clinicopathological Manifestations Autoimmune haemolytic anaemia Erythrocyte membrane Opsonisation and proteins (blood group phagocytosis of antigens) erythrocytes Haemolysis, anaemia Neonatal isoerythrolysis Erythrocyte membrane Opsonisation and proteins (blood group phagocytosis of antigens) erythrocytes Haemolysis, anaemia Pemphigus diseases Proteins in intercellular junctions of epidermal cells (e.g., the epidermal cadherin desmoglein 1) Antibody-mediated activation of Vesiculobullous proteases, disruption (diseases of the skin) of intercellular adhesions Acetylcholine receptor Antibody inhibits acetylcholine binding, Muscle weakness, down-modulates paralysis receptors Myasthenia gravis TYPE III HYPERSENSITIVITY (immune complex hypersensitivity) This reaction occurs through the formation of antigen-antibody complexes that activate complement and result in tissue damage. The cell or tissue injury is similar to type II hypersensitivity reaction, although the underlying pathogenesis is different. Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition. The pathologic reaction is usually initiated when antigen combines with antibody in the circulation, creating immune complexes that typically deposit in different tissues. Less frequently, the complexes may be formed at sites where antigen has been “planted” previously (called in situ immune complexes). The two primary cells involved in a type III reaction are FCR-bearing neutrophils and macrophages. Complement activation leads to the elaboration of factors that are chemotactic and attract neutrophils and macrophages to the site. These cells are activated and produce a number of proinflammatory cytokines. Early in the response, these cells release vasoactive amines that cause increased vascular permeability allowing the immune complexes to lodge within the vessel wall. Phagocytic cells are also stimulated to release their proteolytic enzymes and toxic free radicals, and these processes result in tissue and vascular damage. Antigen-antibody complexes form as a part of a normal immune response and usually facilitate the clearance of antigen by the phagocytic system without resulting in a type III hypersensitivity reaction. The factors determining whether a type III reaction will occur are:   the relationship of the antibody response to the quantity of antigen: when antibody is in great excess of antigen, the antigen-antibody complexes formed are large and insoluble, and easily removed by the phagocytic system. The most pathogenic complexes are of small or intermediate size (formed in slight antigen excess), which bind to phagocytic cells with less avidity and circulate longer. The activity of the phagocytic system: in some instances immune complex hypersensitivity may be the result of the normal phagocytic system being overwhelmed. Immune complex deposition may be localised to a tissue or generalised if the complexes are formed in circulation. Blood vessels, synovial membranes, glomeruli and the choroid plexus are particularly vulnerable to deposition of immune complexes. Diseases associated with type III hypersensitivity reactions ate most commonly associated with a single exposure to a large quantity of antigen (e.g. immune response to systemic infections) or from continuous exposure to small quantities of antigen as in the case of autoimmune disease. In either of these instances, the development of type III hypersensitivity depends on antigen in excess of antibody. A majority of diseases involving type III hypersensitivity reaction are the result of persistent infections, autoimmune disease or inhalation of foreign antigens. Few examples are systemic lupus erythematosus, hypersensitivity pneumonia due to fungal spore inhalation, rheumatoid arthritis, equine infectious anaemia. TYPE IV HYPERSENSITIVITY (delayed-type) This reaction is also known as cell-mediated hypersensitivity because it is the result of the interaction of T lymphocytes and the specific antigen to which they have been sensitised. The hypersensitivity lesion results from an exaggerated interaction between antigen and the normal cell-mediated immune mechanisms. The resulting immune response is mediated either by direct cytotoxicity by CD8+ lymphocytes or by the release of soluble cytokines from CD4+ lymphocytes, which act through mediator cells (mainly macrophages) to produce chronic inflammatory reactions. Because these responses are dependent on sensitised T lymphocytes and require 24 to 48 hours to develop, they are also referred as delayed-type hypersensivity (DTH). Unlike type I, II and III, type IV hypersensitivity is not dependent on antibody. DTH mediated by CD4+ lymphocytes The prototypical reaction is the localised tuberculin response, which is produced by the intracutaneous injection of purified protein derivative (PPD, also called tuberculin), a proteincontaining antigen of the tubercle bacillus. In a previously sensitised individual, reddening and induration of the site appear in 8 to 12 hours, reach a peak in 24 to 72 hours and slowly subside. The inflammatory reactions stimulated by CD4+ T cells can be divided into sequential stages. 1) activation of CD4+ T cells (sensitisation stage): naïve CD4+ T cells recognise peptides displayed by dendritic cells and secrete IL2, which functions as an autocrine growth factors to stimulate proliferation of antigen-responsive T cells. At the time of T-cell activation, APCs produce IL12, which induces differentiation of CD4+ T cells to the Th1 subset. 2) responses of differentiated effector T cells (effector stage): upon prolonged or repeat exposure to an antigen, th1 cells secrete cytokines, mainly IFN-γ, activating macrophages (classically activated macrophages). Activated macrophages serve to eliminate the offending antigen; if the activation is sustained, continued inflammation and tissue injury result. Another example of type IV hypersensitivity reaction is contact allergy in man and other animals. In this disease there is topical sensitisation to an allergen and re-exposure leads to an inappropriate inflammatory response at the cutaneous site of challenge. DTH mediated by cytotoxic T lymphocytes This response is most commonly associated with viral infections, although in humans tissue destruction by CTLs may be an important component of some T cell-mediated diseases, such as type 1 1 diabetes. CD8+ T lymphocytes, bearing viral antigen-specific TCRs, kill antigen-expressing target cells by apoptosis. The two principal mechanisms of CTL-mediated apoptosis are (1) the directional delivery of cytotoxic proteins and (2) the interaction of membrane-bound Fas ligand on the CTL with the Fas receptor on the target cell. Perforins and granzymes are preformed cytotoxic proteins contained in the granules of CTL. Perforin forms pores in the plasma membrane of the target cell, not only causing lysis but also permitting the delivery of granzymes. Granzymes activates caspases, ultimately resulting in apoptotic cell death.