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 not only in protective immunity but also a detectable reaction to challenge with that antigen, called sensitivity, 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 repetitive 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?
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 ). We will use the informative descriptive classifications throughout this chapter, but we will also indicate the numerical designations for each type since they are widely used.
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 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 or type II hypersensitivity.
Antibodies against soluble antigens in the blood may form complexes with the antigens, and the immune complexes may deposit in blood vessels in various tissues, causing inflammation and tissue injury. Such disorders are called immune complex diseases or type III hypersensitivity.
Some diseases result from the reactions of T lymphocytes specific for self antigens or microbes in tissues. These are T cell–mediated diseases or type IV hypersensitivity.
This classification scheme is useful because it distinguishes the mechanisms of immune-mediated 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 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, 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, especially in industrialized societies.
The sequence of events in the development of immediate hypersensitivity reactions includes: 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 IgE-specific Fc receptors of mast cells; on subsequent exposure to the antigen, cross-linking of the bound IgE by the antigen, leading to activation of the mast cells and release of various mediators ( Fig. 11.2 ). 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 ). 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.
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 cells and IL-4–secreting Tfh cells, and the production of IgE antibody (see Fig. 11.2 ). 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 and IL-4-secreting Tfh 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.
In secondary lymphoid organs, IL-4 secreted by Tfh cells stimulates 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. IL-4 and IL-13 secreted by Th2 cells induce some of the responses of tissues in allergic reactions, such as intestinal motility and excess mucus secretions. Th2 cells also secrete IL-5, which promotes eosinophilic inflammation that is characteristic of tissues affected by allergic diseases. Because the majority of Th2 cells migrate to peripheral tissues, whereas Tfh cells remain in secondary lymphoid organs, they likely serve different roles in allergic responses. Switching to IgE occurs mainly in the lymphoid organs and therefore helper function is provided by Tfh cells. Th2 cells may contribute to any isotype switching that occurs in peripheral sites of allergic reactions, and, more importantly, are responsible for inflammation and eosinophil activation at these sites.
The propensity toward differentiation of IL-4 and IL-5 producing T cells, and resulting atopic diseases such as asthma, has a strong genetic basis. A major known risk for developing allergies is a family history of atopic disease, and gene association studies indicate that many different genes play contributory roles. Some of these genes encode cytokines or receptors known to be involved in T and B lymphocyte responses, including IL-4, IL-5, and IL-13, and IL-4 receptor; how these gene variants contribute to atopic diseases is not known. Mutations of filaggrin, a protein required for barrier function of skin, increases risk for atopic dermatitis in early childhood, and subsequent allergic diseases including asthma.
Various environmental factors besides exposure to allergens, including air pollution and exposure to microbes, have a profound influence on the propensity to develop allergies, and this may be one reason why the incidence of allergic diseases, especially asthma, is increasing in industrialized societies.
Activation of Mast Cells and Secretion of Mediators
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 ). 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 it 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 because many antigens may elicit small IgE responses, and the amount of IgE specific for any one antigen is not enough to cause immediate hypersensitivity reactions upon exposure to that antigen.
Mast cells are present in all connective tissues, especially under epithelia, and they are usually located adjacent to blood vessels. Which of the body’s mast cells are activated by binding of an allergen often depends on the route of entry of the allergen. For example, inhaled allergens activate mast cells in the submucosal tissues of the bronchus, whereas ingested allergens activate mast cells in the wall of the intestine. Allergens that enter the blood via absorption from the intestine or by direct injection may be delivered to all tissues, resulting in systemic mast cell activation.
The high-affinity receptor for IgE, called FcεRI, consists of three polypeptide chains, one of which binds the Fc portion of the ε heavy chain very strongly, with a K d of approximately 10 −11 M. (The concentration of IgE in the plasma is approximately 10 −9 M, which explains why even in normal individuals, mast cells are always coated with IgE bound to FcεRI.) The other two chains of the receptor are signaling proteins. The same FcεRI is also present on basophils, which are circulating cells with many of the features of mast cells, but normally the number of basophils in the blood is very low and they are not present in tissues, so their role in immediate hypersensitivity is not as well established as the role of mast cells.
When mast cells sensitized by IgE are exposed to the allergen, they are activated to secrete inflammatory mediators ( Fig. 11.4 ). Mast cell activation results from binding of the allergen to two or more IgE antibodies on the cell. When this happens, the FcεRI molecules that are carrying the IgE are cross-linked, triggering biochemical signals from the signal-transducing chains of FcεRI. The signals lead to the release of inflammatory mediators.
The most important mediators produced by mast cells are vasoactive amines and proteases stored in and released from granules, newly generated and secreted products of arachidonic acid metabolism, and cytokines (see Fig. 11.4 ). These mediators have different actions. The major amine, histamine, causes increased vascular permeability and vasodilation, leading to the leak of fluid and plasma proteins into tissues, and stimulates the transient contraction of bronchial and intestinal smooth muscle. Proteases may cause damage to local tissues. Arachidonic acid metabolites include prostaglandins, which cause vascular dilation, and leukotrienes, which stimulate prolonged bronchial smooth muscle contraction. Cytokines induce local inflammation (the late-phase reaction, described next). Thus, mast cell mediators are responsible for acute vascular and smooth muscle reactions and more prolonged inflammation, the hallmarks of immediate hypersensitivity.
Cytokines produced by mast cells stimulate the recruitment of leukocytes, which cause the late-phase reaction. The principal leukocytes involved in this reaction are eosinophils, neutrophils, and Th2 cells. Mast cell–derived tumor necrosis factor (TNF) and IL-4 promote neutrophil- and eosinophil-rich inflammation. Chemokines 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. Eosinophils are prominent in 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 and innate lymphoid cells.
Clinical Syndromes and Therapy
Immediate hypersensitivity reactions have diverse clinical and pathologic features, all of which are attributable to mediators produced by mast cells in different amounts and in different tissues ( Fig. 11.5 ).
Some mild manifestations, such as allergic rhinitis and sinusitis, which are common in hay fever , are reactions to inhaled allergens, such as a protein of ragweed pollen. 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.
In food allergies , ingested allergens trigger mast cell degranulation, and the released histamine and other mediators causes increased peristalsis, resulting in vomiting and diarrhea.
Asthma is a clinical syndrome characterized by difficulty in breathing, cough, and wheezing, related to intermittent obstruction of expiratory airflow. The most common cause of asthma is respiratory allergy in which inhaled allergens 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. Some cases of asthma are not associated with IgE production and may be triggered by cold or exercise; how either of these causes bronchial hyperreactivity is unknown.
The most severe form of immediate hypersensitivity is anaphylaxis , a systemic reaction characterized by edema in many tissues, including the larynx, accompanied by a fall in blood pressure (anaphylactic shock) and bronchoconstriction. 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, and it is life threatening because of the sudden fall in blood pressure and airway obstruction.