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Chapter 25 : Hypersensitivity

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Abstract:

This chapter deals with the types of hypersensitive reactions; immunological mechanisms of hypersensitivity; factors that predispose to hypersensitivity and clinical manifestations of hypersensitivity. The allergic diseases have been known since antiquity, but there was little insight into their causes until the late 19th century, when advances in histology led to the early delineation of the hematopoietic and mesenchymal cell lineages at the heart of all allergic reactions. At that time, three broad classes of cells were identified-mast cells, granulocytes, and mononuclear cells-that play different roles in hypersensitivity diseases. Allergy encompasses two different kinds of responses: immunity and hypersensitivity. Pathologic examination of the airways from patients with advanced asthma demonstrates infiltration by eosinophils and monocytes, increased size and number of the mucus-producing goblet cells, and damage to the protective epithelial lining of the airway. Food allergies can be the result of sensitization of the immune system through any of the four Gell and Coombs types of hypersensitivity, but IgE-mediated immediate hypersensitivity is probably involved in most cases.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25

Key Concept Ranking

Immune Systems
0.6607161
Innate Immune System
0.6492609
Type I Hypersensitivity
0.595671
Type III Hypersensitivity
0.57074696
Type IV Hypersensitivity
0.56385833
Type II Hypersensitivity
0.5444048
Major Histocompatibility Complex
0.49874505
0.6607161
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Figures

Image of Figure 25.1
Figure 25.1

Cellular actors in hypersensitivity reactions. A mast cell. The German immunologist Paul Ehrlich first coined the term “Mastzellen,” German for “well-fed cells,” to describe the granule-laden appearance of these cells, which reside in the dermal layer of the skin and in the connective tissues of the mucous membranes. Granulocytes. Similar granules are found in the cytoplasm of granulocytes, which circulate in the blood and are capable of entering sites of infection or inflammation as they are needed. Granulocytes of particular interest in the study of hypersensitivity are the eosinophils and basophils, which are distinguished by their respective affinities for acidic and basic dyes under microscopic examination. Neutrophils, also known as PMNs, are a third type of granulocyte with an important role in hypersensitivity reactions. They are perhaps better known for their role in antibacterial immune responses. Mononuclear cells. These cells are central to virtually all acquired immune responses and play a more subtle part in allergic diseases. Molecular techniques have shown that the class of mononuclear cells can be further divided into monocytes and the diverse lymphocytic lineages.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.2
Figure 25.2

Types of hypersensitivity responses. () Salient features of immediate, intermediate, and delayed- type hypersensitivity responses. () Gell and Coombs classification of hypersensitivity responses. () Typical manifestations of each response.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.3
Figure 25.3

Immediate hypersensitivity. Exposure to allergen activates B cells to become IgE-secreting plasma cells. The IgE molecules from multiple plasma cell clones bind to IgE-specific receptors on mast cells and basophils. A second exposure to the allergen results in cross-linking of the bound IgE and the release of mediators, including vasoactive amines such as histamine. The mediators cause the contraction of smooth muscle, vasodilation, and increased vascular permeability that underlie, for example, hay fever symptoms.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.4
Figure 25.4

The dual role of complement in mast cell activation. In serosal mast cell populations found in skin, muscle, and the peritoneal cavity, binding by the anaphylatoxins C3a and C5a to receptors specific for these complement cleavage factors on the cell surface results in degranulation even in the absence of IgE cross-linking. In mucosal mast cell populations found, for example, in the intestine, C3a binds to a different receptor, the β chain of the FcεRI receptor, blocking IgE binding and, hence, cross-linking and degranulation even in the presence of allergen.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.5
Figure 25.5

Arachidonic acid (AA) metabolites. Cross-linking of FcεRI on the surface of mast cells results in activation of phospholipase A, which acts to convert phosphatidylcholine to AA. AA serves as the precursor in two pathways: the linear pathway initiated by the enzyme 5-lipoxygenase (5-LO), ultimately resulting in production of the leukotrienes (LT); and the cyclic pathway initiated by the enzymes cyclooxygenase 1 and 2 (COX1 and COX2), resulting in production of the prostaglandins (PG) and thromboxanes (TX). Inhibitors of these pathways (in pink type) include drugs used to treat arthritis (celecoxib and rofecoxib) and asthma (montelukast and zafirlukast).

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.6
Figure 25.6

Properties of the IgEbinding Fc receptors. () The high-affinity receptor (FcεRI) present on mast cell and basophils. This receptor consists of four chains: an α chain with two 90-amino-acid domains homologous to the immunoglobulin- fold structure; a β chain that links the α chain to a γ homodimer, each chain of which has an immunoreceptor tyrosine-based activation motif (ITAM) important for cell activation through interaction with tyrosine kinases. The immunoglobulin- like folds of the α chain interact with the C3/C3 and C4/C4 domains of the IgE molecule. () The low-affinity receptor (FcεRII) found on B cells, alveolar macrophages, and eosinophils. This receptor appears to play a role in regulating the intensity of the IgE response. The soluble form, generated by proteolysis, enhances IgE production by B cells.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.7
Figure 25.7

Recruitment of eosinophils in the early response to allergen. After irritation by allergens or injury , respiratory epithelial cells express the chemoattractive proteins RANTES, IL-16, and eotaxin . Tissue damage or antigen exposure causes cells lining the mucosal surface to release cytokines, including ECF-A and IL-5 released by mast cells and IL-5 released by neighboring γδ T lymphocytes . These cytokines act in concert to recruit eosinophils from the circulation , and eosinophils are then mobilized into the airways . Free alveolar macrophages in the airspaces, like eosinophils, are scavengers for particles, such as pollen grains. Free alveolar macrophages and eosinophils are capable of trafficking back into the tissues , although their role in triggering the IgE response is uncertain.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.8
Figure 25.8

Common allergens. () Exposure to environmental allergens may vary dramatically according to the season and location, as shown in the chart depicting pollencount data compiled by the American Academy of Allergy, Asthma, and Immunology (http://www.aaaai.org). () A partial listing of allergens associated with type I hypersensitivity reactions.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.9
Figure 25.9

Initial step in mast cell activation. Cross-linking of the highaffinity IgE receptor (FcεRI) on the surface of the mast cell by rough allergen binding or any of numerous other methods () leads to activation of protein tyrosine kinases associated with the cytoplasmic domains of the β and γ chains of the receptor complex. The signaling cascade ultimately results in a sustained elevation in the intracellular calcium concentration, a step necessary for degranulation. Elevating the intracellular calcium concentration through incorporation of calcium ionophores into the mast-cell plasma membrane drives degranulation without the need for receptor cross-linking ().

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.10
Figure 25.10

Mast cell activation and degranulation. Cross-linking of FcεRI by allergen-bound IgE results in activation of adenylate cyclase, resulting in transient elevation of cyclic adenosine monophosphate (cAMP) and activation of protein kinase A. Cross-linking also activates protein tyrosine kinases (PTK) that, in turn, activate phospholipase C (PLC). PLC converts phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and IP. DAG activates protein kinase C (PKC), necessary for microtubule assembly and granule fusion. IP3 mobilizes calcium from internal stores, which opens calcium channels in the plasma membrane to allow sustained elevation of intracellular calcium concentrations. Cross-linking also activates an enzyme that converts phosphatidylserine (PhS) to phosphatidylethanolamine (PE), which is then methylated by the phospholipid methyl transferase enzymes I and II (PMT I and II) to form phosphatidylcholine (PC). Influx of calcium activates phospholipase A, which converts PC into lyso-PC and arachidonic acid. Arachidonic acid is the precursor for a variety of mediators. PKC phosphorylates proteins on the membrane of the granule, changing the permeability to water and calcium. The granules swell and, through the action of microtubules and microfilaments, are pulled to the surface, fuse, and release their contents. Time course of mast cell activation events.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.11
Figure 25.11

Asthma. Cross-sectional representations of airways before an asthma exacerbation and during the early and the late inflammatory response are shown. In the early response, note the vasodilation, increased secretion of mucus by glands and goblet cells, and bronchoconstriction. The late response is characterized by worsening bronchoconstriction and remodeling of the airways with thickened lamina propria packed with eosinophils and lymphocytes. LTC, leukotriene; PAF, platelet-activating factor; PGD, prostaglandin D.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.12
Figure 25.12

Intermediate type II (cytotoxic) hypersensitivity. Antibodies to self proteins or altered self proteins allow cells such as NK cells, macrophages, monocytes, neutrophils, and eosinophils to release a variety of mediators, including lytic enzymes, perforin, tumor necrosis factor, or granzymes to mediate target-cell killing. Alternatively, complement is activated and cells are lysed via the membrane attack complex. Two examples of type II hypersensitivity are as follows. Autoantibodies to pancreatic beta cells may contribute to insulin-dependent diabetes mellitus through destruction of the insulin-producing cells via antibody-dependent cell-mediated cytotoxicity. Hemolytic anemia is caused by adsorption of antibiotics, such as penicillin and certain cephalosporins, to proteins on RBC membranes, followed by IgM and IgG antibody production and complement lysis of the RBC.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.13
Figure 25.13

Development of erythroblastosis fetalis or hemolytic disease of the newborn results when an Rh mother carries an Rh fetus and becomes sensitized to the Rh factor antigen at delivery. During a subsequent pregnancy with another Rh fetus, maternal antibodies to Rh cross the placenta and destroy fetal red blood cells. Sensitization can be blocked if the mother receives anti-Rh antibodies, Rhogam, within 24 to 48 hours after the first delivery.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.14
Figure 25.14

ABO blood groups and transfusion reactions. Structure of the terminal sugars of the A, B, and O blood antigens, which constitute the distinguishing epitopes. ABO genotype, phenotypes, agglutinins, and isoagglutinins. Examples of immediate and delayed hemolytic transfusion reactions caused by transfusion of blood incompatible with major ABO blood-group and incompatible with minor blood-group antigen. The most common blood-group antigens that produce delayed transfusion reactions are Rh, Kidd, Kell, and Duffy. Symptoms of immediate reactions result from massive intravascular hemolysis of the transfused cells by IgM plus complement. The delayed reaction results from incomplete extravascular hemolysis mediated primarily by IgG.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.15
Figure 25.15

Goodpasture disease. Deposition of IgG directed at the type IV collagen found in the kidney glomeruli and capillaries of the lung results in complement activation and influx of neutrophils. Neutrophil destruction of both tissues ultimately leads to respiratory and renal failure. The bottom left photo shows green fluorescent labeling of anti-basement membrane antibodies on a kidney glomerulus, highlighting the extensive pathology of the disease. Lung micrographs courtesy of Martha Warnock.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.16
Figure 25.16

Time course of serum sickness. After antigen (bovine serum albumin [BSA]) is injected into a rabbit at day 0, antibody forms and complexes with the antigen to form immune complexes. The immune complexes are deposited in joints, kidneys, and capillaries, initiating the symptoms of serum sickness. Note that the serum sickness symptoms correspond with the peak of immune complex formation. As the immune complexes are cleared, free antibody appears in the blood and symptoms resolve. Based on F. G. Germuth, Jr., 257, 1953.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.17
Figure 25.17

Immune complex hypersensitivity reaction (Arthus reaction). Injection of a medicine may induce immune complex formation (), which results in complement activation via the classical pathway (). The complement intermediates bind to mast cells (), resulting in degranulation, and to neutrophils, mediating chemotaxis () and the release of lytic enzymes ().

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.18
Figure 25.18

DTH. After initial contact with antigen, TH cells become sensitized, proliferate, and differentiate into TDTH cells. When these sensitized T cells come into contact with the same antigen again, they secrete cytokines that attract and activate macrophages, which function as the effector cell in the hypersensitivity reaction. MCAF, macrophage chemotactic and activating factor; MIF, macrophage-inhibition factor.

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.19
Figure 25.19

infection. enters the respiratory tract () and subsequently the lamina propria of the respiratory bronchioles via M cells (). Digested antigen is taken up by dendritic cells (), which travel to regional lymph nodes and present antigens to TH1 cells. These TH1 cells proliferate () and may return to the site of initial infection. Restimulation by local APCs () results in production of IFN-γ and activation of macrophages. Failure to clear the organism results in granuloma formation ().

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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Image of Figure 25.20
Figure 25.20

Contact sensitivity. Development of a DTH reaction after a second exposure to poison ivy occurs in 80 to 90% of Americans. Urushiol diffuses through the skin () and binds to self proteins that are engulfed by Langerhans cells. The Langerhans cell presents the hapten urushiol to a sensitized TDTH cell, which secretes a variety of cytokines (). Approximately 48 to 72 hours after the exposure, macrophages accumulate at the site and release lytic enzymes, causing the characteristic rash and pustules ().

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
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References

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1. Burks, W. 2002. Current understanding of food allergy. Ann. N. Y. Acad. Sci. 964:112.
2. Herz, U.,, P. Lacy,, H. Renz,, and K. Erb. 2000. The influence of infections on the development and severity of allergic disorders. Curr. Opin. Immunol. 12:632640.
3. James, D. G. 2000. A clinicopathological classification of granulomatous disorders. Postgrad. Med. J. 76:457465.
4. Kay, A. B. 2001. Allergic diseases and their treatment. N. Engl. J. Med. 344:109113.
5. Kobayashi, K.,, K. Kaneda,, and T. Kasama. 2001. Immunopathogenesis of delayed-type hypersensitivity. Microsc. Res. Tech. 53:241245.
6. Repka-Ramirez, M. S.,, and J. N. Baraniuk. 2002. Histamine in health and disease. Clin. Allergy Immunol. 17:125.
7. Sabroe, I.,, C. M. Lloyd,, M. K. Whyte,, S. K. Dower,, T. J. Williams,, and J. E. Pease. 2002. Chemokines, innate and adaptive immunity, and respiratory disease. Eur. Respir. J. 19:350355.
8. Toda, M.,, and S. J. Ono. 2002. Genomics and proteomics of allergic disease. Immunology 106:110.
9. Umetsu, D. T.,, J. J. McIntire,, O. Akbari,, C. Macaubas,, and R. H. DeKruyff. 2002. Asthma: an epidemic of dysregulated immunity. Nat. Immunol. 3:715720.
10. Wollenberg, A.,, S. Kraft,, T. Oppel,, and T. Bieber. 2000. Atopic dermatitis: pathogenetic mechanisms. Clin. Exp. Dermatol. 25:530534.
11. Yazdanbakhsh, M.,, P. G. Kremsner,, and R. van Ree. 2002. Allergy, parasites, and the hygiene hypothesis. Science 296:490494.

Tables

Generic image for table
Table 25.1

Trends in allergy

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
Generic image for table
Table 25.2

Mediators of type I hypersensitivity reactions

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
Generic image for table
Table 25.3

Type I hypersensitivity responses

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
Generic image for table
Table 25.4

Genes associated with an increased risk of atopy

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
Generic image for table
Table 25.5

Loci associated with an increased risk of atopy

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25
Generic image for table
Table 25.6

Factors influencing immune complex pathogenicity

Citation: Whelan J, Cannon C. 2004. Hypersensitivity, p 595-623. In Pier G, Lyczak J, Wetzler L (ed), Immunology, Infection, and Immunity. ASM Press, Washington, DC. doi: 10.1128/9781555816148.ch25

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