Hypersensitivity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... BOOK CHAPTER Hypersensitivity Abul K. Abbas MBBS, Andrew H. Lichtman MD, PhD and Shiv Pillai MBBS, PhD Basic Immunology: Functions and Disorders of the Immune System, Chapter 11, 231-247 The concept that the immune system is required for defending the host against infections has been emphasized throughout this book. However, immune responses are themselves capable of causing tissue injury and disease. Injurious, or pathologic, immune reactions are called hypersensitivity reactions. An immune response to an antigen may result in sensitivity to challenge with that antigen, and therefore hypersensitivity is a reflection of excessive or aberrant immune responses. Hypersensitivity reactions may occur in two situations. First, responses to foreign antigens (microbes and noninfectious environmental antigens) may cause tissue injury, especially if the reactions are repetitious or poorly controlled. Second, the immune responses may be directed against self (autologous) antigens, as a result of the failure of self-tolerance (see Chapter 9 ). Responses against self antigens are termed autoimmunity, and disorders caused by such responses are called autoimmune diseases. This chapter describes the important features of hypersensitivity reactions and the resulting diseases, focusing on their pathogenesis. Their clinicopathologic features are described only briefly and can be found in other medical textbooks. The following questions are addressed: • What are the mechanisms of different types of hypersensitivity reactions? • What are the major clinical and pathologic features of diseases caused by these reactions, and what principles underlie treatment of such diseases? Types of Hypersensitivity Reactions Hypersensitivity reactions are classified on the basis of the principal immunologic mechanism that is responsible for tissue injury and disease ( Fig. 11-1 (f0010) ). We prefer the more informative descriptive designations rather than numeric terms, so these descriptors are used 1 of 22 9/21/16, 2:05 PM Hypersensitivity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... throughout this chapter. • Immediate hypersensitivity, or type I hypersensitivity, is a type of pathologic reaction that is caused by the release of mediators from mast cells. This reaction most often depends on the production of immunoglobulin E (IgE) antibody against environmental antigens and the binding of IgE to mast cells in various tissues. • Antibodies other than IgE that are directed against cell or tissue antigens can damage these cells or tissues or can impair their function. These diseases are said to be antibody mediated and represent type II hypersensitivity. • Antibodies against soluble antigens may form complexes with the antigens, and the immune complexes may deposit in blood vessels in various tissues, causing inflammation and tissue injury. Such diseases are called immune complex diseases and represent type III hypersensitivity. • Some diseases result from the reactions of T lymphocytes, often against self antigens in tissues. These T cell–mediated diseases represent type IV hypersensitivity. 2 of 22 9/21/16, 2:05 PM Hypersensitivity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... FIGURE 11-1 Types of hypersensitivity reactions. In the four major types of hypersensitivity reactions, different immune effector mechanisms cause tissue injury and disease. CTLs , Cytotoxic T lymphocytes; Ig , immunoglobulin. This classification scheme is useful because it distinguishes the mechanisms of immune-mediated 3 of 22 9/21/16, 2:05 PM Hypersensitivity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... tissue injury. In many human immunologic diseases, however, the damage may result from a combination of antibody-mediated and T cell–mediated reactions, so it is often difficult to classify these diseases neatly into one type of hypersensitivity. Immediate Hypersensitivity 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. Disorders in which IgE-mediated immediate hypersensitivity is prominent are also called allergy , or atopy , and individuals with a propensity to develop these reactions are said to be atopic. Immediate hypersensitivity may affect various tissues and may be of varying severity in different individuals. Common types of allergies include hay fever, food allergies, bronchial asthma, and anaphylaxis. Allergies are the most frequent disorders of the immune system, estimated to affect 10% to 20% of people, and the incidence of allergic diseases has been increasing in industrialized societies. 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 ( Fig. 11-2 (f0015) ). Some mast cell mediators cause a rapid increase in vascular permeability and smooth muscle contraction, resulting in many of the symptoms of these reactions ( Fig. 11-3 (f0020) ). This vascular and smooth muscle reaction 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. 4 of 22 9/21/16, 2:05 PM Hypersensitivity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... FIGURE 11-2 The sequence of events in immediate hypersensitivity. Immediate hypersensitivity reactions are initiated by the introduction of an allergen, which stimulates Th2 and IL-4/IL- 13–producing Tfh cells and immunoglobulin E (IgE) production. IgE binds to Fc receptors (FcεRI) on mast cells, and subsequent exposure to the allergen activates the mast cells to secrete the mediators that are responsible for the pathologic reactions of immediate hypersensitivity. 5 of 22 9/21/16, 2:05 PM Hypersensitivity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... FIGURE 11-3 Immediate hypersensitivity. A, Kinetics of the immediate and late-phase reactions. The immediate vascular and smooth muscle reaction to allergen develops within minutes after challenge (allergen exposure in a previously sensitized individual), and the late-phase reaction develops 2 to 24 hours later. B, Morphology of the immediate reaction is characterized by vasodilation, congestion, and edema. C, The late-phase reaction is characterized by an inflammatory infiltrate rich in eosinophils, neutrophils, and T cells. (Micrographs courtesy Dr. Daniel Friend, Department of Pathology, Brigham and Women′s Hospital, Boston.) With this background, we proceed to a discussion of the steps in immediate hypersensitivity reactions. Activation of Th2 Cells and Production of IgE Antibody In individuals who are prone to allergies, exposure to some antigens results in the activation of Th2 and Tfh cells and the production of IgE antibody (see Fig. 11-2 (f0015) ). Most individuals do not mount strong Th2 responses to environmental antigens. For unknown reasons, when some individuals encounter certain antigens, such as proteins in pollen, certain foods, insect venoms, or animal dander, or if they are treated with certain drugs such as penicillin, there is a strong Th2 response. Immediate hypersensitivity develops as a consequence of the activation of Th2 cells in response to protein antigens or chemicals that bind to proteins. Antigens that elicit immediate hypersensitivity (allergic) reactions often are called allergens. Any atopic individual may be allergic to one or more of these antigens. It is not understood why only a small subset of common environmental antigens elicit Th2-mediated reactions and IgE production, or what characteristics of these antigens are responsible for their behavior as allergens. Two of the cytokines secreted by Th2 cells or by Tfh cells activated by the same antigen are IL-4 and IL-13. These cytokines 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. The propensity toward development of IL-4–producing T cells, IgE production, and immediate hypersensitivity has a strong genetic basis; a major known risk for developing allergies is a family history of atopic disease. Many different genes appear to play contributory roles, but the mechanisms by which these genes influence the development of allergies are poorly understood. Activation of Mast Cells and Secretion of Mediators 6 of 22 9/21/16, 2:05 PM Hypersensitivity - ClinicalKey https://www.clinicalkey.com/#!/content/book/3-s2.0-B978032339... IgE antibody produced in response to an allergen binds to high-affinity Fc receptors, specific for the ε heavy chain, that are expressed on mast cells (see Fig. 11-2 (f0015) ). Thus, in an atopic