And Allergic Disease

A variety of human diseases are caused by immune responses to nonmicrobial environmental antigens that involve Th2 cells, immunoglobulin E (IgE), mast cells, and eosinophils. In these responses, the antigens induce CD4+ Th2 cells, which then help B cells to produce IgE antibodies that are specific for the antigens and bind to Fc receptors on mast cells and basophils. When these cell-associated IgE antibodies are cross-linked by antigen, the cells are activated to rapidly release a variety of mediators. These mediators collectively cause increased vascular permeability, vasodilation, and bronchial and visceral smooth muscle contraction. This reaction is called immediate hypersensitivity because it begins rapidly, within minutes of antigen challenge (immediate), and has major pathologic consequences (hypersensitivity). Following the immediate response, there is a more slowly developing inflammatory component called the late-phase reaction characterized by the accumulation of neutrophils, eosinophils, macrophages, and CD4+ TH2 cells. This later reaction is triggered by cytokines produced by the TH2 cells and by mast cells as well as by lipid mediators secreted by mast cells. The term immediate hypersensitivity is commonly used to describe the combined immediate and late-phase reactions. In clinical medicine, these reactions are called allergy or atopy, and the associated diseases are called allergic, atopic, or immediate hyper-sensitivity diseases. Repeated bouts of these reactions can lead to chronic allergic diseases, with tissue damage and remodeling. Although atopy originally meant "unusual," we now realize that allergy is the most common disorder of immunity, affecting 20% of all individuals in the United States. This chapter focuses on immune reactions mediated by Th2 cells, IgE, and mast cells. We begin by summarizing some important general features of IgE- and mast cell-dependent reactions and proceed to describe the production of IgE, the structure and functions of IgE-specific Fc receptors, and the cellular mediators of immediate hypersensitivity, including mast cells, basophils, and eosinophils. We then describe selected clinical syndromes associated with IgE- and mast cell-dependent reactions and the principles of therapy for these diseases. We conclude with a discussion of the physiologic role of IgE-mediated immune reactions in host defense.

GENERAL FEATURES OF IgE-DEPENDENT IMMUNE REACTIONS, 426

PRODUCTION OF IgE, 427

The Nature of Allergens, 427

Activation of TH2 Cells, 427

Activation of B Cells and Switching to IgE, 428

ROLE OF MAST CELLS, BASOPHILS, AND EOSINOPHILS IN IMMEDIATE HYPERSENSITIVITY, 428

Properties of Mast Cells and Basophils, 428

Binding of IgE to Mast Cells and Basophils: The Fee Receptor, 429

Activation of Mast Cells , 431

Mediators Derived from Mast Cells, 434

Properties of Eosinophils, 436

IgE- AND MAST CELL-DEPENDENT REACTIONS, 437

The Immediate Reaction, 437 The Late-Phase Reaction, 437

GENETIC SUSCEPTIBILITY TO IMMEDIATE HYPERSENSITIVITY, 438

ALLERGIC DISEASES IN HUMANS: PATHOGENESIS AND THERAPY, 439

Systemic Anaphylaxis, 440 Bronchial Asthma, 440

Immediate Hypersensitivity Reactions in the Upper Respiratory Tract, Gastrointestinal Tract, and Skin, 442 Immunotherapy for Allergic Diseases, 442

THE PROTECTIVE ROLES OF IgE- AND MAST CELL-MEDIATED IMMUNE REACTIONS, 442

SUMMARY, 443

GENERAL FEATURES OF IgE-DEPENDENT IMMUNE REACTIONS

All allergic reactions share common features, although they differ greatly in the types of antigens that elicit these reactions and their clinical and pathologic manifestations.

• The hallmarks of allergic diseases are the activation of Th2 cells and the production of IgE antibody. Whereas healthy individuals either do not respond or have harmless T cell and antibody responses to common environmental antigens, atopic individuals develop strong Th2 responses and produce IgE on exposure to these potentially allergenic substances.

• The typical sequence of events in immediate hypersensitivity consists of exposure to an antigen, activation of Th2 cells and B cells specific for the antigen, production of IgE antibody, binding of the antibody to Fc receptors of mast cells, and triggering of the mast cells by re-exposure to the antigen, resulting in the release of mediators from the mast cells and the subsequent pathologic reaction (Fig. 19-1). Binding of IgE to mast cells is also called sensitization because IgE-coated mast cells are ready to be activated on antigen encounter (i.e., they are sensitive to the antigen). We describe each of these steps in the following sections.

• There is a strong genetic predisposition for the development of atopy. Many susceptibility genes are associated with these disorders. These genes are thought to influence different steps in the development and reactions of immediate hypersensitivity. We will discuss some of the major known susceptibility genes and their likely roles later in the chapter.

• The antigens that elicit immediate hypersensitivity, also called allergens, are usually common environmental proteins and chemicals that can modify proteins. Allergens include a wide variety of structurally distinct molecules.

• The cytokines produced by TH2 cells are responsible for many of the features of immediate hypersensitiv-ity. Immediate hypersensitivity is the prototypic TH2-mediated disorder, in contrast to delayed-type hypersensitivity, which is the classical TH1-mediated immune reaction.

• The clinical and pathologic manifestations of immediate hypersensitivity consist of the vascular and smooth muscle reaction that develops rapidly after repeated exposure to the allergen (the immediate reaction) and a delayed inflammatory reaction. All these reactions may be triggered by IgE-mediated mast cell activation, but different mediators are responsible for different components of the immediate and late-phase reactions. Because mast cells are present in connective tissues and under epithelia, these tissues are the most common sites of immediate hypersensitivity reactions. Some immediate hypersensitivity reactions may be triggered by nonimmunologic stimuli, such as exercise and exposure to cold. Such stimuli induce mast cell degranulation and the release of mediators without

First exposure to allergen

Activation of Th2 cells and stimulation of IgE class switching in B cells

Production of IgE

Binding of IgE to FceRI on mast cells

Repeated exposure to allergen

Activation of mast cell release of mediators

Vasoactive amines, lipid mediators

Allergen

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