Porth's Essentials of Pathophysiology, 4e

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Disorders of the Immune Response

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TABLE 16-1 Classification of Hypersensitivity Responses Type of Hypersensitivity Immune Mechanism

Mechanism of Injury

Type I, immediate hypersensitivity Type II, antibody-mediated

IgE antibody IgM, IgG antibodies against cell surface or extracellular matrix

Release of mast cell mediators Phagocytosis and opsonization of cells; complement- and receptor-mediated recruitment and activation of inflammatory cells (neutrophils, macrophages); abnormalities in cellular functioning (e.g., hormone receptor signaling) Complement-mediated recruitment and activation of inflammatory cells Macrophage activation of cytokine-mediated inflammation; direct target cell killing, cytokine-mediated inflammation

Type III, immune complex–mediated Formation of immune complexes involving circulating antigens and IgM or IgG antibodies

Type IV,T-cell–mediated

CD4 + T cells (delayed-type hypersensitivity) or CD8 + cytotoxic T-cell–mediated cytolysis

IgE, immunoglobulin E; IgG, immunoglobulin G; IgM, immunoglobulin M.

allergens include the proteins in plant pollens, house dust mites, animal dander, foods, and chemicals like the antibiotic penicillin. Exposure to the allergen can be through inhalation, ingestion, injection, or skin contact. Depending on the portal of entry, type I reactions may be limited to merely annoying (e.g., seasonal rhinitis), severely debilitating (asthma), or systemic and poten- tially life-threatening (anaphylaxis). Two types of cells are central to a type I hypersensi- tivity reaction: type 2 helper T (T H 2) cells and granule- containing cells, such as mast cells and/or basophils. 1–4 There are two subsets of helper T cells (T H 1 and T H 2) that develop from the same precursor CD4 + T lym- phocyte (see Chapter 15). T H 1 cells differentiate in response to microbes and stimulate the differentiation of B cells into IgM- and IgG-producing plasma cells. T H 2 cell differentiation occurs in response to aller- gens and helminths (intestinal parasites). 1 Cytokines secreted by T H 2 cells stimulate differentiation of B cells into IgE-producing plasma cells, act as growth factors for mast cells, and recruit and activate eosinophils. The tissue-based mast cells and blood-based basophils are both derived from hematopoietic precursor cells in the bone marrow. 1 Mast cells are widely distributed in connective tissue, especially in areas beneath the skin and mucous membranes of the respiratory, gastrointes- tinal, and genitourinary tracts and adjacent to blood and lymph vessels. 5 This location places them near sur- faces that are exposed to environmental antigens and parasites. Basophils, which share many features with mast cells, are granulocytes that circulate in the blood- stream and represent less than 1% of peripheral leuko- cytes (white blood cells). Both mast cells and basophils contain preformed mediators of inflammation that are stored in granules and released at the time of activation, and both have high-affinity receptors for IgE antibodies on their surface. Type I hypersensitivity reactions begin with mast cell or basophil sensitization. During the sensitization or priming stage, allergen-specific IgE antibodies attach to receptors on the surface of mast cells and basophils.

With subsequent exposure, the sensitizing allergen binds to the cell-associated IgE and triggers a series of events that ultimately lead to degranulation of the sensitized mast cells or basophils, causing the release of their preformed mediators (Fig. 16-1). Mast cells are also the source of lipid-derived membrane prod- ucts (e.g., prostaglandins and leukotrienes) and cyto- kines that participate in the continued response to the allergen. Many type I hypersensitivity reactions, such as bronchial asthma, have two well-defined phases: (1) a primary or immediate-phase response characterized by vasodilation, vascular leakage, and smooth muscle contraction, and (2) a secondary or late-phase response characterized by more intense infiltration of tissues with eosinophils and other acute and chronic inflammatory cells, as well as tissue destruction in the form of epithe- lial cell damage. The primary or immediate-phase response usually occurs within 5 to 30 minutes of exposure to antigen and subsides within 60 minutes. It is mediated by mast cell degranulation and the release of preformed media- tors. These mediators include histamine, prostaglandins, leukotrienes, platelet activating-factor, interleukins, and enzymes such as chymase and trypsin that lead to the generation of kinins. 1 Histamine is a potent vasodilator that increases the permeability of capillaries and venules and causes smooth muscle contraction and broncho- constriction. The kinins, which are a group of potent inflammatory peptides, require activation through enzymatic modification. Once activated, these peptide mediators (e.g., bradykinin) produce vasodilation and smooth muscle contraction. The secondary or late-phase response occurs about 2 to 8 hours later and lasts for several days. It results from the action of lipid mediators and cytokines involved in the inflammatory response. The lipid mediators are derived from mast cell membrane phospholipids, which are broken down to form arachidonic acid. Arachidonic acid, in turn, is the parent compound from which the leukotrienes and prostaglandins are synthesized