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Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.

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Immunobiology: The Immune System in Health and Disease. 5th edition.

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The production of IgE

IgE is produced by plasma cells located in lymph nodes draining the site of antigen entry or locally, at the sites of allergic reactions, by plasma cells derived from germinal centers developing within the inflamed tissue. IgE differs from other antibody isotypes in being located predominantly in tissues, where it is tightly bound to the mast-cell surface through the high-affinity IgE receptor known as FcεRI. Binding of antigen to IgE cross-links these receptors and this causes the release of chemical mediators from the mast cells, which may lead to the development of a type I hypersensitivity reaction. Basophils and activated eosinophils also express FcεRI; they can therefore display surface-bound IgE and also take part in the production of type I hypersensitivity reactions. The factors that lead to an antibody response dominated by IgE are still being worked out. Here we will describe our current understanding of these processes before turning to the question of how IgE mediates allergic reactions.

12-1. Allergens are often delivered transmucosally at low dose, a route that favors IgE production

There are certain antigens and routes of antigen presentation to the immune system that favor the production of IgE. CD4 TH2 cells can switch the antibody isotype from IgM to IgE, or they can cause switching to IgG2 and IgG4 (human) or IgG1 and IgG3 (mouse) (see Section 9-4). Antigens that selectively evoke TH2 cells that drive an IgE response are known as allergens.

Much human allergy is caused by a limited number of inhaled small-protein allergens that reproducibly elicit IgE production in susceptible individuals. We inhale many different proteins that do not induce IgE production; this raises the question of what is unusual about the proteins that are common allergens. Although we do not yet have a complete answer, some general principles have emerged (Fig. 12.3). Most allergens are relatively small, highly soluble proteins that are carried on desiccated particles such as pollen grains or mite feces. On contact with the mucosa of the airways, for example, the soluble allergen elutes from the particle and diffuses into the mucosa. Allergens are typically presented to the immune system at very low doses. It has been estimated that the maximum exposure of a person to the common pollen allergens in ragweed (Artemisia artemisiifolia) does not exceed 1 μg per year! Yet many people develop irritating and even life-threatening TH2-driven IgE antibody responses to these minute doses of allergen. It is important to note that only some of the people who are exposed to these substances make IgE antibodies against them.

Figure 12.3. Properties of inhaled allergens.

Figure 12.3

Properties of inhaled allergens. The typical characteristics of inhaled allergens are described in this table.

It seems likely that presenting an antigen transmucosally and at very low doses is a particularly efficient way of inducing TH2-driven IgE responses. IgE antibody production requires TH2 cells that produce interleukin-4 (IL-4) and IL-13 and it can be inhibited by TH1 cells that produce interferon-γ (IFN-γ) (see Fig. 9.7). The presentation of low doses of antigen can favor the activation of TH2 cells over TH1 cells (see Section 10-7), and many common allergens are delivered to the respiratory mucosa by inhalation of a low dose. The dominant antigen-presenting cells in the respiratory mucosa are myeloid dendritic cells (see Section 7-29). These take up and process protein antigens very efficiently and become activated in the process. This in turn induces their migration to regional lymph nodes and differentiation into professional antigen-presenting cells with co-stimulatory activity that favors the differentiation of TH2 cells.

12-2. Enzymes are frequent triggers of allergy

Several lines of evidence suggest that IgE is important in host defense against parasites (see Section 9-23). Many parasites invade their hosts by secreting proteolytic enzymes that break down connective tissue and allow the parasite access to host tissues, and it has been proposed that these enzymes are particularly active at promoting TH2 responses. This idea receives some support from the many examples of allergens that are enzymes.

The major allergen in the feces of the house dust mite (Dermatophagoides pteronyssimus) (Fig. 12.4), which is responsible for allergy in approximately 20% of the North American population, is a cysteine protease homologous to papain, known as Der p 1. This enzyme has been found to cleave occludin, a protein component of intercellular tight junctions. This reveals one possible reason for the allergenicity of certain enzymes. By destroying the integrity of the tight junctions between epithelial cells, Der p 1 may gain abnormal access to subepithelial antigen-presenting cells, resident mast cells, and eosinophils (Fig. 12.5).

Figure 12.4. Scanning electron micrograph of D. pteronyssimus with some of its fecal pellets.

Figure 12.4

Scanning electron micrograph of D. pteronyssimus with some of its fecal pellets. Photograph courtesy E.R. Tovey.

Figure 12.5. The enzymatic activity of some allergens enables penetration of epithelial barriers.

Figure 12.5

The enzymatic activity of some allergens enables penetration of epithelial barriers. The epithelial barrier of the airways is formed by tight junctions between the epithelial cells. Fecal pellets from the house dust mite, D. pteronyssimus, contain a proteolytic enzyme, (more...)

The allergenicity of Der p 1 may also be promoted by its proteolytic action on certain receptor proteins on B cells and T cells. It has been shown to cleave the α subunit of the IL-2 receptor, CD25, from T cells. Loss of IL-2 receptor activity might interfere with the maintenance of TH1 cells, leading to a TH2 bias (see Section 8-9).

The protease papain, derived from the papaya fruit, is used as a meat tenderizer and causes allergy in workers preparing the enzyme; such allergies are called occupational allergies. Another occupational allergy is the asthma caused by inhalation of the bacterial enzyme subtilisin, the ‘biological’ component of some laundry detergents. Injection of enzymatically active papain (but not of inactivated papain) into mice stimulates an IgE response. A closely related enzyme, chymopapain, is used medically to destroy intervertebral discs in patients with sciatica; the major (although rare) complication of this procedure is anaphylaxis, an acute systemic response to allergens (see Fig. 12.1).

Not all allergens are enzymes, however; for example, two allergens identified from filarial worms are enzyme inhibitors. Many protein allergens derived from plants have been identified and sequenced, but their functions are currently obscure. Thus, there seems to be no systematic association between enzymatic activity and allergenicity.

12-3. Class switching to IgE in B lymphocytes is favored by specific signals

There are two main components of the immune response leading to IgE production. The first consists of the signals that favor the differentiation of naive TH0 cells to a TH2 phenotype. The second comprises the action of cytokines and co-stimulatory signals from TH2 cells that stimulate B cells to switch to producing IgE antibodies.

The fate of a naive CD4 T cell responding to a peptide presented by a dendritic cell is determined by the cytokines it is exposed to before and during this response, and by the intrinsic properties of the antigen, antigen dose, and route of presentation. Exposure to IL-4 favors the development of TH2 cells and to IL-12 favors that of TH1 cells. IgE antibodies are important in host defense against parasitic infections and this defense system is distributed anatomically mainly at the sites of entry of parasites—under the skin, under the epithelial surfaces of the airways (the mucosal-associated lymphoid tissues), and in the submucosa of the gut (the gut-associated lymphoid tissues). Cells of the innate and adaptive immune systems at these sites are specialized to secrete predominantly cytokines that drive TH2 responses. The dendritic cells at these sites are of the myeloid phenotype (see Section 7-29); after taking up antigen they migrate to regional lymph nodes where their interaction with naive CD4 T cells drives the T cells to become TH2 cells, which secrete IL-4 and IL-10. It is not known how myeloid dendritic cells induce this differentiation. One possibility is that they express a particular set of cytokines and co-stimulatory molecules yet to be characterized. Another is that they activate a specialized subset of CD4 T cells, the NK1.1+ subset, that produce abundant IL-4 that can induce CD4 T cells to differentiate into TH2 cells following stimulation by antigen. These in turn induce B cells to produce IgE (Fig. 12.6).

Figure 12.6. IgE class switching in B cells is initiated by TH2 cells, which develop in the presence of an early burst of IL-4.

Figure 12.6

IgE class switching in B cells is initiated by TH2 cells, which develop in the presence of an early burst of IL-4. In mice, IL-4 is secreted early in some immune responses by a small subset of CD4 T cells (NK1.1+ CD4 T cells) that interact with antigen-presenting (more...)

Class switching of B cells to IgE production is induced by two separate signals, both of which can be provided by TH2 cells (see Section 9-4). The first of these signals is provided by the cytokines IL-4 or IL-13, interacting with receptors on the B-cell surface. These transduce their signal by activation of the Janus family tyrosine kinases JAK1 and JAK3 (see Section 6-17) which ultimately lead to phosphorylation of the transcriptional regulator STAT6. Mice lacking functional IL-4, IL-13, or STAT6 all show impaired TH2 responses and IgE switching, demonstrating the key importance of these signaling pathways. The second signal for IgE class switching is a co-stimulatory interaction between CD40 ligand on the T-cell surface with CD40 on the B-cell surface. This interaction is essential for all antibody class switching (see Section 9-3); patients with the X-linked hyper IgM syndrome have a deficiency of CD40 ligand and produce no IgG, IgA, or IgE.

The IgE response, once initiated, can be further amplified by basophils, mast cells, and eosinophils, which can also drive IgE production (Fig. 12.7). All three cell types express FcεRI, although eosinophils only express it when activated. When these specialized granulocytes are activated by antigen cross-linking of their FcεRI-bound IgE, they can express cell-surface CD40L and secrete IL-4; like TH2 cells, therefore, they can drive class switching and IgE production by B cells (see Fig. 12.7). The interaction between these specialized granulocytes and B cells can occur at the site of the allergic reaction, as B cells are observed to form germinal centers at inflammatory foci. Blocking this amplification process is a goal of therapy, as allergic reactions can otherwise become self sustaining.

Figure 12.7. Antigen binding to IgE on mast cells leads to amplification of IgE production.

Figure 12.7

Antigen binding to IgE on mast cells leads to amplification of IgE production. IgE secreted by plasma cells binds to the high-affinity IgE receptor on mast cells (illustrated here), basophils, and activated eosinophils. When the surface-bound IgE is cross-linked (more...)

12-4. Genetic factors contribute to the development of IgE-mediated allergy, but environmental factors may also be important

As many as 40% of people in Western populations show an exaggerated tendency to mount IgE responses to a wide variety of common environmental allergens. This state is called atopy and seems to be influenced by several genetic loci. Atopic individuals have higher total levels of IgE in the circulation and higher levels of eosinophils than their normal counterparts. They are more susceptible to allergic diseases such as hay fever and asthma (Image clinical_small.jpgAllergic Asthma, in Case Studies in Immunology, see Preface for details). Studies of atopic families have identified regions on chromosomes 11q and 5q that appear to be important in determining atopy; candidate genes that could affect IgE responses are present in these regions. The candidate gene on chromosome 11 encodes the β subunit of the high-affinity IgE receptor, whereas on chromosome 5 there is a cluster of tightly linked genes that includes those for IL-3, IL-4, IL-5, IL-9, IL-12, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These cytokines are important in IgE isotype switching, eosinophil survival, and mast-cell proliferation. Of particular note, an inherited genetic variation in the promoter region of the IL-4 gene is associated with raised IgE levels in atopic individuals; the variant promoter will direct increased expression of a reporter gene in experimental systems. Atopy has also been associated with a gain-of-function mutation of the α subunit of the IL-4 receptor, which is associated with increased signaling following ligation of the receptor. It is too early to know how important these different polymorphisms are in the complex genetics of atopy.

A second type of inherited variation in IgE responses is linked to the MHC class II region and affects responses to specific allergens. Many studies have shown that IgE production in response to particular allergens is associated with certain HLA class II alleles, implying that particular MHC:peptide combinations might favor a strong TH2 response. For example, IgE responses to several ragweed pollen allergens are associated with haplotypes containing the MHC class II allele DRB1*1501. Many individuals are therefore generally predisposed to make TH2 responses and specifically predisposed to respond to some allergens more than others. However, allergies to common drugs such as penicillin show no association with MHC class II or the presence or absence of atopy.

There is evidence that a state of atopy, and the associated susceptibility to asthma, rhinitis, and eczema, can be determined by different genes in different populations. Genetic associations found in one group of patients have frequently not been confirmed in patients of different ethnic origins. There are also likely to be genes that affect only particular aspects of allergic disease. For example, in asthma there is evidence for different genes affecting at least three aspects of the disease phenotype—IgE production, the inflammatory response, and clinical responses to particular types of treatment. Some of the best-characterized genetic polymorphisms of candidate genes associated with asthma are shown in Fig. 12.8, together with possible ways in which the genetic variation may affect the particular type of disease that develops and its response to drugs.

Figure 12.8. Candidate susceptibility genes for asthma.

Figure 12.8

Candidate susceptibility genes for asthma. May also affect response to bronchodilator therapy with β2-adrenergic agonists. †Patients with alleles associated with reduced enzyme production failed to show a beneficial response to a drug (more...)

The prevalence of atopic allergy, and of asthma in particular, is increasing in economically advanced regions of the world, an observation that is best explained by environmental factors. The four main candidate environmental factors are changes in exposure to infectious diseases in early childhood, environmental pollution, allergen levels, and dietary changes. Alterations in exposure to microbial pathogens is the most plausible explanation at present for the increase in atopic allergy. Atopy is negatively associated with a history of infection with measles or hepatitis A virus, and with positive tuberculin skin tests (suggesting prior exposure and immune response to Mycobacterium tuberculosis). In contrast, there is evidence that children who have had attacks of bronchiolitis associated with respiratory syncytial virus (RSV) infection are more prone to the later development of asthma. Children hospitalized with this disease have a skewed ratio of cytokine production away from IFN-γ towards IL-4, the cytokine that induces TH2 responses. It is possible that infection by an organism that evokes a TH1 immune response early in life might reduce the likelihood of TH2 responses later in life and vice versa. It might be expected that exposure to environmental pollution would worsen the expression of atopy and asthma. The best evidence shows the opposite effect, however. Children from the city of Halle in the former East Germany, which has severe air pollution, had a lower prevalence of atopy and asthma than an ethnically matched population from Munich, exposed to much cleaner air. This does not mean that polluted air is not bad for the lungs. The children from Halle had a higher overall prevalence of respiratory disease than their counterparts from Munich, but this was predominantly not allergic in origin.

While it is clear that allergy is related to allergen exposure, there is no evidence that the rising prevalence of allergy is due to any systematic change in allergen exposure. Nor is there any evidence that changes in diet can explain the increase in allergy in economically advanced populations.


Allergic reactions are the result of the production of specific IgE antibody to common, innocuous antigens. Allergens are small antigens that commonly provoke an IgE antibody response. Such antigens normally enter the body at very low doses by diffusion across mucosal surfaces and therefore trigger a TH2 response. The differentiation of naive allergen-specific T cells into TH2 cells is also favored by the presence of an early burst of IL-4, which seems to be derived from a specialized subset of T cells. Allergen-specific TH2 cells produce IL-4 and IL-13, which drive allergen-specific B cells to produce IgE. The specific IgE produced in response to the allergen binds to the high-affinity receptor for IgE on mast cells, basophils, and activated eosinophils. IgE production can be amplified by these cells because, upon activation, they produce IL-4 and CD40 ligand. The tendency to IgE over-production is influenced by genetic and environmental factors. Once IgE is produced in response to an allergen, reexposure to the allergen triggers an allergic response. We will describe the mechanism and pathology of allergic responses in the next part of the chapter.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2001, Garland Science.
Bookshelf ID: NBK27117


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