Immediate Allergic Reactions
Learning Objectives
• Summarize the immunologic abnormalities associated with atopy
• List preformed mediators released during the early phase of an allergic response
• Compare and contrast the roles of preformed mediators in skin and lung allergic reactions
• Identify the late-phase mediators and their physiologic roles in allergic reactions
• Identify the two common complications of allergic rhinitis
• Design a treatment regimen for allergic rhinitis
• Design a treatment regimen for urticaria
• Explain the wheal-and-flare reaction in a skin test
• Compare and contrast urticaria and atopic dermatitis
• Identify the chemical characteristics of food allergens
• List foods that contain high histamine levels
• Explain the relationship between pollens, fruits, and oral allergy syndrome
• Identify the three physiologic and immunologic components in asthma
• Identify the drugs used to control acute and chronic asthma
• List the three types of asthma that are not immunologically mediated
• Compare and contrast anaphylaxis and anaphylactoid reactions
• Identify antibiotics and therapeutic agents that cause anaphylactoid reactions
• Relate the theory behind the use of hyposensitization therapy
• Identify the major allergens in latex
• List the populations at risk for latex sensitization
• Identify the major house dust mite allergens
Key Terms
Allergic rhinitis
Anaphylaxis
Anaphylactoid
Aspirin-induced asthma
Asthma
Atopic dermatitis
Atopy
Early-phase IgE response
Hyposensitization therapy
Infectious asthma
Late-phase IgE response
Leukotrienes
Prostaglandins
Radioallergosorbent test (RAST)
Skin test
Urticaria
Introduction
Immediate allergic reactions are mediated by the immunoglobulin E (IgE) class of antibodies, and reactions typically occur 15 to 20 minutes after exposure to an allergen. The prevalence of allergies in the United States is estimated to be between 9% and 16% of the population, or 50 million people. Over the last three decades, the incidence and severity of allergic reactions have increased substantially, and allergic diseases are now among the top three causes of illness and disability.
Allergic reactions occur in the skin (urticaria and atopic dermatitis), nose and eyes (rhinitis and conjunctivitis), lungs (asthma), and the intestine (food allergies). Clinical signs and symptoms are related to the time course, the target organ, and the nature of the pharmacologic mediators released from mast cells and basophils.
Atopy
There is often a familial genetic tendency to develop rhinitis, urticaria, and asthma. This condition, called atopy, is characterized by elevated IgE levels directed at common aero-allergens or food allergens. Atopic individuals have increased numbers of CD4Th2 (T helper) cells and elevated interleukin 4 (IL-4) in peripheral blood. These abnormalities skew the immune response to IgE production. In addition, mast cells and basophils from atopic individuals have double the number of Fc receptors for IgE compared with nonatopic individuals. Atopic individuals also have hyperreactive airways that respond to low levels of cholinergic agonists that bind and activate acetylcholine receptors in the lung.
Although atopy is associated with genes on seven different chromosomes, single nucleotide polymorphisms in genes on chromosomes 5, 7, and 11 play a critical role in the frequency and evolution of allergic reactions (Table 15-1). These mutations increase cytokine production, expression of Fc receptors, IgE synthesis, and bronchial hyperreactivity.
Table 15-1
Examples of Chromosomal Locations and Genes Associated with Atopy and Asthma
| Chromosomal Location | Candidate Genes | Putative Role of Gene Products in Disease |
| 5q | Cytokine gene cluster (IL-4, IL-5, IL-13), CD14, β2-adrenergic receptor | Interleukin 4 (IL-4) and IL-13 promote immunoglobulin E (IgE) switching; IL-5 promotes eosinophil growth and activation; CD14 is a component of the lipopolysaccharide (LPS) receptor, which, via interaction with Toll receptor 4 (TLR4), may influence the balance between TH1 and TH2 responses to antigens; β2-adrenergic receptor regulates bronchial smooth muscle contraction |
| 6p | Class II major histocompatibility complex (MHC) | Some alleles may regulate T cell responses to allergens |
| 11a | FcεRI β-chain | Mediates mast cell activation |
| 12q | Stem cell factor, interferon-gamma (IFN-γ), STAT6 | Stem cell factor regulates mast cell growth and differentiation; IFN-γ opposes actions of IL-4; STAT6 mediates IL-4 signal transduction |
| 16 | IL-4 receptor α-chain | Subunit of both IL-4 and IL-13 receptors |
| 20p | ADAM33 | Metalloproteinase involved in airway remodeling |
| 2q | DPP10 | Peptidase that may regulate chemokine and cytokine activity |
| 13q | PHF11 | Transcriptional regulator involved in B cell clonal expansion and immunoglobulin expression |
Chromosome 5q genes regulate the production of cytokines (e.g., IL-4, IL-5, and IL-13). IL-4 and IL-13 drive isotypic switching to IgE production, and IL-5 promotes the growth and activation of eosinophils. IL-13 also increases bronchial mucus secretion. Tandem repeats in chromosome 11q13 are associated with polymorphisms in the FcεRI–beta chain and the number of Fc receptors expressed by mast cells and basophils. The FcεRI receptor acts as a trigger for immediate allergic reactions by stabilizing the receptor and amplifying intracellular signals. Bronchial hyperreactivity is controlled by the genes on chromosome 7.
Evolution of an Immediate Allergic Reaction
Initial Exposure to an Allergen
During initial exposure, allergens are processed by macrophages and allergenic epitopes presented to CD4Th2 cells in the context of class II molecules. In allergic or atopic individuals, T cells secrete IL-4, IL-5, and IL-13, which promote the rapid isotypic switching and IgE production by plasma cells. Secreted IgE binds specifically to Fc receptors on tissue mast cells and circulating basophils.
Second Exposure to an Allergen
Upon second exposure, the allergen cross-links two cell-bound IgEs, which initiates an energy-dependent mechanism that culminates in a biphasic immune response. The early-phase response, which occurs within 20 minutes of exposure, involves IgE–antigen interactions and is mediated by preformed pharmacologic mediators. A late-phase response, which occurs 4 to 8 hours following exposure, does not involve antibodies and is facilitated by the newly synthesized products of the arachidonic acid pathway.
Early-Phase Reactions and Preformed Mediators
In the early-phase reaction, granules containing preformed pharmacologic mediators are extruded from mast cells and basophils. The major preformed mediators include histamine, heparin, eosinophil chemotactic factor (ECF), and neutrophil chemotactic factor (NCF). Histamine is a vasoactive amine that has tissue-dependent, physiologic effects. In the skin, histamine interacts with receptors (H1 receptor) on vascular endothelial cells to create gaps between adjacent cells and increase vascular permeability (H2 receptor). Fluid from blood escapes through the gaps, causing swelling or edema in the tissue. Histamine also irritates peripheral nerve endings, causing itching and pain (pruritus). Heparin, which is also released from mast cells and basophils, potentiates the tissue edema by binding to antithrombin and preventing the activation of the normal coagulation pathway.
In the lung, histamine reacts with H1 receptors on smooth muscle in the bronchioles. Muscular contraction of the airways reduces the airway diameter, impeding the flow of air. The chemotactic factors ECF and NCF act on circulating cells and cause an influx of eosinophils and granulocytes at the site of the allergic reaction. Although the role of eosinophils in allergic reactions has not been fully delineated, enzymes released from eosinophils are known to inactivate histamine.
Late-Phase Reactions and Synthesized Mediators
Mast cells and basophils synthesize and release late-phase mediators over the course of 4 to 8 hours. These mediators include prostaglandins, leukotrienes, and platelet activating factor (PAF) (Figure 15-1).
Prostaglandins and leukotrienes are the products of the arachidonic acid pathway. Two prostaglandins (PGD2 and PGE2) play critical roles in late-phase reactions by increasing vascular permeability, contracting smooth muscle, and acting as an NCF. Leukotrienes are 20 carbon unsaturated fatty acids (LTA4, LTB4, LTC4, LTD4, and LTE4) that cause bronchoconstriction, increased mucus production, and sustained inflammation. PAF released from polymorphonuclear cells, endothelial cells, and monocytes causes bronchoconstriction, retraction of endothelial cells, and vasodilation. Late-phase reactions occur in some, but not all, individuals.
Types of Immunoglobulin E–Mediated Allergic Reactions
Asthma
Asthma is a disease characterized by partial airway obstruction that is partially reversible either spontaneously or with treatment. The hallmark of allergic asthma is an early-phase allergic response. Approximately half of the patients with asthma also have late-phase responses. Chronic airway inflammation, airway injury, and airway repair (airway remodeling) also contribute to the pathogenesis of asthma and permanent abnormalities in lung function.
Chronic asthma has an inflammatory component. Cells involved in the inflammatory response include T cells, eosinophils, and mast cells. Cytokines released from activated macrophages mediate the inflammatory process. Tumor necrosis factor alpha (TNF-α) upregulates endothelial cell adhesion factors that bind neutrophils, monocytes, and eosinophils. The accumulation of cells forms the asthma inflammatory nidus.
If the airway inflammation is not resolved, reactive oxygen species produced by inflammatory cells injure the airways, and the tissue must be repaired and restructured. The interaction between lymphocyte CD28 and dendritic cell B7 activates dendritic cells and promotes the synthesis of proinflammatory cytokines. In tissue, L-arginine is converted to L-ornithine, which initiates cell proliferation, collagen synthesis, smooth muscle hypertrophy, and goblet cell hyperplasia. These changes culminate in the thickening of the sub-basement membrane, subepithelial fibrosis, and permanent damage to the bronchioles.
Treatment of Asthma
The clinician uses different medications to control the immediate reactions, the late-phase reaction, and chronic airway inflammation. Slow-acting β2-agonists and oral corticosteroids are used to relieve the acute exacerbations of asthma. Therapeutics used to control long-term and chronic pulmonary symptoms are mast cells stabilizers, leukotriene antagonists, long-acting β2-agonists, inhaled corticosteroids, and methylxanthines.
A new therapy uses a humanized monoclonal antibody, known as omalizumab, which is directed at IgE. It binds to soluble IgE and prevents binding to Fc receptors on mast cells and basophils. Omalizumab is usually prescribed to patients with moderate to severe asthma triggered by ubiquitous year-round allergens.
Allergic Rhinitis
Allergic rhinitis (AR)
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