Immunology_Janeway

Immunology_Janeway. We are all exposed regularly to common environmental agents that can cause allergic reactions in some individuals. While most of the population does not develop clinically significant allergic reactions to the majority of potential allergens, in some surveys over half of the population shows an allergic response to at least one substance in the environment. Some individuals manifest allergic responses to multiple common antigens. A predisposition to become IgE-sensitized to environmental allergens is called atopy, and later in the chapter we discuss the various factors—both genetic and environmental— that may contribute to this predisposition. Genetic factors clearly play a role in predisposing an individual to IgE-mediated allergic disease. If both parents are atopic, a child has a 40–60% chance of developing an IgE-mediated allergy, whereas the risk is much lower, on the order of 10%, if neither parent is atopic. IgE and IgE-mediated allergic diseases.


Immunology_Janeway

Immunology_Janeway. IgE and IgE-mediated allergic diseases. Effector mechanisms in IgE-mediated allergic reactions. Non-IgE-mediated allergic diseases. Fig. 14.1 IgE-mediated reactions to extrinsic antigens. All IgE-mediated responses involve mast-cell degranulation, but the symptoms experienced by the patient can be very different depending, for example, on whether the allergen is injected directly into the bloodstream, is eaten, or comes into contact with the mucosa of the ocular or respiratory tract.


Immunology_Janeway

Immunology_Janeway. IgE is prominent in the defense against extracellular parasitic organisms, especially helminths and protozoa (see Section 11-9). These parasitic organisms are prevalent in developing nations, but most serum IgE in developed nations is directed against innocuous antigens, sometimes causing allergic symptoms (Fig. 14.1). Almost half the population of North America and Europe is sensitized to one or more common environmental antigens, and, although rarely life-threatening, allergic diseases initiated by contact with a specific allergen can cause much distress and lost time from school and work. The burden of allergic diseases in the Western world is considerable, with their prevalence having more than doubled in the past 20 years. Consequently, most clinical and scientific attention paid to IgE has been directed toward its pathologic roles in allergic disease rather than its protective capacity. Until the last decade, developing countries in Africa and the Middle East reported a


Immunology_Janeway

Immunology_Janeway. paid to IgE has been directed toward its pathologic roles in allergic disease rather than its protective capacity. Until the last decade, developing countries in Africa and the Middle East reported a relatively low prevalence of allergy; however, this situation is rapidly changing, probably as a result of Western-style modernization.


Immunology_Janeway

Immunology_Janeway. In this chapter we first consider the mechanisms that favor the sensitization of an individual to an allergen, resulting in the production of antigen-specific IgE. We then describe the IgE-mediated allergic reaction itself—the pathological consequences of the interaction between allergen and the IgE bound to the high-affinity Fcε receptor on mast cells and basophils. Finally, we consider the causes and consequences of other types of immunological hypersensitivity reaction. IgE and IgE-mediated allergic diseases. Immediate hypersensitivity reactions are those allergic reactions caused by activation of mast cells and basophils by multivalent antigen bridging IgE bound to their cell surfaces. IgE differs from other antibody isotypes in being predominantly localized in the tissues, where it is tightly bound to the surfaces IgE and IgE-mediated allergic diseases.


Immunology_Janeway

Immunology_Janeway. Fig. 14.2 Sensitization to an inhaled allergen. Der p 1 is a (third panel), and this IgE becomes bound to Fc receptors on common respiratory allergen that is found in fecal pellets of the resident submucosal mast cells. On a subsequent encounter with house dust mite. When an atopic individual first encounters Der p 1, Der p 1, the allergen binds to the mast cell-bound IgE, triggering subepithelial dendritic cells ingest the allergenic protein and traffic mast-cell activation and the release of mast-cell granule contents, to the draining lymph node, where TH2 cells specific for Der p 1 are which cause the symptoms of the allergic reaction (last panel). produced (first and second panels). Interaction of these T cells with Der p 1 is a protease that cleaves occludin, a protein that helps to Der p 1-specific B cells leads to the production of class-switched maintain epithelial tight junctions; the enzymatic activity of Der p 1 is plasma cells producing Der p 1-specific IgE in the mucosal


Immunology_Janeway

Immunology_Janeway. Der p 1-specific B cells leads to the production of class-switched maintain epithelial tight junctions; the enzymatic activity of Der p 1 is plasma cells producing Der p 1-specific IgE in the mucosal tissues thought to help it pass through the epithelium.


Immunology_Janeway

Immunology_Janeway. of mast cells and some other cell types through the high-affinity IgE receptor FcεRI (see Section 10-24). Binding of antigen to IgE cross-links the high-affinity IgE receptors, causing the release of chemical mediators from the mast cells that can lead to allergic disease (Fig. 14.2). How an initial antibody response to environmental antigens comes to be dominated by IgE production in atopic individuals is still being worked out. In this part of the chapter we describe the current understanding of the factors that contribute to this process. 14-1 Sensitization involves class switching to IgE production on first contact with an allergen.


Immunology_Janeway

Immunology_Janeway. To produce an allergic reaction against a given antigen, an individual must first be exposed to the antigen under conditions that result in the production of IgE antibodies. Allergic symptoms occur when an individual who has been sensitized in this fashion has subsequent exposure to the antigen. Exposure can lead to different clusters of symptoms, characterized by the tissues that are most prominently affected. The most common forms of allergic response in developed countries are to airborne allergens, causing symptoms that affect predominantly the nasal passages (allergic rhinitis), the eyes (allergic conjunctivitis), or the lower airways and lungs (asthma). Ingested allergens can lead to food allergy, sometimes affecting only the gastrointestinal tract (for example, eosinophilic esophagitis), but not infrequently involving locations distant from the site of antigen entry. Reactions that occur at locations distant from the site of entry of the challenging antigen are considered to be


Immunology_Janeway

Immunology_Janeway. but not infrequently involving locations distant from the site of antigen entry. Reactions that occur at locations distant from the site of entry of the challenging antigen are considered to be systemic reactions, and are thought to occur because of spread of the antigen throughout the body via the blood circulation. Systemic reactions can be limited to a single distant organ, causing hives (also called urticaria) when they target the skin, wheezing (or bronchospasms) when they involve the lungs, and life-threatening lowering of the blood pressure when they target the vascular system. Serious systemic reactions are designated by the term anaphylaxis. It is not known why sensitization with a particular allergen in one individual leads to local reactions at the time of allergen challenge, whereas sensitization with the same allergen can yield anaphylaxis in another individual. In fact, even in a single individual, a challenge that usually yields only a mild local reaction can be


Immunology_Janeway

Immunology_Janeway. whereas sensitization with the same allergen can yield anaphylaxis in another individual. In fact, even in a single individual, a challenge that usually yields only a mild local reaction can be followed at the time of another challenge by a severe systemic reaction.


Immunology_Janeway

Immunology_Janeway. Atopic individuals often develop sensitization to many different antigens, and can express multiple forms of allergic symptoms, which depend on the route and quantity of allergen—for example, atopic eczema that develops in childhood in response to sensitization to food antigens is followed in a sizable proportion of those individuals developing allergic rhinitis and/or asthma in response to airborne allergens. This progression of allergic responses in some individuals from atopic eczema in childhood to allergic rhinitis and eventually to asthma in later life has been termed the atopic march. Allergic reactions in non-atopic people, in contrast, are predominantly due to sensitization to one specific allergen, such as bee venom or a drug such as penicillin, and can develop at any time of life. It is important to remember, however, that not all encounters with a potential allergen will lead to sensitization, and not all sensitizations will lead to a symptomatic allergic response, even in


Immunology_Janeway

Immunology_Janeway. It is important to remember, however, that not all encounters with a potential allergen will lead to sensitization, and not all sensitizations will lead to a symptomatic allergic response, even in atopic individuals.


Immunology_Janeway

Immunology_Janeway. The immune response leading to IgE production in response to antigen is driven by two main groups of signals that together are typical of type 2 immune reactions. The first consists of signals that favor the differentiation of naive T cells to a TH2 phenotype. The second comprises TH2 cytokines and co-stimulatory signals that stimulate B cells to switch to the production of IgE. As described in Section 9-21, the fate of a naive CD4 T cell responding to an antigenic 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, the antigen dose, and the route of presentation. Exposure to IL-4, IL-5, IL-9, and IL-13 favors the development of TH2 cells, whereas exposure to IFN-γ and IL-12 (and its relative IL-27) favors TH1-cell development.


Immunology_Janeway

Immunology_Janeway. Immune defenses against multicellular parasites are found mainly at the sites of parasite entry, namely, under the skin and in the mucosal tissues of the airways and the gut. Cells of the innate and adaptive immune systems at these sites are specialized to secrete cytokines that promote a type 2 response to parasitic infection. In the presence of an invading parasite, dendritic cells taking up antigens in these tissues migrate to regional lymph nodes, where they tend to drive antigen-specific naive CD4 T cells to become effector TH2 cells. TH2 cells themselves secrete IL-4, IL-5, IL-9, and IL-13, thus maintaining an environment in which further differentiation of TH2 cells is favored. The cytokine IL-33, which can be produced by activated mast cells and by damaged or injured epithelial cells, also contributes to amplification of the TH2 response. IL-33 can act directly on TH2 cells via the IL-33 receptors that these cells express. Allergic responses against common environmental


Immunology_Janeway

Immunology_Janeway. cells, also contributes to amplification of the TH2 response. IL-33 can act directly on TH2 cells via the IL-33 receptors that these cells express. Allergic responses against common environmental antigens are normally avoided because mucosal dendritic cells that encounter antigen in the absence of danger signals such as those provoked by microbial infection generally induce naive CD4 T cells to differentiate into antigen-specific regulatory T cells (T cells). The T cells suppress T-cell responses and contribute to a state of tolerance to the antigen (see Section 12-8) rather than allowing the production of effector or helper cells that might support the production of an allergic response.


Immunology_Janeway

Immunology_Janeway. The cytokines and chemokines produced by TH2 cells both amplify the TH2 response and stimulate the class switching of activated B cells to IgE production. As we saw in Chapter 10, IL-4 or IL-13 provides the first signal that switches B cells to IgE production. IL-4 and IL-13 acting on T and B lymphocytes activate the Janus-family tyrosine kinases Jak1 and Jak3 (see Section 7-20), ultimately leading to phosphorylation (and thereby activation) of the transcriptional regulator STAT6. Mice lacking functional IL-4, IL-13, or STAT6 have impaired TH2 responses and an impaired ability to switch to production of IgE, demonstrating the key importance of these cytokines and their signaling pathways in the IgE response. The second signal for IgE production is a co-stimulatory interaction between CD40 ligand on the T-cell surface and CD40 on the B-cell surface. This interaction is essential for all antibody class switching. Patients with a genetic deficiency of CD40 ligand produce no IgG, IgA, or


Immunology_Janeway

Immunology_Janeway. ligand on the T-cell surface and CD40 on the B-cell surface. This interaction is essential for all antibody class switching. Patients with a genetic deficiency of CD40 ligand produce no IgG, IgA, or IgE, and display a hyper-IgM syndrome phenotype (see Section 13-9).


Immunology_Janeway

Immunology_Janeway. Murine mast cells and basophils can also produce the signals that drive IgE production by B cells. Mast cells and basophils express FcεRI, and when they are activated by antigen cross-linking their FcεRI-bound IgE, they express cell-surface CD40 ligand and secrete IL-4. Similar data exist for human basophils that have also been primed by inflammatory stimuli (Fig. 14.3). Like TH2 cells, they can induce class switching and IgE production by B cells. Generally, class switching to IgE occurs in lymph nodes (secondary lymphoid organs) that drain the site of antigen entry or in inducible lymphoid follicles (also called tertiary lymphoid tissues) that form in mucosal and other tissues at sites of persistent inflammation. The potential for formation in mucosal tissues of tertiary lymphoid follicles with germinal centers containing B cells that have switched to production of IgE means that mast cells or basophils can amplify the B-cell response close to the site of the allergic reaction. One


Immunology_Janeway

Immunology_Janeway. with germinal centers containing B cells that have switched to production of IgE means that mast cells or basophils can amplify the B-cell response close to the site of the allergic reaction. One goal of therapy for allergies is to block this amplification process and thus prevent allergic reactions from becoming self-sustaining.


Immunology_Janeway

Immunology_Janeway. In humans, the IgE response, once initiated, can also be amplified by the capture of IgE by Fcε receptors on dendritic cells. Some populations of human immature dendritic cells—for example, the Langerhans cells of the skin— express surface FcεRI in an inflammatory setting, and once anti-allergen IgE antibodies have been produced, they can bind to these receptors. The bound IgE forms a highly effective trap for allergen, which is then efficiently processed by the dendritic cell for presentation to naive T cells, thus maintaining and reinforcing the TH2 response to the allergen. Eosinophils have also been reported to express IgE receptors, but this is still controversial. Eosinophils may act as antigen-presenting cells to T cells in a standard fashion after upregulation of eosinophil MHC class II and co-stimulatory molecules; however, this probably occurs in tissues where activated T cells have migrated rather than in lymph nodes where naive T cells are primed by dendritic cells.


Immunology_Janeway

Immunology_Janeway. 14-2 Although many types of antigens can cause allergic sensitization, proteases are common sensitizing agents. Most airborne allergens are relatively small, highly soluble proteins that are carried on dry particles such as pollen grains or mite feces (Fig. 14.4). On contact with the mucus-covered epithelia of the eyes, nose, or airways, the soluble allergen is eluted from the particle and diffuses into the mucosa, where it can be picked up by dendritic cells and provoke sensitization (see Fig. 14.2). At mucosal surfaces, allergens are typically presented to the immune system at low concentrations. It has been estimated that the maximum exposure of a person to the common pollen allergens in ragweed (Ambrosia species) does not exceed 1 μg per year. It is thought that low-dose sensitization favors formation of a strong TH2 response. Consequently, these minute doses of allergen can provoke irritating and even life-threatening TH2-driven IgE antibody responses in atopic individuals.


Immunology_Janeway

Immunology_Janeway. Antigen exposures that lead to allergic responses do not always involve such low doses of antigen, especially at other tissue sites. For example, bee venom is a frequent cause of allergic sensitization, and individual bee stings result in the injection into the skin of 20–75 μg of bee venom (1 to 2 orders of magnitude more than the total dose of ragweed antigen that is inhaled into the airways). In the case of food allergy, ingestion of many grams of an allergenic food into the gastrointestinal tract over prolonged periods of time can lead to sensitization. Sensitization can also occur in response to small or large doses of injected antigens. For example, before the introduction of recombinant


Immunology_Janeway

Immunology_Janeway. Top panel: IgE secreted by plasma cells binds to the high-affinity IgE receptor on basophils (illustrated here) and mast cells. Bottom panel: when the surface-bound IgE is cross-linked by antigen, these cells express CD40 ligand (CD40L) and secrete IL-4, which in turn binds to IL-4 receptors (IL-4R) on the activated B cell. Together with ligation of B-cell CD40 by basophil CD40L, this activates class switching by the B cell and the production of more IgE. These interactions can occur in vivo at the site of allergen-triggered inflammation, for example, in bronchus-associated lymphoid tissue.


Immunology_Janeway

Immunology_Janeway. human insulin, individuals with diabetes could develop allergy to porcine insulin, usually administered in doses of 1–2 milligrams per injection. In contrast, doses of penicillin-type drugs (including cephalosporins and other β-lactam-containing antibiotics) that can lead to sensitization when administered by intramuscular or intravenous injection are usually in the 1to 2-gram per injection range. Considerable effort has been directed toward identifying physical, chemical, or functional characteristics that might be common for all allergens, but no common characteristics of all allergens have emerged. Thus, it appears that in a susceptible host, essentially any antigenic molecule can elicit an allergic response.


Immunology_Janeway

Immunology_Janeway. While any type of molecule appears to be able to elicit an allergic response, the search for common features of allergenic molecules has demonstrated that some clinically significant allergens are proteases. One ubiquitous protease allergen is the cysteine protease Der p 1, which is present in the feces of the house dust mite Dermatophagoides pteronyssinus. Der p 1 provokes allergic reactions in about 20% of the North American population. This enzyme has been found to cleave occludin, a protein component of intercellular tight junctions in the airway mucosa. 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 (see Fig. 14.2). The tendency of proteases to induce IgE production is highlighted by individuals with Netherton’s syndrome (Fig. 14.5), which is characterized by high levels of IgE and multiple allergies.


Immunology_Janeway

Immunology_Janeway. 14.2). The tendency of proteases to induce IgE production is highlighted by individuals with Netherton’s syndrome (Fig. 14.5), which is characterized by high levels of IgE and multiple allergies. This disease is caused by a mutation in SPINK5 (serine protease inhibitor Kazaltype 5), which encodes the serine protease inhibitor LEKTI (lymphoepithelial Kazal type-related inhibitor). LEKTI is expressed in the most differentiated viable layer of the skin (the granular cell layer), just internal to the cornified cell layer of the epidermis. Absence of LEKTI in Netherton’s syndrome results in overly active epidermal kallikreins, proteases that can cleave desmosomes in the skin, leading to keratinocyte shedding and disturbed skin barrier function. Overly active kallikrein 5 leads to overexpression in the skin of TNF-α, ICAM-1, IL-8, and thymic stromal lymphopoietin (TSLP). TSLP is a major agonist of allergic manifestations in the skin, and is essential for the development of both the


Immunology_Janeway

Immunology_Janeway. in the skin of TNF-α, ICAM-1, IL-8, and thymic stromal lymphopoietin (TSLP). TSLP is a major agonist of allergic manifestations in the skin, and is essential for the development of both the eczematous skin lesions and the allergic manifestations (including food allergy) seen in Netherton’s syndrome. Additionally, LEKTI is thought to inhibit the proteases released by bacteria such as Staphylococcus aureus. This may be of special significance in the eczematous process, since a very large fraction of individuals with chronic eczema show persistent colonization with S. aureus and resolution of the eczema is facilitated by elimination of the Staphylococcus, in addition to suppression of the inflammatory response.


Immunology_Janeway

Immunology_Janeway. The observation that loss-of-function mutations in a protease inhibitor in Netherton’s syndrome led to the development of multiple allergies provides additional support for the possibility that protease inhibitors might be novel therapeutic targets in some allergic disorders. Furthermore, the cysteine protease papain, derived from the papaya fruit, is used as a meat. Papain can


Immunology_Janeway

Immunology_Janeway. Fig. 14.5 Netherton’s syndrome illustrates the association of proteases with the development of high levels of IgE and allergy. This 26-year-old man with Netherton’s syndrome, caused by a deficiency in the protease inhibitor SPINK5, had persistent erythroderma (redness of the skin), recurrent infections of the skin and other tissues, and multiple food allergies associated with high serum IgE levels. In the top photograph, large erythematous plaques covered with scales and erosions are visible over the upper trunk. The lower panel shows a section through the skin of the same patient. Note the psoriasis-like hyperplasia of the epidermis. Neutrophils are also present in the epidermis. In the dermis, a perivascular infiltrate is evident. Although not discernible at this magnification, the infiltrate contains both mononuclear cells and neutrophils. Source: Sprecher, E., et al.: Clin. Exp. Dermatol. 2004, 29:513–517.


Immunology_Janeway

Immunology_Janeway. cause allergic reactions in workers preparing the enzyme. Allergies caused by environmental allergens present in the workplace are called occupational allergies. Although Der p 1 and papain are potent allergens, not all allergens are enzymes. In fact, two allergens identified from filarial worms are enzyme inhibitors, and, in general, most allergenic pollen-derived proteins do not seem to possess enzymatic activity.


Immunology_Janeway

Immunology_Janeway. Knowledge of the identity of allergenic proteins can be important to public health and can have economic significance, as illustrated by the following cautionary tale. Some years ago, the gene for 2S albumin from Brazil nuts, a protein that is rich in methionine and cysteine, was transferred by genetic engineering into soybeans intended for animal feed. This was done to improve the nutritional value of soybeans, which are intrinsically poor in these sulfur-containing amino acids. This experiment led to the discovery that 2S albumin is the major Brazil nut allergen. Injection of extracts of the genetically modified soybeans into the epidermis triggered an allergic skin response in people allergic to Brazil nuts. As there could be no guarantee that the modified soybeans could be kept out of the human food chain if they were produced on a large scale, development of this genetically modified food was abandoned.


Immunology_Janeway

Immunology_Janeway. 14-3 Genetic factors contribute to the development of IgE-mediated allergic disease. Susceptibility to development of allergic disease has both genetic and environmental components. In studies performed in Western industrialized countries, up to 40% of the test population shows an exaggerated tendency to mount IgE responses to a wide variety of common environmental allergens. Atopic individuals often develop two or more allergic diseases such as allergic rhinoconjunctivitis, allergic asthma, or allergic eczema. Individuals who manifest all three of these disorders are said to express the atopic triad.


Immunology_Janeway

Immunology_Janeway. Genome-wide association studies (GWASs) have uncovered more than 40 susceptibility genes for the allergic skin condition atopic eczema (also known as atopic dermatitis) and for allergic asthma (Fig. 14.6). Some of the susceptibility genes are common to both atopic eczema and allergic asthma, suggesting that some aspects of the atopic diathesis (that is, predisposition) are governed by similar genetic factors regardless of the organs that are the targets of the allergic response. For example, specific alleles at the IL-33 receptor and IL-13 loci show strong association with both allergic asthma and atopic eczema. This sharing of genetic risk alleles by allergic asthma and atopic eczema is consistent with the finding that these two disorders are commonly found together in atopic families, with some family members manifesting both disorders, while other family members may manifest only atopic eczema or allergic asthma, but not both. There are, however, alleles of many genes (especially


Immunology_Janeway

Immunology_Janeway. with some family members manifesting both disorders, while other family members may manifest only atopic eczema or allergic asthma, but not both. There are, however, alleles of many genes (especially genes that regulate skin-barrier function) that show linkage to atopic eczema without enhancing the risk for allergic asthma or allergic rhinoconjunctivitis, indicating that other genetic factors contribute importantly to the phenotype of allergic responsiveness any individual may express. In addition, there are many ethnic differences in the susceptibility genes for a given allergic disease. Several of the chromosome regions associated with allergy or asthma are also associated with the inflammatory disease psoriasis and with autoimmune diseases, suggesting that these loci contain genes that are involved in exacerbating inflammation.


Immunology_Janeway

Immunology_Janeway. One candidate susceptibility gene for both allergic asthma and atopic eczema resides at chromosome 11q12–13 and encodes the β subunit of the high-affinity IgE receptor FcεRI. Another region of the genome associated with allergic disease, 5q31–33, contains at least four types of candidate genes that might be responsible for increased susceptibility. First, there is a cluster of tightly linked genes for cytokines that enhance IgE class switching, eosinophil Fig. 14.6 Susceptibility loci for asthma. Loci that have shown linkage on the basis of GWAS or targeted gene analysis are listed, separated into genes that are expressed in epithelial cells of the airways, genes that regulate the differentiation and/or function of CD4 T cells and ILC2s, and genes with other miscellaneous or unknown functions.


Immunology_Janeway

Immunology_Janeway. survival, and mast-cell proliferation, all of which help to produce and maintain an IgE-mediated allergic response. This cluster includes the genes for IL-3, IL-4, IL-5, IL-9, IL-13, and granulocyte–macrophage colony-stimulating factor (GM-CSF). In particular, genetic variation in the promoter region of the gene encoding IL-4 has been associated with raised IgE levels in atopic individuals. The variant promoter directs increased expression of a reporter gene in experimental systems and thus might produce increased IL-4 in vivo. Atopy has also been associated with a gain-of-function mutation of the α subunit of the IL-4 receptor, with the mutation causing increased signaling after ligation of the receptor.


Immunology_Janeway

Immunology_Janeway. A second set of genes in this region of chromosome 5 belongs to the TIM family (for T cell, immunoglobulin domain, and mucin domain). The genes in this set encode three T-cell-surface proteins (Tim-1, -2, and -3) and one protein expressed primarily on antigen-presenting cells (Tim-4). In mice, Tim-3 protein is specifically expressed on TH1 cells and negatively regulates TH1 responses, whereas Tim-2 (and to a lesser extent Tim-1) is preferentially expressed in TH2 cells and negatively regulates them. Mouse strains that carry different variants of the Tim genes differ both in their susceptibility to allergic inflammation of the airways and in the production of IL-4 and IL-13 by their T cells. Although no homolog of the mouse Tim-2 gene has been found in humans, inherited variation in the three human TIM genes has been correlated with airway hyperreactivity or hyperresponsiveness. In this condition, contact not only with allergen but also with nonspecific irritants causes airway


Immunology_Janeway

Immunology_Janeway. the three human TIM genes has been correlated with airway hyperreactivity or hyperresponsiveness. In this condition, contact not only with allergen but also with nonspecific irritants causes airway narrowing (bronchoconstriction), with wheezy breathlessness similar to that seen in asthma. The third candidate susceptibility gene in this part of the genome encodes p40, one of the two subunits of IL-12 and IL-23. These cytokines promote TH1 and TH17 responses, and genetic variation in p40 expression that could cause reduced production of IL-12 and IL-23 was found to be associated with more severe asthma. A fourth candidate susceptibility gene which encodes the β-adrenergic receptor is also located in this region. Variation in this receptor might be associated with alteration in smooth muscle responsiveness to endogenous and pharmacological ligands.


Immunology_Janeway

Immunology_Janeway. The detection of multiple potential susceptibility genes illustrates a common challenge in identifying the genetic basis of complex disease traits. Relatively small regions of the genome, identified as containing genes for altered disease susceptibility, may contain many good candidates, judging by their known physiological activities. Identifying the gene, or genes, that truly lead to expression of the disease may require studies of several very large populations of patients and controls. For chromosome 5q31–33, for example, it is still too early to know how important each of the different polymorphisms is in the complex genetics of atopy.


Immunology_Janeway

Immunology_Janeway. A second type of inherited variation in IgE responses is linked to the HLA class II region (the human MHC class II region), and it affects responses to specific allergens, rather than a general susceptibility to atopy. IgE production in response to particular allergens is associated with certain HLA class II alleles, implying that particular peptide:MHC combinations might favor a strong TH2 response; for example, IgE responses to several ragweed pollen allergens are associated with haplotypes containing the HLA class II allele DRB1*1501. Many people are therefore generally predisposed to make TH2 responses and are specifically predisposed to respond to some allergens more than others. Allergic responses to drugs such as penicillin were originally thought to show no association with HLA class II or with the presence or absence of atopy. Recent studies, however, have shown evidence that some drugs can interact with specific HLA alleles in a way that changes the structure of peptide


Immunology_Janeway

Immunology_Janeway. class II or with the presence or absence of atopy. Recent studies, however, have shown evidence that some drugs can interact with specific HLA alleles in a way that changes the structure of peptide antigens bound in the groove of the HLA molecule so that these altered peptides elicit an autoimmune-type reaction. An example of this is the binding of the seizure medication carbamazepine with HLA-B15:02 and peptide bound in this HLA-B allele. The immune response to this carbamazepine:peptide:HLA-B complex can lead to development of toxic epidermal necrolysis, a severe immune-mediated skin reaction in which widespread skin loss occurs due to necrosis, leaving the skin looking scalded.


Immunology_Janeway

Immunology_Janeway. There are also likely to be genes that affect only particular aspects of allergic disease. In asthma, for example, there is evidence that different genes affect at least three aspects of the disease—IgE production, the inflammatory response, and clinical responses to particular treatments. On chromosome 20, polymorphism of the gene encoding ADAM33, a metalloproteinase expressed by bronchial smooth muscle cells and lung fibroblasts, has been associated with asthma and bronchial hyperreactivity. This is likely to be an example of genetic variation in the pulmonary inflammatory response and in the pathological anatomical changes that occur in the airways (airway remodeling). In the skin, filaggrin importantly contributes to normal skin barrier function by binding keratin molecules into the lipid envelope of cornifying keratinocytes. Loss-of-function mutations in the gene encoding filaggrin lead to the development of eczema. Through unknown mechanisms, filaggrin mutations also can


Immunology_Janeway

Immunology_Janeway. the lipid envelope of cornifying keratinocytes. Loss-of-function mutations in the gene encoding filaggrin lead to the development of eczema. Through unknown mechanisms, filaggrin mutations also can contribute to the development of asthma. Almost half of people in the United States who suffer from severe eczema have at least one mutated filaggrin allele. Between 7 and 10% of Caucasians carry a loss-of-function mutation in filaggrin, and the frequency of this mutation is considerably higher in individuals with asthma.


Immunology_Janeway

Immunology_Janeway. 14-4 Environmental factors may interact with genetic susceptibility to cause allergic disease. Studies of susceptibility suggest that environmental factors and genetic variation each account for about 50% of the risk of developing atopy. The prevalence of atopic allergic diseases, and of asthma in particular, is increasing in economically advanced regions of the world, and this is likely due to the impact of changes in certain environmental factors on individuals with genetic backgrounds that predispose them toward atopy. Interestingly, although the incidence of asthma is lower in economically underdeveloped regions of Africa, Americans of African ancestry show increased asthma frequency and severity compared with Americans not of African ancestry. This shows a clear impact of environment on the expressivity of genetic influences.


Immunology_Janeway

Immunology_Janeway. The prevalence of atopy and especially allergic asthma has been steadily increasing in the developed world for the past 50–60 years. One hypothesis for this steady increase is changes in exposure to infectious diseases in early childhood as our population has moved increasingly from rural into urban environments. This shift has meant less early-life exposure to microorganisms associated with farm animals and microorganisms in the soil. This change in exposure is thought to lead to alterations in the intestinal microbiota, which performs an important immunomodulatory function (discussed in Chapter 12). Changes in exposure to ubiquitous microorganisms as a possible cause of increased atopy was first suggested in 1989, ultimately giving rise to the hygiene hypothesis (Fig. 14.7). The original proposition was that less hygienic environments, particularly those encountered in less developed rural settings, predispose to infections early in childhood, which help to protect against the


Immunology_Janeway

Immunology_Janeway. proposition was that less hygienic environments, particularly those encountered in less developed rural settings, predispose to infections early in childhood, which help to protect against the development of atopy and allergic asthma. It was originally proposed that the protective effect might be due to mechanisms that skew immune responses away from the production of TH2 cells (and their associated cytokines, which dispose toward IgE production) and toward the production of TH1 cells. This would impede responses that favor the production of IgE and promote responses that suppress class switching to IgE.


Immunology_Janeway

Immunology_Janeway. Suggesting that this interpretation was overly simplistic was the strong negative correlation between infection by helminths (such as hookworms and schistosomes) and the development of allergic disease. A study in Venezuela showed that children treated for a prolonged period with antihelminthic agents had


Immunology_Janeway

Immunology_Janeway. Fig. 14.7 Genes, the environment, and atopic allergic diseases. Both inherited and environmental factors are important determinants of the likelihood of developing allergic disease. Many genes are known to influence the development of asthma (see Fig. 14.6). The postulate of the ‘hygiene hypothesis’ is that exposure to some infections and to common environmental microorganisms in infancy and childhood drives the immune system toward a general state of non-atopy. In contrast, children who have a genetic susceptibility to atopy and who live in an environment with low exposure to infectious disease and environmental microorganisms, or who received multiple courses of antibiotics in infancy and early childhood, are thought not to develop efficient immunoregulatory mechanisms and to be most susceptible to the development of atopic allergic disease.


Immunology_Janeway

Immunology_Janeway. a higher prevalence of atopy than did untreated and heavily parasitized children. As helminths provoke a strong TH2-mediated IgE response, this seemed inconsistent with the hygiene hypothesis.


Immunology_Janeway

Immunology_Janeway. One possible explanation for this apparent inconsistency suggests that all types of infection might protect against the development of atopy because the host responses they elicit include the production of cytokines such as IL-10 and TGF-β, perhaps as part of the homeostatic responses that occur as the infection is being controlled. IL-10 and TGF-β suppress the formation of both TH1 and TH2 responses, and IL-10 suppresses TH17 responses (see Sections 9-21 and 9-23). A large proportion of allergic reactions are initiated by antigens that enter though mucosal surfaces such as the respiratory or intestinal epithelium. As described in Chapter 12, the human mucosal immune system has evolved mechanisms of regulating responses to commensal flora and environmental antigens (such as food antigens) that involve the generation of IL-10/TGF-βproducing Treg cells. The idea underlying the current version of the hygiene hypothesis is that decreased early exposure to common microbial pathogens and


Immunology_Janeway

Immunology_Janeway. that involve the generation of IL-10/TGF-βproducing Treg cells. The idea underlying the current version of the hygiene hypothesis is that decreased early exposure to common microbial pathogens and commensals in some way makes the body less efficient at producing these Treg cells, thus increasing the risk of making an allergic response to a common environmental antigen.


Immunology_Janeway

Immunology_Janeway. In support of a role for disturbed immunoregulatory pathways in susceptibility to asthma is evidence that exposure to certain types of childhood infection, with the important exception of some respiratory infections that we consider below, helps to protect against the development of allergic disease. Younger children from families with three or more older siblings and children aged less than 6 months who are exposed to other children in daycare facilities— situations linked to a greater exposure to infections—appear to be partially protected against atopy and asthma. Additionally, children with early-life exposure to a farm or ones having a dog are also somewhat protected against development of atopy and asthma, presumably because of their exposure to farmor pet-associated microbes. Furthermore, early colonization of the gut by commensal bacteria such as lactobacilli and bifidobacteria, or infection by gut pathogens such as Toxoplasma gondii or Helicobacter pylori, is associated with


Immunology_Janeway

Immunology_Janeway. early colonization of the gut by commensal bacteria such as lactobacilli and bifidobacteria, or infection by gut pathogens such as Toxoplasma gondii or Helicobacter pylori, is associated with a reduced prevalence of allergic disease. There is also emerging evidence that, conversely, repeated exposure to antibiotics in early life increases the risk of developing asthma.


Immunology_Janeway

Immunology_Janeway. A history of infection with hepatitis A virus also seems to have a negative association with atopy. A possible explanation for this association is that the human counterpart of the murine Tim-1 protein (see Section 14-3) is the cellular receptor for hepatitis A virus (designated HAVCR1). The infection of T cells by hepatitis A virus could thus directly influence their differentiation and cytokine production, limiting the development of an IgE-generating response.


Immunology_Janeway

Immunology_Janeway. In contrast to these negative associations between childhood infection and the development of atopy and asthma is evidence that children who have had attacks of bronchiolitis associated with respiratory syncytial virus (RSV) infection are more prone to developing asthma later on. Children hospitalized with RSV infection have a skewed ratio of cytokine production away from IFN-γ toward IL-4, presumably increasing their likelihood of developing TH2 responses and increased production of IgE. This effect of RSV appears to depend on age at first infection. Experimental infection of neonatal mice with RSV was followed by lower increases in the production of IFN-γcompared with mice that received experimental RSV infection at 4 or 8 weeks of age. When the mice were rechallenged at 12 weeks of age with RSV infection, animals that had been primarily infected as neonates had more severe lung inflammation than animals first infected at 4 or 8 weeks of age.


Immunology_Janeway

Immunology_Janeway. Other environmental factors that might contribute to the increase in atopic disease are changes in diet, allergen exposure, atmospheric pollution, and tobacco smoke. Pollution has been blamed for an increase in the prevalence of nonallergic cardiopulmonary diseases such as chronic bronchitis, but an association with allergic disease has been more difficult to demonstrate. There is, however, increasing evidence for an interaction between allergens and pollution, particularly in genetically susceptible individuals. Diesel exhaust particles are the best-studied pollutant in this context; they increase IgE production 20to 50-fold when combined with allergen, with an accompanying shift to TH2 cytokine production. Reactive oxidant chemicals such as ozone are generated as a result of such pollution, and individuals less able to deal with this onslaught may be at increased risk of allergic disease.


Immunology_Janeway

Immunology_Janeway. Genes that might be governing this aspect of susceptibility are GSTP1 and GSTM1, members of the glutathione-S-transferase superfamily that are important in preventing oxidant stress. Individuals who were allergic to ragweed pollen and who carried particular variant alleles of these genes showed an increased airway hyperreactivity when challenged with the allergen-plus-diesel exhaust particles, compared with the allergen alone. A study in Mexico City on the effects of atmospheric ozone levels on atopic children with allergic asthma also found that the children carrying the null allele of GSTM1 were more susceptible than noncarriers to airway hyperreactivity when exposed to given levels of ozone. Underscoring the potential for reactive oxygen species such as ozone and superoxide to contribute to asthma exacerbation, studies using mice indicate that airway myeloid cells that produce high levels of super-oxide worsen antigen-induced airway hyperreactivity. Inhibitors of NADPH oxidase,


Immunology_Janeway

Immunology_Janeway. to asthma exacerbation, studies using mice indicate that airway myeloid cells that produce high levels of super-oxide worsen antigen-induced airway hyperreactivity. Inhibitors of NADPH oxidase, required for the production of superoxide, reduce antigen-induced airway hyperreactivity in sensitized and challenged animals, whereas adoptive transfer of superoxide-producing myeloid cells into the airways of sensitized and challenged mice causes marked exacerbation of hyperresponsiveness.


Immunology_Janeway

Immunology_Janeway. 14-5 Regulatory T cells can control allergic responses.


Immunology_Janeway

Immunology_Janeway. The observation that treatment of peripheral blood mononuclear cells (consisting primarily of lymphocytes and monocytes) from atopic individuals with anti-CD3 and anti-CD28 stimulates production of substantial quantities of TH2 cytokines, whereas similar treatment of cells from non-atopic individuals does not, suggests that circulating leukocytes in atopic individuals have been previously stimulated in a fashion that programs them to generate type 2 responses. An increasing number of studies suggest that regulatory mechanisms that normally serve to suppress overly aggressive type 2 responses are also abnormal in subjects with atopy. When peripheral blood CD4+CD25+ Treg cells from atopic individuals are co-cultured with polyclonally activated CD4+ T cells, they are less effective at suppressing TH2 cytokine production compared with similar Treg cells from non-atopic individuals, and this defect is even more pronounced during the pollen season. More evidence for a role for Treg cells in


Immunology_Janeway

Immunology_Janeway. TH2 cytokine production compared with similar Treg cells from non-atopic individuals, and this defect is even more pronounced during the pollen season. More evidence for a role for Treg cells in atopy comes from mice deficient in the transcription factor FoxP3, the master switch for producing both natural (thymus-derived) and some types of induced Treg cells. These mice develop several manifestations of atopy, including increased numbers of blood eosinophils and increased levels of circulating IgE, as well as spontaneous allergic airway inflammation. Manipulation of the Treg pathway can ameliorate experimental asthmatic inflammation in mice. Increasing expression of the anti-inflammatory enzyme indoleamine 2,3-dioxygenase (IDO) by treatment with IFN-γ or by unmethylated CpG DNA can induce the generation or activation of Treg cells. Induction of IDO activity in resident dendritic cells in the lung by stimulation with CpG DNA enhances Treg activity and ameliorates experimental asthma in


Immunology_Janeway

Immunology_Janeway. the generation or activation of Treg cells. Induction of IDO activity in resident dendritic cells in the lung by stimulation with CpG DNA enhances Treg activity and ameliorates experimental asthma in mice. These findings suggest that therapies aiming to enhance Treg function could be beneficial in asthma and other atopic disorders. Other immunoregulatory molecules that might serve as immunotherapeutic agents for treatment of asthma include the cytokines IL-35 and IL-27, which, like IL-10, can inhibit TH2 responses. Alternatively, blockade of the cytokine IL-31 is anticipated to be therapeutically beneficial since IL-31 promotes TH2-driven inflammation.


Immunology_Janeway

Summary.

Immunology_Janeway. Summary.


Immunology_Janeway

Immunology_Janeway. Allergens are generally innocuous antigens that commonly provoke an IgE antibody response in susceptible individuals. Such antigens normally enter the body at very low doses by diffusion across mucosal surfaces and trigger a type 2 immune response. The differentiation of naive allergen-specific T cells into TH2 cells is favored by cytokines such as IL-4 and IL-13. Allergen-specific TH2 cells producing IL-4 and IL-13 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 and basophils. IgE production can be amplified by these cells because, upon activation, they produce IL-4 and express CD40 ligand. The tendency to IgE overproduction is influenced by both genetic and environmental factors. Once IgE has been produced in response to an allergen, reexposure to the allergen triggers an allergic response. We describe the mechanism and pathology of the allergic responses themselves in the


Immunology_Janeway

Immunology_Janeway. Once IgE has been produced in response to an allergen, reexposure to the allergen triggers an allergic response. We describe the mechanism and pathology of the allergic responses themselves in the next part of the chapter.


Immunology_Janeway

Immunology_Janeway. Effector mechanisms in IgE-mediated allergic reactions.


Immunology_Janeway

Immunology_Janeway. Allergic reactions are triggered when allergens cross-link preformed IgE bound to the high-affinity receptor FcεRI on mast cells. Mast cells line external mucosal surfaces and serve to alert the immune system to local infection. Once activated, they induce inflammatory reactions by secreting pharmacological mediators such as histamine stored in preformed granules and by synthesizing prostaglandins, leukotrienes, and platelet-activating factor from the plasma membrane. They also release various cytokines and chemokines after activation. In the case of an allergic reaction, they provoke unpleasant reactions to innocuous antigens that are not associated with invading pathogens that need to be expelled. The consequences of IgE-mediated mast-cell activation depend on the dose of antigen and its route of entry; symptoms range from the swollen eyes and rhinitis associated with contact of pollen with the conjunctiva of the eye and the nasal epithelium, to the life-threatening circulatory


Immunology_Janeway

Immunology_Janeway. its route of entry; symptoms range from the swollen eyes and rhinitis associated with contact of pollen with the conjunctiva of the eye and the nasal epithelium, to the life-threatening circulatory collapse that occurs in anaphylaxis (Fig. 14.8). The immediate reaction caused by mast-cell degranulation is followed, to a greater or lesser extent depending on the disease, by a more sustained inflammation, which is due to the recruitment of other effector leukocytes, notably TH2 lymphocytes, eosinophils, and basophils.


Immunology_Janeway

Immunology_Janeway. Fig. 14.8 Mast-cell activation has different effects on different tissues. Increased ˜uid in tissues causing increased ˜ow of lymph to lymph nodes, increased cells and protein in tissues, increased effector response in tissues Hypotension potentially leading to anaphylactic shock Congestion and blockage of airways (wheezing, coughing, phlegm) Swelling and mucus secretion in nasal passages Ocular itching Sneezing Expulsion of gastrointestinal tract contents (diarrhea, vomiting) Decreased airway diameter, increased mucus secretion Eyes, nasal passages, and airways Mast-cell activation and granule release Increased ˜uid secretion, increased peristalsis Increased blood ˜ow, increased permeability Gastrointestinal tract Blood vessels 14-6 Most IgE is cell-bound and engages effector mechanisms of the immune system by pathways different from those of other antibody isotypes.


Immunology_Janeway

Immunology_Janeway. Antibodies engage effector cells such as mast cells by binding to receptors specific for their Fc constant regions. Most antibodies engage Fc receptors only after their antigen-binding sites have bound specific antigen, forming an immune complex of antigen and antibody. IgE is an exception, because it is captured by the high-affinity Fcε receptor (FcεRI) in the absence of bound antigen. This means that, unlike other antibodies, which are found mainly in body fluids, IgE is mostly found fixed on cells that carry this receptor—mast cells in tissues, and basophils in the circulation and at sites of inflammation. The ligation of the cell-bound IgE antibody by specific multivalent antigen triggers the activation of these cells at the sites of antigen entry into the tissues. The release from these activated mast cells of inflammatory lipid mediators, cytokines, and chemokines at sites of IgE-triggered reactions recruits eosinophils and basophils to augment the allergic response. It also


Immunology_Janeway

Immunology_Janeway. these activated mast cells of inflammatory lipid mediators, cytokines, and chemokines at sites of IgE-triggered reactions recruits eosinophils and basophils to augment the allergic response. It also recruits TH2 cells, which can then mount a local type 2 cellular response.


Immunology_Janeway

Immunology_Janeway. There are two types of IgE-binding Fc receptors. The first, FcεRI, expressed on mast cells and basophils, is a high-affinity receptor of the immunoglobulin superfamily (see Section 10-24). When IgE bound to this receptor is cross-linked by specific antigen, it transduces an activating signal through the receptor-bound Lyn tyrosine kinase, which phosphorylates ITAMs on the intracellular domain of the receptor. This recruits and activates the amplifying tyrosine kinase Syk, which phosphorylates and activates a broad range of downstream effector pathways. High levels of IgE, such as those that exist in people with allergic diseases or parasite infections, can result in a marked increase in FcεRI on the surface of mast cells, an enhanced sensitivity of such cells to activation by low concentrations of specific antigen, and a markedly increased, IgE-dependent release of chemical mediators and cytokines.


Immunology_Janeway

Immunology_Janeway. The second IgE receptor, FcεRII, usually known as CD23, is a C-type lectin and is structurally unrelated to FcεRI; it binds IgE with low affinity. CD23 is present on many cell types, including B cells, activated T cells, monocytes, eosinophils, platelets, follicular dendritic cells, and some thymic epithelial cells. This receptor was thought to be crucial for the regulation of IgE levels, but mouse strains in which the gene for CD23 has been inactivated still develop relatively normal polyclonal IgE responses. Nevertheless, CD23 does seem to be involved in enhancing IgE antibody levels in some situations. Responses against a specific antigen are known to be increased in the presence of the antigen complexed with IgE, but such enhancement fails to occur in mice that lack the gene for CD23. This has been interpreted to indicate that CD23 on antigen-presenting cells has a role in the capture of antigen that is complexed with IgE.


Immunology_Janeway

Immunology_Janeway. 14-7 Mast cells reside in tissues and orchestrate allergic reactions. When Paul Ehrlich described mast cells found in the mesentery of rabbits, he called them Mastzellen (‘fattened cells’). Like basophils, mast cells contain granules rich in acidic proteoglycans that take up basic dyes. Mast cells are derived from hematopoietic stem cells but mature locally, often residing near surfaces exposed to pathogens and allergens, such as mucosal tissues and the connective tissues surrounding blood vessels. Mucosal mast cells differ in some of their properties from submucosal or connective tissue mast cells, but both can be involved in allergic reactions. Fig. 14.9 Molecules released by activated mast cells. Mast cells release a wide variety of biologically active proteins and other chemical mediators. The enzymes and toxic mediators listed in the first two rows are released from the preformed granules. The cytokines, chemokines, and lipid mediators are mostly synthesized after activation.


Immunology_Janeway

Immunology_Janeway. The major factors for mast-cell growth and development include stem-cell factor (the ligand for the receptor tyrosine kinase Kit), IL-3, and TH2-associated cytokines such as IL-4 and IL-9. Mice with defective Kit lack differentiated mast cells, and although they produce IgE, they cannot make IgE-mediated inflammatory responses. This shows that such responses depend almost exclusively on mast cells. Mast-cell activation depends on the activation of phosphatidylinositol 3-kinase (PI 3-kinase) in mast cells by Kit, and pharmacological inactivation of the p110δ isoform of PI 3-kinase has been shown to protect mice against allergic responses. Inhibitors of the amplifying tyrosine kinase Syk are also showing promise as blockers of IgE-dependent mast-cell responses.


Immunology_Janeway

Immunology_Janeway. Mast cells express FcεRI constitutively on their surface and are activated when antigens cross-link IgE bound to these receptors (see Fig. 10.43). A relatively low level of allergen is sufficient to trigger degranulation. There are many mast-cell precursors in tissues, and they can rapidly differentiate into mature mast cells in conditions of allergic inflammation, thus aiding the continuation of the allergic response. Mast-cell degranulation begins within seconds of antigen binding, releasing an array of preformed and newly generated inflammatory mediators (Fig. 14.9). Granule contents include the short-lived vasoactive amine histamine, serine esterases, and proteases such as chymase and tryptase.


Immunology_Janeway

Immunology_Janeway. Histamine has four known receptors through which it acts—H1 through H4, each a G-protein-coupled receptor. Histamine acts via the H1 receptor on local blood vessels to cause an immediate increase in local blood flow and vessel permeability. This leads to edema and local inflammation. Histamine is also a major stimulus for itching and sneezing, by virtue of its activation of neural receptors. Acting through the H1 receptor on dendritic cells, histamine can increase antigen-presenting capacity and TH1 cell priming; acting through the H1 receptor on T cells, it can enhance TH1 cell proliferation and IFN-γproduction. By acting through H2, H3, and H4 receptors on a variety of leukocytes and tissue cells, histamine participates in atopic dermatitis, chronic urticaria, and several autoimmune disorders.


Immunology_Janeway

Immunology_Janeway. Human mast cells are classified into subtypes on the basis of their protease content and tissue location. Mast cells in mucosal epithelia express tryptase as their primary serine protease. These cells are designated MCT. Mast cells in the submucosa and other connective tissues predominantly express chymase, tryptase, carboxypeptidase A, and cathepsin G and are designated MCCT. The proteases released by the mast cells activate matrix metalloproteinases, which break down extracellular matrix proteins, causing tissue disintegration and damage. These proteases can exert beneficial effects such as degrading snake and bee venoms, thus helping to suppress allergic responses to these agents.


Immunology_Janeway

Immunology_Janeway. Following activation through FcεRI, in addition to releasing preformed mediators such as histamine and serine proteases that are stored in their intracellular granules, mast cells also synthesize de novo and release chemokines, cytokines, and lipid mediators—prostaglandins, leukotrienes, thromboxanes (collectively called eicosanoids), and platelet-activating factor. MCT and MCCT mast cells, for example, produce the cytokine IL-4, which helps perpetuate type 2 immune responses. These secreted products contribute to both acute and chronic inflammation. The lipid mediators, in particular, can act both rapidly and persistently to cause smooth muscle contraction, increased vascular permeability, and the secretion of mucus, as well as induce the influx and activation of leukocytes, which contribute to allergic inflammation.


Immunology_Janeway

Immunology_Janeway. Eicosanoids derive mainly from the membrane-associated fatty acid arachidonic acid. This is cleaved from membrane phospholipids by phospholipase A2, which is activated at the plasma membrane as a result of cell activation. Arachidonic acid can be modified by either of two pathways to give rise to lipid mediators. Modification via the cyclooxygenase pathway produces the prostaglandins and thromboxanes, whereas leukotrienes are produced via the lipoxygenase pathway. Prostaglandin D2 is the major prostaglandin produced by mast cells and recruits TH2 cells, eosinophils, and basophils, all of which express its receptor (PTGDR). Prostaglandin D2 is critical to the development of allergic diseases such as asthma, and polymorphisms in the PTGDR gene have been linked to an increased risk of developing asthma. The leukotrienes, especially C4, D4, and E4, are also important in sustaining inflammatory responses in tissues. Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen exert


Immunology_Janeway

Immunology_Janeway. asthma. The leukotrienes, especially C4, D4, and E4, are also important in sustaining inflammatory responses in tissues. Nonsteroidal anti-inflammatory drugs such as aspirin and ibuprofen exert their effects by preventing prostaglandin production. They inhibit the cyclooxygenases that act on arachidonic acid to form the ring structure present in prostaglandins.


Immunology_Janeway

Immunology_Janeway. Large amounts of the cytokine tumor necrosis factor (TNF)-α are also released by mast cells after activation. Some comes from stores in the granules; some is newly synthesized by the activated mast cells. TNF-α activates endothelial cells, resulting in increased expression of adhesion molecules, which in turn promotes the influx of pro-inflammatory leukocytes and lymphocytes into the affected tissue (see Chapter 3). Additionally, mast-cell TNF-α contributes importantly to the influx of leukocytes into regional lymph nodes in response to microbial infection of peripheral tissues.


Immunology_Janeway

Immunology_Janeway. Through the action of all of these mediators, IgE-mediated mast-cell activation orchestrates a broad inflammatory cascade that is amplified by the recruitment of several types of leukocytes including eosinophils, basophils, TH2 lymphocytes, and B cells. The biological role of this reaction in normal host immunity is as a defense against parasite infection (see Section 10-25). In an allergic reaction, however, the acute and chronic inflammatory reactions triggered by mast-cell activation have important pathophysiological consequences, as seen in the diseases associated with allergic responses to environmental antigens. The role of mast cells is not, however, limited to IgE-driven pro-inflammatory responses. Increasingly, mast cells are also considered to have a role in immunoregulation. They can be stimulated by neuropeptides such as substance P and by TLR ligands. In response to multiple stimuli, they can secrete the immunosuppressive cytokine IL-10, suppressing


Immunology_Janeway

Immunology_Janeway. Fig. 14.10 Eosinophils secrete a range of highly toxic granule proteins and other inflammatory mediators. As for mast cells (see Fig. 14.9), enzymes and toxic mediators released by eosinophils are largely stored preformed in granules. In contrast, cytokines, chemokines, and lipid mediators are largely synthesized after eosinophil activation. T-cell responses. Conversely, interactions between mast cells and regulatory T cells can prevent mast-cell degranulation. 14-8 Eosinophils and basophils cause inflammation and tissue damage in allergic reactions.


Immunology_Janeway

Immunology_Janeway. Eosinophils are granulocytic leukocytes that originate in bone marrow. They are so called because their granules, which contain arginine-rich basic proteins, are colored bright orange by the acidic stain eosin. In healthy humans, these cells represent less than 6% of the leukocytes in the circulation; most eosinophils are found in tissues, especially in the connective tissue immediately underneath respiratory, gut, and urogenital epithelium, implying a likely role for these cells in defense against invading organisms at these sites. They possess numerous cell-surface receptors, including receptors for cytokines (such as IL-5), Fcγ and Fcα receptors, and the complement receptors CR1 and CR3, through which they can be activated and stimulated to degranulate. For example, parasites coated with IgG, C3b, or IgA can cause eosinophil degranulation. In allergic tissue reactions, the large concentrations of IL-5, IL-3, and GM-CSF that are typically present are likely to contribute to


Immunology_Janeway

Immunology_Janeway. with IgG, C3b, or IgA can cause eosinophil degranulation. In allergic tissue reactions, the large concentrations of IL-5, IL-3, and GM-CSF that are typically present are likely to contribute to degranulation.


Immunology_Janeway

Immunology_Janeway. When activated, eosinophils express two kinds of effector function. First, they can release highly toxic granule proteins and free radicals, which can kill microorganisms and parasites but also can cause significant damage to host tissues in allergic reactions (Fig. 14.10). Second, they can synthesize chemical mediators, including prostaglandins, leukotrienes, and cytokines. These amplify the inflammatory response by activating epithelial cells and by recruiting and activating more eosinophils and leukocytes. In chronic inflammatory responses, eosinophils can contribute to airway tissue remodeling.


Immunology_Janeway

Immunology_Janeway. What were later to be defined as eosinophils were observed in the 19th century in the first pathological description of fatal status asthmaticus (an episode of severe asthma that does not respond to treatment and leads to respiratory failure and death), but the precise role of these cells in allergic disease generally is still unclear. In allergic tissue reactions, for example, those that lead to chronic asthma, mast-cell degranulation, and TH2 activation cause eosinophils to accumulate in large numbers and to become activated. Among other things, eosinophils secrete TH2-type cytokines and in vitro can promote the apoptosis of TH1 cells by their expression of IDO and consequent production of kynurenine, which acts on the TH1 cells. Their apparent promotion of TH2cell expansion may thus be partly due to a relative reduction in TH1-cell numbers. The continued presence of eosinophils is characteristic of chronic allergic inflammation, and eosinophils are thought to be major contributors


Immunology_Janeway

Immunology_Janeway. partly due to a relative reduction in TH1-cell numbers. The continued presence of eosinophils is characteristic of chronic allergic inflammation, and eosinophils are thought to be major contributors to tissue damage. However, the observation that eosinophils accumulate at sites where there are high levels of cell turnover and considerable local stem-cell activity bolsters a growing consensus that eosinophils play an important role in restoring tissue homeostasis after infection and other types of tissue damage.


Immunology_Janeway

Immunology_Janeway. The activation and degranulation of eosinophils is strictly regulated, because their inappropriate activation is harmful to the host. The first level of control acts on the production of eosinophils by the bone marrow. Few eosinophils are produced in the absence of infection or other immune stimulation. But when TH2 cells are activated, cytokines they produce such as IL-5 and GM-CSF increase the production of eosinophils in the bone marrow and their release into the circulation. However, transgenic animals overexpressing IL-5 have increased numbers of eosinophils (eosinophilia) in the circulation but not in their tissues, indicating that the migration of eosinophils from the circulation into tissues is regulated separately, by a second set of controls. The key molecules in this case are the CC chemokines that have been named eotaxins because of their specificity for eosinophils: CCL11 (eotaxin 1), CCL24 (eotaxin 2), and CCL26 (eotaxin 3).


Immunology_Janeway

Immunology_Janeway. The eotaxin receptor on eosinophils, CCR3, is quite promiscuous and binds other CC chemokines, including CCL5, CCL7, and CCL13, which also induce eosinophil chemotaxis and activation. Identical or similar chemokines stimulate mast cells and basophils. For example, eotaxins attract basophils and cause their degranulation. TH2 cells also carry the receptor CCR3 and migrate toward eotaxins.


Immunology_Janeway

Immunology_Janeway. Basophils are also present at the site of an inflammatory reaction, and growth factors for basophils are very similar to those for eosinophils; they include IL-3, IL-5, and GM-CSF. There is evidence for reciprocal control of the maturation of the stem-cell population into basophils or eosinophils. For example, TGF-β in the presence of IL-3 suppresses eosinophil differentiation and enhances that of basophils. Basophils are normally present in very low numbers in the circulation and seem to have a similar role to that of eosinophils in defense against pathogens. Like eosinophils, they are recruited to the sites of IgE-mediated allergic reactions. Basophils express high-affinity FcεRI on their cell surfaces and so have IgE bound. On activation by antigen binding to IgE or by cytokines, they release histamine from their granules and also produce IL-4 and IL-13.


Immunology_Janeway

Immunology_Janeway. Eosinophils, mast cells, and basophils can interact with each other. Eosinophil degranulation releases major basic protein (see Fig. 14.10), which in turn causes the degranulation of mast cells and basophils. This effect is augmented by any of the cytokines that affect eosinophil and basophil growth, differentiation, and activation, such as IL-3, IL-5, and GM-CSF. 14-9 IgE-mediated allergic reactions have a rapid onset but can also lead to chronic responses. Under laboratory conditions, the clinical response of a sensitized individual to challenge by intradermal allergen or inhalation of allergen can be divided into an ‘immediate reaction’ and a ‘late-phase reaction’ (Fig. 14.11). The immediate Fig. 14.11 Allergic reactions in response to test antigens can be divided into an immediate response and a late-phase response.


Immunology_Janeway

Immunology_Janeway. Left panel: the response to an inhaled antigen can be divided into early and late responses. An asthmatic response in the lungs with narrowing of the airways caused by the constriction of bronchial smooth muscle and development of edema can be measured as a fall in the peak expiratory flow rate (PEFR). The immediate response peaks within minutes after antigen inhalation and then subsides, returning to near baseline PEFR. Six to eight hours after antigen challenge, there can be a late-phase response that also results in a fall in the PEFR. The immediate response is caused by the direct effects on blood vessels, nerves, and smooth muscle of rapidly metabolized mediators such as histamine and lipid mediators released by mast cells. The late-phase response is caused by the continued production of these mediators, by the production of vasoactive compounds that dilate blood vessels, and by recruitment of lymphocytes and myeloid cells, which together lead to the production of edema. Right


Immunology_Janeway

Immunology_Janeway. of these mediators, by the production of vasoactive compounds that dilate blood vessels, and by recruitment of lymphocytes and myeloid cells, which together lead to the production of edema. Right panel: a wheal-and-flare allergic reaction develops within a minute or two of intradermal injection of antigen and lasts for up to 30–60 minutes. The more widespread edematous response characteristic of the late phase develops approximately 6 hours later and can persist for up to 2 or 3 days. The photograph shows an intradermal skin challenge with allergen resulting in a wheal-and-flare (early-phase) reaction observed 15 minutes after allergen challenge (left) and a late-phase reaction occurring 6 hours after challenge (right). The allergen was grass pollen extract. Photograph courtesy of S.R. Durham.


Immunology_Janeway

Immunology_Janeway. reaction is due to IgE-mediated mast-cell activation and starts within seconds of allergen exposure. It is the result of the actions of histamine, prostaglandins, and other preformed or rapidly synthesized mediators released by mast cells. These mediators cause a rapid increase in vascular permeability, resulting in visible edema and reddening of the skin (in a skin response) and airway narrowing as result of edema and the constriction of smooth muscle (in an airway response). In the skin, histamine acting on H1 receptors on local blood vessels causes an immediate increase in vascular permeability, which leads to extravasation of fluid and edema. Histamine also acts on H1 receptors on local nerve endings, leading to reflex vasodilation of cutaneous blood vessels and local reddening of the skin. The resulting skin lesion is called a wheal-andflare reaction (see Fig. 14.11, right panel).


Immunology_Janeway

Immunology_Janeway. Whether a late-phase reaction occurs depends on allergen dose and on aspects of the cellular immune activation that are difficult to quantify. At doses of intradermally administered allergen that are deemed safe for skin testing of subjects with allergic asthma, for example, a late reaction occurs in about 50% of individuals who show an immediate response (see Fig. 14.11, right panel). The late reaction peaks between 3 and 9 hours after antigen challenge, and in skin tests becomes obvious as a much increased area and degree of edema (see Fig. 14.11, right panel) that can persist for 24 hours or longer. The late-phase reaction is caused by the continued synthesis and release of inflammatory mediators by mast cells, especially vasoactive mediators such as calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF), which cause vasodilation and vascular leakage that result in edema and the recruitment of eosinophils, basophils, monocytes, and lymphocytes. The


Immunology_Janeway

Immunology_Janeway. (CGRP) and vascular endothelial growth factor (VEGF), which cause vasodilation and vascular leakage that result in edema and the recruitment of eosinophils, basophils, monocytes, and lymphocytes. The importance of this cellular influx is shown by the ability of glucocorticoid medications to block the late-phase response through their inhibition of cell recruitment, whereas glucocorticoids do not block the immediate response. A late-phase reaction can also occur after aerosol exposure to allergen, and is characterized by a second phase of airway narrowing with sustained edema and cellular infiltration into the peribronchial spaces (see Fig. 14.11, left panel).


Immunology_Janeway

Immunology_Janeway. In patients with a clinical history of allergic disease, allergists use the immediate response to help assess and confirm sensitization, and to determine which allergens are responsible. Minute amounts of potential allergens are introduced into the skin by a skin prick—one site for each allergen—and if the individual is sensitive to any of the allergens tested, a wheal-and-flare reaction will occur at the site within a few minutes (see Fig. 14.11, right panel). Although the reaction after the administration of such small amounts of allergen is usually very localized, there is a small risk of inducing anaphylaxis. Another standard test for allergy is to measure the circulating concentration of IgE antibody specific for a particular allergen in a sandwich ELISA (see Appendix I, Section A-4).


Immunology_Janeway

Immunology_Janeway. The late-phase reaction described above occurs under controlled experimental conditions to a single, relatively high dose of allergen and so does not reflect all the effects of long-term natural exposure. In IgE-mediated allergic diseases, a long-term consequence of allergen exposure can be chronic allergic inflammation, which consists of a persistent type 2 immune response with a dominant cellular quality that is driven by TH2 lymphocytes, basophils, eosinophils, and macrophages. These chronic reactions contribute importantly to serious long-term illnesses, such as chronic asthma. In long-standing asthma, for example, the cytokines released by TH2 cells and vasoactive mediators such as calcitonin gene-related peptide and vascular endothelial growth factor result in persistent edema, which results in persistent narrowing of the airways. They can also lead to airway tissue remodeling, which changes the bronchial tissue via smooth muscle hypertrophy (an increase in the size of the


Immunology_Janeway

Immunology_Janeway. which results in persistent narrowing of the airways. They can also lead to airway tissue remodeling, which changes the bronchial tissue via smooth muscle hypertrophy (an increase in the size of the muscle cells) and hyperplasia (an increase in the number of cells), subepithelial deposition of collagen, and often goblet cell hyperplasia. Although TH2 cytokines appear to predominate in this chronic phase of asthma, TH1 cytokines (such as IFN-γ) and TH17 cytokines (IL-17, IL-21, and IL-22) can also participate.


Immunology_Janeway

Immunology_Janeway. In the natural situation, the clinical symptoms produced by an IgE-mediated allergic reaction depend critically on several variables: the amount of allergen-specific IgE present, the route by which the allergen is introduced, the dose of allergen, and most probably some underlying defect in barrier function in the particular tissue or organ affected. The outcomes produced by different combinations of allergen dose and route of entry are summarized in Fig. 14.12. When exposure to allergen in a sensitized individual triggers an allergic reaction, both the immediate and the chronic effects are focused on the site at which mast-cell degranulation occurs and they involve the recruitment of many soluble and cellular components of effector pathways. 14-10 Allergen introduced into the bloodstream can cause anaphylaxis.


Immunology_Janeway

Immunology_Janeway. If allergen is introduced directly into the bloodstream, for example, by a bee or wasp sting, or is rapidly absorbed into the bloodstream from the gut in a sensitized individual, connective-tissue mast cells associated with blood vessels throughout the body can become immediately activated, resulting in a widespread release of histamine and other mediators that causes the systemic reaction called anaphylaxis. The symptoms of anaphylaxis can range in severity from mild urticaria (hives) to fatal anaphylactic shock (see Fig. 14.12, first and last panels). Acute urticaria is a response to foreign allergens that are delivered to the skin via the systemic blood circulation. Activation of mast cells in the skin by allergen causes them to release histamine, which in turn causes itchy, red swellings all over the body—a disseminated version of the wheal-and-flare reaction. Although acute urticaria is commonly caused by an IgE-mediated reaction against an allergen, the causes of chronic


Immunology_Janeway

Immunology_Janeway. swellings all over the body—a disseminated version of the wheal-and-flare reaction. Although acute urticaria is commonly caused by an IgE-mediated reaction against an allergen, the causes of chronic urticaria, in which the urticarial rash persists or recurs over long periods, remain incompletely defined. Some cases of chronic urticaria are caused by autoantibodies


Immunology_Janeway

Immunology_Janeway. Connective tissue mast cells (MCCT) Mucosal mast cells (MCC) Route of allergen entry Intravenous Subcutaneous Inhalation Ingestion Widespread release of histamine, Local release of histamine which acts on blood vessels to causes wheal-and-fare reaction. increase permeability, leading to Airborne or topical allergens hives (low dose, ˜g or less) or penetrating skin can also be a anaphylactic shock (medium to high cause of atopic eczema dose, milligrams to grams)


Immunology_Janeway

Immunology_Janeway. Fig. 14.12The route of administration of allergen determines the type of IgE-mediated allergic reaction that results. There are two main anatomical distributions of mast cells: those associated with vascularized connective tissues and called connective tissue mast cells (MCCT), and those found in submucosal layers of the gut and respiratory tract and called mucosal mast cells (MCC). In an allergic individual, all of these mast cells are coated through their cell-surface Fcε receptors with IgE directed against specific allergens. The response to an allergen then depends on which mast cells are activated. Allergen in the bloodstream (intravenous) activates connective tissue mast cells throughout the body, resulting in the systemic release of histamine and other mediators. Entry of allergen through the skin activates local connective tissue mast cells, leading to a local inflammatory reaction. After an experimental skin


Immunology_Janeway

Immunology_Janeway. Allergic rhinitis (upper airway), Contraction of intestinal smooth muscle caused by increased mucus induces vomiting. Outfow of fuid into production and nasal irritation. gut causes diarrhea. Antigen diffuses


Immunology_Janeway

Immunology_Janeway. Asthma (lower airway) due to into blood vessels and is widely contraction of bronchial smooth muscle disseminated, causing urticaria (hives), and increased mucus secretion anaphylaxis, or atopic eczema prick with allergen or bite from an insect to which the individual is sensitized, this manifests as a wheal-and-flare reaction. In atopic individuals, airborne or topically applied allergens that penetrate the skin may lead to atopic eczema. Inhaled allergen that penetrates respiratory mucosal epithelia activates mainly mucosal mast cells, causing increased secretion of mucus by the mucosal epithelium and irritation in the nasal mucosa, leading to allergic rhinitis—or to asthma if constriction of smooth muscle in the lower airways occurs. Ingested allergen penetrates the gut epithelium, causing vomiting due to intestinal smooth muscle contraction and diarrhea due to outflow of fluid across the gut epithelium. Food allergens can also be disseminated in the bloodstream, causing widespread


Immunology_Janeway

Immunology_Janeway. vomiting due to intestinal smooth muscle contraction and diarrhea due to outflow of fluid across the gut epithelium. Food allergens can also be disseminated in the bloodstream, causing widespread urticaria (hives) when the allergen reaches the skin, or they may cause eczema.


Immunology_Janeway

Immunology_Janeway. against either the α chain of FcεRI or against IgE itself, and thus can be considered a form of autoimmunity. Interaction of the autoantibody with the receptor triggers mast-cell degranulation, with resulting urticaria. In some patients, treatment with omalizumab (a therapeutic monoclonal anti-IgE antibody) leads to resolution of hives, demonstrating a role for IgE in these individuals, even though the antigen that elicited the IgE often cannot be identified. In anaphylactic shock, a widespread increase in vascular permeability and smooth muscle contraction results from a massive release of histamine and other mast celland basophil-derived mediators such as leukotrienes.


Immunology_Janeway

Immunology_Janeway. The consequences are a catastrophic reduction of blood pressure, culminating in hypotensive shock, (a condition in which low blood pressure leads to inadequate supply of blood to vital organs, often leading to death), and constriction of the airways, culminating in respiratory failure. The most common causes of anaphylaxis are allergic reactions to wasp and bee stings, ingested or injected medications, or allergic responses to foods in sensitized individuals. For example, anaphylaxis in individuals allergic to peanuts is relatively common. Severe anaphylactic shock can be rapidly fatal if untreated, but can usually be controlled by the immediate injection of epinephrine, which via stimulation of β-adrenergic receptors causes relaxation of airway smooth muscles, and via stimulation of α-adrenergic receptors reverses the life-threatening cardiovascular effects.


Immunology_Janeway

Immunology_Janeway. Systemic allergic reactions can occur following repeated treatment with many classes of drugs. A relatively common inducer of IgE-mediated allergic reaction is penicillin and other drugs that share aspects of its structure and immunological reactivity. In people who have developed IgE antibodies against penicillin, injection of the drug can cause anaphylaxis and even death. While administration of oral penicillin to an allergic individual can also cause anaphylaxis, the symptoms after oral ingestion are usually less severe and very rarely result in death. One of the reasons that penicillin is particularly prone to inducing allergic reactions is that it acts as a hapten (see Appendix I, Section A-1); it is a small molecule with a highly reactive β-lactam ring that is crucial for its antibacterial activity. This ring reacts with amino groups on host proteins to form covalent conjugates. When penicillin is ingested or injected, it forms conjugates with self proteins, and the


Immunology_Janeway

Immunology_Janeway. its antibacterial activity. This ring reacts with amino groups on host proteins to form covalent conjugates. When penicillin is ingested or injected, it forms conjugates with self proteins, and the penicillin-modified self peptides are recognized as foreign and elicit a host immune response. A large proportion of individuals who are treated with intravenous penicillin develop IgG antibodies against the drug, but these usually cause no symptoms. In some individuals, self proteins conjugated with penicillin provoke a TH2 response that activates penicillin-binding B cells to produce IgE antibody against the penicillin hapten. Thus, penicillin acts both as the B-cell antigen and, by modifying self peptides, as the T-cell antigen. When penicillin is injected intravenously into an allergic individual, the penicillin-modified proteins can cross-link IgE molecules on tissue mast cells and circulating basophils and thus cause anaphylaxis. Great care should be taken to avoid giving a drug to


Immunology_Janeway

Immunology_Janeway. the penicillin-modified proteins can cross-link IgE molecules on tissue mast cells and circulating basophils and thus cause anaphylaxis. Great care should be taken to avoid giving a drug to patients with a past history of allergy to that drug or a close structural relative.


Immunology_Janeway

Immunology_Janeway. As is true for individuals with sensitivity to inhalant allergens, patients with a past history of anaphylactic-type reactions to penicillin or other β-lactam antibiotics can be evaluated by skin-prick testing. A positive skin test, manifested by the formation of a wheal-and-flare reaction at the site of the test, is associated with a substantial risk of developing an anaphylactic reaction when treated with therapeutic doses of the drug. 14-11 Allergen inhalation is associated with the development of rhinitis and asthma.


Immunology_Janeway

Immunology_Janeway. The respiratory tract is an important route of allergen entry (see Fig. 14.12, third panels). Many atopic people react to airborne allergens with an IgEmediated allergic reaction known as allergic rhinitis. This results from the activation of mucosal mast cells beneath the nasal epithelium by allergens such as pollens that, when they contact the epithelium, release their soluble protein contents, which then diffuse across the mucous membranes of the nasal passages. Allergic rhinitis is characterized by intense itching and sneezing; local edema leading to blocked nasal passages; a nasal discharge, which is typically rich in eosinophils; and irritation of the nasal mucosa as a result of histamine release. A similar reaction to airborne allergens deposited on the conjunctiva of the eye is called allergic conjunctivitis. Allergic rhinitis and conjunctivitis are commonly caused by environmental allergens that are present only during certain seasons of the year. For example, hay fever


Immunology_Janeway

Immunology_Janeway. is called allergic conjunctivitis. Allergic rhinitis and conjunctivitis are commonly caused by environmental allergens that are present only during certain seasons of the year. For example, hay fever (known


Immunology_Janeway

Immunology_Janeway. Fig. 14.13 Histologic evidence of chronic inflammation in the airways of an asthmatic patient. Panel a shows a section through a bronchus of a patient who died of asthma; there is almost total occlusion of the airway by a mucus plug. In panel b, a close-up view of the bronchial wall shows injury to the epithelium lining the bronchus, accompanied by a dense inflammatory infiltrate. Although not discernable at this magnification, the infiltrate includes eosinophils, neutrophils, and lymphocytes. Photographs courtesy of T. Krausz.


Immunology_Janeway

Immunology_Janeway. clinically as seasonal allergic rhinoconjunctivitis) is caused by a variety of allergens, including certain grass and tree pollens. Symptoms in the late summer or autumn are commonly caused by weed pollen, such as that of ragweed, or the spores of fungi such as Alternaria. Ubiquitous allergens such as Fel d 1 in cat dander, Der p 1 in the feces of house dust mites, and Bla g 1 in cockroach can be a cause of year-round, or perennial, allergic rhinoconjunctivitis.


Immunology_Janeway

Immunology_Janeway. A more serious IgE-mediated respiratory disease is allergic asthma, which is triggered by allergen-induced activation of submucosal mast cells in the lower airways. This can lead within seconds to bronchial constriction and an increased secretion into the airways of fluid and mucus, making breathing more difficult by trapping inhaled air in the lungs. Patients with allergic asthma usually need treatment, and severe asthmatic attacks can be life threatening. The same allergens that cause allergic rhinitis and conjunctivitis commonly cause asthma attacks. For example, respiratory arrest caused by severe attacks of asthma in the summer or autumn has been associated with the inhalation of Alternaria spores.


Immunology_Janeway

Immunology_Janeway. Chronic allergen exposure leads to an important feature of asthma, namely, chronic inflammation of the airways, which is characterized by the continued presence of increased numbers of pathologic lymphocytes, eosinophils, neutrophils, basophils, and other leukocytes (Fig. 14.13). The concerted actions of these cells cause airway hyperreactivity and remodeling—a thickening of the airway walls due to hyperplasia and hypertrophy of the smooth muscle layer, with the eventual development of fibrosis. Fibrotic remodeling leads to a permanent narrowing of the airways, and is responsible for many of the clinical manifestations of chronic allergic asthma. In chronic asthmatics, a general hyperreactivity of the airways to nonimmunological stimuli such as perfumes or volatile irritants also often develops.


Immunology_Janeway

Immunology_Janeway. It has become apparent that there are many different phenotypic subtypes of asthma. These subtypes are being recognized because patients differ widely in responsiveness to different therapies, in the nature of the inflammatory cell infiltrates that are present in their airways, and in the molecular signature of inflammatory mediators that can be recovered from the airways. Many investigators refer to these subtypes as asthma ‘endotypes.’ The expectation is that classification of patients’ asthmas by endotype will elucidate differences in the underlying pathophysiology of their disease and will improve therapeutic outcomes by permitting their therapy to be matched to the underlying molecular disorder that is leading to symptoms. Some of the most common endotypes include common allergic asthma, exercise-induced asthma, neutrophil-predominant (as opposed to eosinophil-predominant) asthma, and steroid-resistant severe asthma. The fundamental driver of the allergic response in allergic


Immunology_Janeway

Immunology_Janeway. asthma, exercise-induced asthma, neutrophil-predominant (as opposed to eosinophil-predominant) asthma, and steroid-resistant severe asthma. The fundamental driver of the allergic response in allergic asthma is thought to be pathologically activated TH2 cells, and eosinophils and basophils are prominent in the inflammatory infiltrates in the lungs. In severe, steroid-resistant asthma, TH17 cells appear to play a larger role, and neutrophils are prominent in the inflammatory infiltrates. TH17 cells also appear to be major inducers of the asthmatic syndrome allergic bronchopulmonary aspergillosis (ABPA). Other endotypes are characterized by the participation of additional leukocyte subsets and different effector-cell populations. The endotype of asthma of any individual patient is thought to be the result of the specific conditions under which the individual was sensitized to allergen and the specific predisposition of the individual based on inherited genetic factors and environmentally


Immunology_Janeway

Immunology_Janeway. be the result of the specific conditions under which the individual was sensitized to allergen and the specific predisposition of the individual based on inherited genetic factors and environmentally determined epigenetic factors.


Immunology_Janeway

Immunology_Janeway. For the following discussion of mechanisms of asthma, we will focus on the most common endotype, common allergic asthma. In patients with allergic asthma, allergen challenge can cause activation of mast cells in an antigen-specific, IgE-dependent fashion, leading to mast-cell mediator release. Allergens can also stimulate the airway epithelium directly, through TLRs and other damage receptors, to release IL-25 and IL-33. These cytokines can lead to the activation of submucosal type 2 innate lymphoid cells (ILC2s), inducing them to release IL-4, IL-5, IL-9, and IL-13. At the same time, bronchial epithelial cells can produce at least two of the chemokine ligands—CCL5 and CCL11—that bind to the receptor CCR3 expressed on TH2 cells, macrophages, eosinophils, and basophils. Thus, these chemokines, together with the products of activated ILC2s, enhance the type 2 response by attracting more TH2 cells and eosinophils to the damaged lungs. The direct effects of ILC2and TH2 cell-derived


Immunology_Janeway

Immunology_Janeway. together with the products of activated ILC2s, enhance the type 2 response by attracting more TH2 cells and eosinophils to the damaged lungs. The direct effects of ILC2and TH2 cell-derived cytokines and chemokines on airway smooth muscle cells and fibroblasts lead to the apoptosis of epithelial cells and airway remodeling. The remodeling is induced in part by the production of TGF-β, which has numerous effects on the epithelium, ranging from inducing apoptosis to stimulating cell proliferation. The direct action of additional TH2-type cytokines such as IL-9 and IL-13 on airway epithelial cells may also have a dominant role in another major feature of chronic allergic asthma, the induction of goblet-cell metaplasia, which is the increased differentiation of epithelial cells into goblet cells, and a consequent increase in mucus secretion. CD1d-restricted invariant NKT cells (iNKTs, a type of innate-like lymphocyte; see Sections 3-27, 6-18, and 8-26) also seem to have an important role


Immunology_Janeway

Immunology_Janeway. and a consequent increase in mucus secretion. CD1d-restricted invariant NKT cells (iNKTs, a type of innate-like lymphocyte; see Sections 3-27, 6-18, and 8-26) also seem to have an important role in the development of airway hyperreactivity, whether allergen-induced or nonspecific, and this function can be enhanced by the cooperation of ILC2s. Animal models of asthma have shown that airway hyperreactivity is exacerbated by the presence of iNKT cells. Additionally, in mouse models, superoxide-producing myeloid lineage regulatory cells also appear to play pathological roles in the establishment of airway hyperreactivity.


Immunology_Janeway

Immunology_Janeway. Mice do not naturally develop asthma, but a disease resembling human asthma develops in mice that lack the transcription factor T-bet. This transcription factor is required for TH1 differentiation (see Section 9-21). When T-bet is absent, T-cell responses are skewed toward the TH2 phenotype. T-bet-deficient mice have increased levels of the TH2 cytokines IL-4, IL-5, and IL-13, and develop airway inflammation involving lymphocytes and eosinophils (Fig. 14.14). T-bet+/+ T-bet–/– Normal lung biopsy Airway in˜ammation with lymphocytes and eosinophils Normal airway Airway remodeling with increased collagen deposited around airway Fig. 14.14 Mice lacking the transcription factor T-bet develop allergic airway inflammation and T-cell responses polarized toward TH2.


Immunology_Janeway

Immunology_Janeway. Fig. 14.14 Mice lacking the transcription factor T-bet develop allergic airway inflammation and T-cell responses polarized toward TH2. T-bet binds to the promoter of the gene encoding IL-2 and is present in TH1 but not TH2 cells. Mice with a gene-targeted deletion of T-bet (T-bet–/–) manifest impaired TH1 responses, and show spontaneous differentiation of TH2 cells and development of an asthma-like phenotype in the lungs. Left-hand panels: lung and airways in normal mice. Right-hand panels: T-betdeficient mice show lung inflammation, with lymphocytes and eosinophils around the airway and blood vessels (top) and airway remodeling with increased collagen around the airway (bottom). Photographs courtesy of L. Glimcher.


Immunology_Janeway

Immunology_Janeway. They also develop nonspecific airway hyperreactivity to nonimmunological stimuli, similar to what is seen in human asthma. These changes occur in the absence of any exogenous inflammatory stimulus and show that, in extreme circumstances, a genetic imbalance toward TH2 responses can cause allergic disease. The availability of a large number of genetically deficient mouse strains has permitted testing of the roles of many inflammatory effector cells and cytokines in this experimental model, providing hypotheses that are now being tested in human asthma.