Hypersensitivity reactions.doc

PAGE PAGE 11 Lecture notes: Hypersensitivity reactions Hypersensitivity The terms hypersensitivity and allergy refer to inappropriate immune responses that can have very damaging effects on the host. Immediate hypersensitivity Symptoms develop within minutes or hours after a sensitized individual encounters antigen. Initiated by antibody or antigen-antibody complexes. Delayed type hypersensitivity (DTH) Symptoms develop days after a sensitized individual encounters antigen. Initiated by sensitized T cells. Gell and Coombs classification Hypersensitivity reactions are divided into four types (Gell and Coombs classification scheme): Type I or IgE-mediated hypersensitivity Type II or antibody-mediated cytotoxic hypersensitivity Type III or immune complex-mediated hypersensitivity Type IV or cell-mediated/delayed type hypersensitivity Types I, II, and III are due to humoral immune mechanisms and are mediated by antibody or antigen-antibody complexes. They are thus forms of immediate hypersensitivity. Type IV is due to cell-mediated immune mechanisms, and is thus a form of delayed type hypersensitivity. The types of hypersensitivity reactions reflect different mechanisms, cells, and effector molecules. Type I or IgE-mediated hypersensitivity The characteristic feature of a type I hypersensitivity reaction is the inappropriate production of IgE in response to an antigen. The term allergen is used to refer to antigens capable of stimulating type I hypersensitivity in individuals. Tissue mast cells and blood basophils express a receptor that binds the Fc region of IgE with high affinity (Fc?RI). Mast cells are found throughout connective tissue, particularly near blood and lymphatic vessels. The skin and mucus surfaces of the respiratory and gastrointestinal tracts contain high concentrations of mast cells. Another IgE receptor with lower affinity (Fc?RII or CD23) is present on some other cell types, notably eosinophils. IgE produced in response to an allergen binds to Fc receptors on the surface of mast cells or basophils (and, less importantly, eosinophils). Re-exposure to the same antigen causes cross-linking of the membrane-bound IgE, resulting in (i) degranulation (release of the contents of granules stored in the cytoplasm), and (ii) synthesis and secretion of pharmacologically active substances such as leukotrienes and prostaglandins. Mast cell and basophil granules contain histamine (most importantly) as well as proteases and chemokines. Note that mast cell degranulation is also initiated by the anaphylatoxins C3a, C4a, and C5a, but this is more relevant in the context of other inflammatory processes. Pharmacologically active mediators produced by mast cells and basophils The effects of histamine are observed within minutes of degranulation. Histamine binds to receptors on target cells, resulting in (i) dilation and increased permeability of blood vessels, (ii) contraction of smooth muscle in the respiratory tract and gastrointestinal tract, and (iii) increased mucus secretion. The effects of leukotrienes and prostaglandins are similar to those of histamine, but they are more pronounced and longer lasting. Cytokines produced by activated mast cells contribute to later effects (hours) of type I hypersensitivity reactions. For example: IL-5 promotes eosinophil development (bone marrow) and maturation; TNF-? increases expression of CAMs on vascular endothelial cells. A consequence is a late-phase accumulation of neutrophils and eosinophils. Eosinophils also carry receptors for IgE, and allergen cross-linking leads to degranulation of eosinophils and the release of additional inflammatory mediators Clinical manifestations of type I hypersensitivity reactions The term anaphylaxis is used to describe type I hypersensitivity reactions (the opposite of prophylaxis). Anaphylaxis can be systemic or localized. Systemic anaphylaxis in susceptible individuals can be induced by various venoms (bee and wasp stings), drugs (penicillin), and foods (seafood, nuts). This often fatal condition results from systemic vasodilation and increased vascular permeability, and smooth muscle contraction. Localized anaphylaxis is restricted to specific target tissue, e.g. respiratory tract (asthma), gastrointestinal tract (food allergies). What makes an allergen? Individuals usually contact allergens at mucosal surfaces and in very low doses ? a situation that favors TH2 responses and IgE production. Most human allergy is caused by a small number of inhaled protein allergens. Most allergens are small, very soluble proteins that are carried on dried particles such as pollen grains and mite feces (thus, the allergen must be stable in the desiccated particle). On contact with the mucosa (e.g. the airways), the soluble allergen separates from the particle and diffuses into the mucosa. The major allergen in the feces of the house dust mite is a papain-like protease called Der p 1. This enzyme can cleave a component of the tight junctions between mucosal epithelial cells, and thus can readily pass through this barrier and enter the sub-epithelial tissue. Probably the most important factor in the development of type I hypersensitivity is the genetic makeup of the individual. The prevalence of asthma is increasing in economically advanced regions of the world. A current theory (the hygiene hypothesis) is that this is due to decreased exposure to various infectious diseases. Childhood infections that generate TH1 responses may reduce the likelihood of TH2 responses later in life. Type II or antibody-mediated cytotoxic hypersensitivity Type II hypersensitivity reactions involve antibody-mediated destruction of cells. This can occur in the following ways: Antibody binding to an antigen expressed on a cell can activate complement, resulting in cell lysis. Antibody binding to an antigen on a cell can mediate ADCC by cells with Fc receptors. Antibody binding to an antigen on a cell can serve as an opsonin, enabling phagocytosis of the cell by phagocytes with Fc receptors. Examples of type II hypersensitivity reactions are (i) transfusion reactions, and (ii) hemolytic disease of the newborn. Transfusion reactions Transfusion reactions are commonly associated with ABO blood group incompatibilities. Individuals may have the ?A? antigen on their RBCs (type A), the ?B? antigen (type B), both ?A? and ?B? antigens (type AB), or neither ?A? nor ?B? antigens (type O). The enzymes responsible for generating the ?A? antigen and the ?B? antigen (the ?A? enzyme and the ?B? enzyme, respectively) are encoded by alleles at a single genetic locus. Individuals with only the ?A? antigen on their RBCs may recognize ?B?-like epitopes on intestinal microorganisms and produce antibodies (usually IgM) against the ?B?-like epitopes. These antibodies, called isohemagglutinins, can bind to RBCs with the ?B? antigen. Of course, a type A individual would not produce antibodies against ?A?-like epitopes on intestinal microorganisms because these ?A?-like epitopes would be equivalent to self. If a type A individual is transfused with blood containing type B RBCs, a transfusion reaction occurs because anti-?B? isohemagglutinins bind to the ?B? RBCs, leading to the complement-mediated lysis of the transfused RBCs. Hemolytic disease of the newborn Hemolytic disease of the newborn most commonly develops when an Rh- mother (does not express the Rh antigen on RBCs) has an Rh+ fetus (expresses the Rh antigen on RBCs). During delivery, Rh+ RBCs from a fetus can enter an Rh- mother?s circulation, resulting in the production of Rh-specific plasma cells and memory B cells. In a subsequent pregnancy with an Rh+ fetus, small numbers of Rh+ RBCs entering the maternal circulation from the fetus are sufficient to activate the Rh-specific memory B cells in the mother. This generates Rh-specific IgG antibodies, which cross the placenta and damage the fetal RBCs. Hemolytic disease of the newborn can be prevented by giving an Rh- mother antibodies against the Rh antigen within 24-48 hours after the first delivery of an Rh+ fetus. These antibodies (called Rhogam) bind to any Rh+ fetal RBCs that enter the maternal circulation, resulting in clearance of the RBCs before Rh-specific B cells can be activated and memory B cells generated. Type III or immune complex-mediated hypersensitivity Type III hypersensitivity reactions develop when antibody and antigen combine to form immune complexes which deposit in tissues and generate inflammation. The inflammation results from activation of the classical complement pathway, with generation of anaphylatoxins C3a, C4a, and C5a, and the MAC. Anaphylatoxins cause mast cells to degranulate, leading to an influx of neutrophils and further tissue damage as the neutophils try to phagocytose C3b-coated immune complexes. Reactions can be localized when (for example) antigens are deposited in the skin (e.g. insect bite) or are inhaled into the lung. Formation of immune complexes in the bloodstream generates reactions wherever the immune complexes are deposited, which is usually in blood vessel walls (vasculitis), on the glomerular basement membrane of the kidney (glomerulonephritis), and in the synovial membranes of joints (arthritis). Note that C3b has a critical role in the removal on immune complexes, and a deficiency in C3b formation results in type III hypersensitivity reactions. Type IV or delayed type hypersensitivity DTH reactions are mediated by antigen-specific effector T cells. They can be either CD4+ TH cells or CD8+ TC cells, depending on the pathway by which antigen is processed. Most commonly, DTH reactions are mediated by CD4+ TH1 cells. DTH responses occur in individuals who carry effector and memory T cells generated by previous exposure to an antigen (i.e. sensitized T cells). It is important to appreciate that T cells participating in DTH responses are functioning in the same way as T cells participating in ?normal? immune responses. The tuberculin test or the PPD test The tuberculin test, or more recently the PPD test, generates a classic example of a DTH reaction when administered to individuals who have had previous exposure to Mycobacterium tuberculosis (either by infection with the organism or by vaccination with BCG, an attenuated form of M. tuberculosis). PPD (purified protein derivative; a protein derived from the cell wall of M. tuberculosis) is given intradermally, and previously sensitized individuals will develop a red, slightly swollen lesion at the site in 1-3 days. The sequence of events is as follows: (i) APCs at the injection site take up and process the antigen and present peptides in association with class II MHC molecules. (ii) Sensitized TH1 cells enter the site (some memory TH1 cells may already be present at the site) and are activated by peptide-class II MHC on the APC. (iii) The activated TH1 cells produce cytokines (especially IFN-? and TNF-?) and chemokines that activate the endothelium (increased CAM expression), attract macrophages, and activate macrophages. (iv) The products of activated macrophages amplify the response. The key features of a DTH reaction are (i) a delay before the reaction becomes apparent, and (ii) a cellular infiltrate consisting predominantly of macrophages. Note that the influx and activation of macrophages that is characteristic of a DTH response is a key element in defense against microorganisms that live inside host cells and out of the reach of antibodies. Activated macrophages release lytic enzymes in the area of infection, resulting in non-specific destruction of host cells and thus the destruction of intracellular pathogens. Contact sensitivity: a form of DTH Many forms of contact hypersensitivity, including responses to divalent metal cations (e.g. nickel), agents in cosmetics and hair dyes, and poison oak and poison ivy, are DTH reactions. Contact hypersensitivity is typically caused by small, highly-reactive molecules that penetrate the skin and bind to a variety of skin proteins. The resulting molecules are taken up by APCs in the skin, which present peptides modified by the contact-sensitizing agent in association with class II MHC molecules and activate CD4+ TH cells (endocytic processing pathway). Note that the activation/sensitization of TH cells that occurs on first exposure to the contact-sensitizing agent takes place in the draining lymph nodes and generates effector and memory TH1 cells. Re-exposure to the contact-sensitizing agent results in activation of effector and memory TH1 cells in the skin. T cell cytokines and chemokines are produced, resulting in the influx and activation of macrophages described above. The rash produced by contact with poison oak and poison ivy is due to a chemical in the leaf (pentadecacatechol compounds) that crosses the skin and forms a complex with skin proteins. This chemical can also cross cell membranes, bind to intracellular proteins, and give rise to modified peptides that are presented on class I MHC molecules (cytosolic processing pathway). As a result, CD8+ TC cells are activated that can kill host cells displaying modified peptide/class I MHC, and also produce cytokines and chemokines. Thus, the lesions associated with poison oak and poison ivy exposure are generated by sensitized TH1 cells and TC cells.