Аllergic diseases. Immunopathology of the аllergy. Other allergic (non-atopic) diseases: types, immunopathogenesis, immunodiagnostic, immunotherapy.
Allergy
Allergic reactions occur when an individual who has produced IgE antibody in response to an innocuous antigen, or allergen, subsequently encounters the same allergen.
The allergen triggers the activation of IgE-binding mast cells in the exposed tissue, leading to a series of responses that are characteristic of allergy. As we learned, there are circumstances in which IgE is involved in protective immunity, especially in response to parasitic worms, which are prevalent in less developed countries. In the industrialized countries, however, IgE responses to innocuous antigens predominate and allergy is an important cause of disease. Almost half the populations of North
Hypersensitivity reactions were classified into four types by Coombs and Gell. Allergy is often equated with type I hypersensitivity (immediate-type hypersensitivity reactions mediated by IgE), and will be used in this sense here.
In this chapter we will first consider the mechanisms that favor the production of
IgE. We then describe the pathophysiological consequences of the interaction between antigen and IgE that is bound by the high-affinity Fc receptor (
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 on whether the allergen is injected, inhaled, or eaten, and depending also on the dose of the allergen.
There are four types of hypersensitivity reaction mediated by immunological mechanisms that cause tissue damage.
Types I-III are antibody-mediated and are distinguished by the different types of antigens recognized and the different classes of antibody involved. Type I responses are mediated by IgE, which induces mastcell activation, whereas types II and III are mediated by IgG, which can engage Fc-receptor and complementmediated effector mechanisms to varying degrees, depending on the subclass of IgG and the nature of the antigen involved. Type II responses are directed against cell-surface or matrix antigens, whereas type III responses are directed against soluble antigens, and the tissue damage involved is caused by responses triggered by immune complexes. Type IV hypersensitivity reactions are T cell-mediated and can be subdivided into three groups. In the first group, tissue damage is caused by the activation of macro-phages by TH1 cells, which results in an inflammatory response. In the second, damage is caused by the activation by TH2 cells of inflammatory responses in which eosinophils predominate; in the third, damage is caused directly by cytotoxic T cells (CTL).
The production of IgE.
IgE is produced by plasma cells located in lymph nodes draining the site of antigen entry or locally, at the sites of allergic reactions, by plasma cells derived from germinal
centers developing within the inflamed tissue. IgE differs from other antibody isotypes in being located predominantly in tissues, where it is tightly bound to the mast-cell surface through the high-affinity IgE receptor known as Fc RI. Binding of antigen to IgE cross-links these receptors and this causes the release of chemical mediators from the mast cells, which may lead to the development of a type I hypersensitivity reaction. Basophils and activated eosinophils also express
Properties of inhaled allergens.
It seems likely that presenting an antigen transmucosally and at very low doses is a particularly efficient way of inducing TH2-driven IgE responses. IgE antibody production requires TH2 cells that produce interleukin-4 (IL-4) and IL-13 and it can be inhibited by TH1 cells that produce interferon-γ (IFN-γ). The presentation of low doses of antigen can favor the activation of TH2 cells over TH1 cells, and many common allergens are delivered to the respiratory mucosa by inhalation of a low dose. The dominant antigen-presenting cells in the respiratory mucosa are myeloid dendritic cells. These take up and process protein antigens very efficiently and become activated in the process. This in turn induces their migration to regional lymph nodes and differentiation into professional antigen-presenting cells with co-stimulatory activity that favors the differentiation of TH2 cells.
Different cytokines induce switching to different isotypes.
The individual cytokines induce or inhibit production of certain isotypes. Much of the inhibitory effect is probably the result of directed switching to a different isotype. These data are drawn from experiments with mouse cells.
Enzymes are frequent triggers of allergy. Several lines of evidence suggest that IgE is important in host defense against parasites. Many parasites invade their hosts by secreting proteolytic enzymes that break down connective tissue and allow the parasite access to host tissues, and it has been proposed that these enzymes are particularly active at promoting TH2 responses. This idea receives some support from the many examples of allergens that are enzymes. The major allergen in the feces of the house dust mite (Dermatophagoides pteronyssimus), which is responsible for allergy in approximately 20% of the North American population, is a cysteine protease homologous to papain, known as Der p 1. This enzyme has been found to cleave occludin, a protein component of intercellular tight junctions. This reveals one possible reason for the allergenicity of certain enzymes. By destroying the integrity of the tight junctions between epithelial cells,
Der p 1 may gain abnormal access to subepithelial antigen-presenting cells, resident mast cells, and eosinophils. The allergenicity of Der p 1 may also be promoted by its proteolytic action on certain receptor proteins on B cells and T cells. It has been shown to cleave the α subunit of the IL-2 receptor, CD25, from T cells. Loss of IL-2 receptor activity might interfere with the maintenance of TH1 cells, leading to a TH2 bias. The protease papain, derived from the papaya fruit, is used as a meat tenderizer and causes allergy in workers preparing the enzyme; such allergies are called occupational allergies. Another occupational allergy is the asthma caused by inhalation of the bacterial enzyme subtilisin, the ‘biological’ component of some laundry detergents. Injection of enzymatically active papain (but not of inactivated papain) into mice stimulates an IgE response. A closely related enzyme, chymopapain, is used medically to destroy intervertebral discs in patients with sciatica; the major (although rare) complication of this procedure is anaphylaxis, an acute systemic response to allergens. Not all allergens are enzymes, however; for example, two allergens identified from filarial worms are enzyme inhibitors. Many protein allergens derived from plants have been identified and sequenced, but their functions are currently obscure. Thus, there seems to be no systematic association between enzymatic activity and allergenicity.
The enzymatic activity of some allergens enables penetration of epithelial barriers.
The epithelial barrier of the airways is formed by tight junctions between the epithelial cells. Fecal pellets from the house dust mite, D. pteronyssimus, contain a proteolytic enzyme, Der p 1, that acts as an allergen. It cleaves occludin, a protein that helps maintain the tight junctions, and thus destroys the barrier function of the epithelium. Fecal antigens can then pass through and be taken up by dendritic cells in subepithelial tissue. Der p 1 is taken up by dendritic cells, which are activated and move to lymph nodes (not shown), where they act as antigen-presenting cells, inducing the production of TH2 cells specific for Der p 1 and the production of Der p 1-specific IgE. Der p 1 may then bind directly to specific IgE on the resident mast cells, triggering mast-cell activation.
Class switching to IgE in B lymphocytes is favored by specific signals.
There are two main components of the immune response leading to IgE production. The first consists of the signals that favor the differentiation of naive TH0 cells to a TH2 phenotype. The second comprises the action of cytokines and co-stimulatory signals from TH2 cells that stimulate B cells to switch to producing IgE antibodies.
The fate of a naive CD4 T cell responding to a peptide presented by a dendritic cell is determined by the cytokines it is exposed to before and during this response, and by the intrinsic properties of the antigen, antigen dose, and route of presentation. Exposure to IL-4 favors the development of TH2 cells and to IL-12 favors that of TH1 cells. IgE antibodies are important in host defense against parasitic infections and this defense system is distributed anatomically mainly at the sites of entry of parasites under the skin, under the epithelial surfaces of the airways (the mucosal-associated lymphoid tissues), and in the submucosa of the gut (the gut-associated lymphoid tissues). Cells of the innate and adaptive immune systems at these sites are specialized to secrete predominantly cytokines that drive TH2 responses. The dendritic cells at these sites are of the myeloid phenotype; after taking up antigen they migrate to regional lymph nodes where their interaction with naive CD4 T cells drives the T cells to become TH2 cells, which secrete IL-4 and IL-10. It is not known how myeloid dendritic cells induce this differentiation. One possibility is that they express a particular set of cytokines and co-stimulatory molecules yet to be characterized. Another is that they activate a specialized subset of CD4 T cells, the NK1.1+ subset, that produce abundant IL-4 that can induce CD4 T cells to differentiate into TH2 cells following stimulation by antigen. These in turn induce B cells to produce IgE.
Class switching of B cells to IgE production is induced by two separate signals, both of which can be provided by TH2 cells. The first of these signals is provided by the cytokines IL-4 or IL-13, interacting with receptors on the B-cell surface. These transduce their signal by activation of the Janus family tyrosine kinases JAK1 and JAK3 which ultimately lead to phosphorylation of the transcriptional regulator STAT6. Mice lacking functional IL-4, IL-13, or STAT6 all show impaired TH2 responses and IgE switching, demonstrating the key importance of these signaling pathways. The second signal for IgE class switching is a co-stimulatory interaction between CD40 ligand on the T-cell surface with CD40 on the B-cell surface. This interaction is essential for all antibody class switching; patients with the X-linked hyper IgM syndrome have a deficiency of CD40 ligand and produce no IgG, IgA, or IgE.
The IgE response, once initiated, can be further amplified by basophils, mast cells, and eosinophils, which can also drive IgE production. All three cell types express
IgE class switching in B cells is initiated by TH2 cells, which develop in the presence of an early burst of IL-4.
In mice, IL-4 is secreted early in some immune responses by a small subset of CD4 T cells (NK1.1+ CD4 T cells) that interact with antigen-presenting cells bearing the nonclassical MHC class I-like molecule CD1 (first panel). Naive T cells being primed by their first encounter with antigen carry receptors for IL-4 (IL-4R) and are driven to differentiate into TH2 cells in the presence of this early burst of IL-4 (second panel). When these TH2 effector cells interact with B cells specific for the same antigen, they induce isotype-switching so that IgE is produced.
Antigen binding to IgE on mast cells leads to amplification of IgE production.
IgE secreted by plasma cells binds to the high-affinity IgE receptor on mast cells (illustrated here), basophils, and activated eosinophils. When the surface-bound IgE is cross-linked by antigen, these cells express CD40L and secrete IL-4, which in turn binds to IL-4 receptors (IL-4R) on the activated B cell, stimulating isotype switching by B cells and the production of more IgE. These interactions can occur in vivo at the site of allergen-triggered inflammation, for example in bronchial-associated lymphoid tissue.
Genetic factors contribute to the development of IgE-mediated allergy, but environmental factors may also be important.
As many as 40% of people in Western populations show an exaggerated tendency to mount IgE responses to a wide variety of common environmental allergens. This state is called atopy and seems to be influenced by several genetic loci. Atopic individuals have higher total levels of IgE in the circulation and higher levels of eosinophils than their normal counterparts. They are more susceptible to allergic diseases such as hay fever and asthma. Studies of atopic families have identified regions on chromosomes 11q and 5q that appear to be important in determining atopy; candidate genes that could affect IgE responses are present in these regions. The candidate gene on chromosome 11 encodes the β subunit of the high-affinity IgE receptor, whereas on chromosome 5 there is a cluster of tightly linked genes that includes those for IL-3, IL-4, IL-5, IL-9, IL-12, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF). These cytokines are important in IgE isotype switching, eosinophil survival, and mast-cell proliferation. Of particular note, an inherited genetic variation in the promoter region of the IL-4 gene is associated with raised IgE levels in atopic individuals; the variant promoter will direct increased expression of a reporter gene in experimental systems. Atopy has also been associated with a gain-of-function mutation of the α subunit of the IL-4 receptor, which is associated with increased signaling following ligation of the receptor. It is too early to know how important these different polymorphisms are in the complex genetics of atopy.
A second type of inherited variation in IgE responses is linked to the MHC class II region and affects responses to specific allergens. Many studies have shown that IgE production in response to particular allergens is associated with certain HLA class II alleles, implying that particular MHC:peptide combinations might favor a strong TH2 response.
Effector mechanisms in allergic reactions.
Allergic reactions are triggered when allergens cross-link preformed IgE bound to the high-affinity receptor
Mast-cell activation has different effects on different tissues.
Most IgE is cell-bound and engages effector mechanisms of the immune system by different pathways from other antibody isotypes.
Most antibodies are found in body fluids and engage effector cells, through receptors specific for the Fc constant regions, only after binding specific antigen through the antibody variable regions. IgE, however, is an exception as it is captured by the high-affinity Fc receptor in the absence of bound antigen. This means that IgE is mostly found fixed in the tissues on mast cells that bear this receptor, as well as on circulating basophils and activated eosinophils.
The ligation of cell-bound IgE antibody by specific antigen triggers activation of these cells at the site of antigen entry into the tissues. The release of inflammatory lipid mediators, cytokines, and chemokines at sites of IgEtriggered reactions results in the recruitment of eosinophils and basophils to augment the type I response.
There are two types of IgE-binding Fc receptor. The first,
The second IgE receptor, Fc RII, usually known as CD23, is a C-type lectin and is structurally unrelated to
Mast cells reside in tissues and orchestrate allergic reactions.
Mast cells were described by Ehrlich in the mesentery of rabbits and named Mastzellen (‘fattened cells’). Like basophils, mast cells contain granules rich in acidic proteoglycans that take up basic dyes. However, in spite of this resemblance, and the similar range of mediators stored in these basophilic granules, mast cells are derived from a different myeloid lineage than basophils and eosinophils. Mast cells are highly specialized cells, and are prominent residents of mucosal and epithelial tissues in the vicinity of small blood vessels and postcapillary venules, where they are well placed to guard against invading pathogens. Mast cells are also found in subendothelial connective tissue. They home to tissues as agranular cells; their final differentiation, accompanied by granule formation, occurs after they have arrived in the tissues. The major growth factor for mast cells is stem-cell factor (SCF), which acts on the cell-surface receptor c-Kit. Mice with defective c-Kit lack differentiated mast cells and cannot make IgE-mediated inflammatory responses. This shows that such responses depend almost exclusively on mast cells. Mast cells express
IgE antibody cross-linking on mast-cell surfaces leads to a rapid release of inflammatory mediators.
Mast cells are large cells found in connective tissue that can be distinguished by secretory granules containing many inflammatory mediators. They bind stably to monomeric IgE antibodies through the very highaffinity
Molecules released by mast cells on activation.
Mast cells produce 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 synthesized after activation.
Eosinophils are normally under tight control to prevent inappropriate toxic responses.
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. Only very small numbers of these cells are normally present 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. Eosinophils have two kinds of effector function. First, on activation they release highly toxic granule proteins and free radicals, which can kill microorganisms and parasites but can also cause significant tissue damage in allergic reactions. Second, activation induces the synthesis of chemical mediators such as prostaglandins, leukotrienes, and cytokines, which amplify the inflammatory response by activating epithelial cells, and recruiting and activating more eosinophils and leukocytes.
Eosinophils can be detected easily in tissue sections by their bright refractile orange coloration.
In this light micrograph, a large number of eosinophils are seen infiltrating a tumor of Langherhans‘ cells known as Langerhans‘ cell histiocytosis. The tissue section is stained with hematoxylin and eosin; it is the eosin that imparts the characteristic orange color to the eosinophils. Eosinophils secrete a range of highly toxic granule proteins and other inflammatory mediators.
Allergic reactions can be divided into an immediate response and a late-phase response.
A whealand-flare allergic reaction develops within a minute or two of superficial injection of antigen into the epidermis and lasts for up to 30 minutes. The reaction to an intracutaneous injection of house dust mite antigen is shown in the upper left panel and is labeled ‘HDM;’ the area labeled ‘saline’ shows the absence of any response to a control injection of saline solution. A more widespread edematous response, as shown in the upper right panel, develops approximately 8 hours later and can persist for some hours. Similarly, the response to an inhaled antigen can be divided into early and late responses (bottom panel). An asthmatic response in the lungs with narrowing of the airways caused by the constriction of bronchial smooth muscle can be measured as a fall in the forced expired volume of air in one second (FEV1). The immediate response peaks within minutes after antigen inhalation and then subsides.
Approximately 8 hours after antigen challenge, there is a late-phase response that also results in a fall in the FEV1.
The immediate response is caused by the direct effects on blood vessels and smooth muscle of rapidly metabolized mediators such as histamine released by mast cells. The late-phase response is caused by the effects of an influx of inflammatory leukocytes attracted by chemokines and other mediators released by mast cells during and after the immediate response.
Eosinophils and basophils cause inflammation and tissue damage in allergic reactions.
In a local allergic reaction, mast-cell degranulation and TH2 activation cause eosinophils to accumulate in large numbers and to become activated. Their continued presence is characteristic of chronic allergic inflammation and they are thought to be major contributors to tissue damage. Basophils are also present at the site of an inflammatory reaction. Basophils share a common stem-cell precursor with eosinophils; growth factors for basophils are very similar to those for eosinophils and include IL-3, IL-5, and GMCSF.
There is evidence for reciprocal control of the maturation of the stem-cell population into basophils or eosinophils. For example, transforming growth factor (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 eosinophils in defense against pathogens. Like eosinophils, they are recruited to the sites of allergic reactions. Basophils express
Eosinophils, mast cells, and basophils can interact with each other. Eosinophil degranulation releases major basic protein, which in turn causes 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.
An allergic reaction is divided into an immediate response and a late-phase response.
The inflammatory response after IgE-mediated mast-cell activation occurs as an immediate reaction, starting within seconds, and a late reaction, which takes up to 8 12 hours to develop. These reactions can be distinguished clinically The immediate reaction is due to the activity of histamine, prostaglandins, and other preformed or rapidly synthesized mediators that cause a rapid increase in vascular permeability and the contraction of smooth muscle. The late-phase reaction is caused by the induced synthesis and release of mediators including leukotrienes, chemokines, and cytokines from the activated mast cells. These recruit other leukocytes, including eosinophils and TH2 lymphocytes, to the site of inflammation. Although the late-phase reaction is clinically less marked than the immediate response, it is associated with a second phase of smooth muscle contraction, sustained edema, and the development of one of the cardinal features of allergic asthma: airway hyperreactivity to non-specific bronchoconstrictor stimuli such as histamine and methacholine.
The late-phase reaction is an important cause of much serious long-term illness, as for example in chronic asthma. This is because the late reaction induces the recruitment of inflammatory leukocytes, especially eosinophils and TH2 lymphocytes, to the site of the allergen-triggered mast-cell response. This late response can easily convert into a chronic inflammatory response if antigen persists and stimulates allergen-specific TH2 cells, which in turn promote eosinophilia and further IgE production.
The clinical effects of allergic reactions vary according to the site of mast-cell activation.
When reexposure to allergen triggers an allergic reaction, the effects are focused on the site at which mast-cell degranulation occurs. In the immediate response, the preformed mediators released are short-lived, and their potent effects on blood vessels and smooth muscles are therefore confined to the vicinity of the activated mast cell. The more sustained effects of the late-phase response are also focused on the site of initial allergen-
triggered activation, and the particular anatomy of this site may determine how readily the inflammation can be resolved. Thus, the clinical syndrome produced by an allergic reaction depends critically on three variables: the amount of allergenspecific IgE present; the route by which the allergen is introduced; and the dose of allergen. If an allergen is introduced directly into the bloodstream or is rapidly absorbed from the gut, the connective tissue mast cells associated with all blood vessels can become activated. This activation causes a very dangerous syndrome called systemic anaphylaxis. Disseminated mast-cell activation has a variety of potentially fatal effects: the widespread increase in vascular permeability leads to a catastrophic loss of blood pressure; airways constrict, causing difficulty in breathing; and swelling of the epiglottis can cause suffocation. This potentially fatal syndrome is called anaphylactic shock. It can occur if drugs are administered to people who have IgE specific for that drug, or after an insect bite in individuals allergic to insect venom. Some foods, for example peanuts or brazil nuts, can cause systemic anaphylaxis in susceptible individuals. This syndrome can be rapidly fatal but can usually be controlled by the immediate injection of epinephrine, which relaxes the smooth muscle and inhibits the cardiovascular effects of anaphylaxis.
The most frequent allergic reactions to drugs occur with penicillin and its relatives. In people with IgE antibodies against penicillin, administration of the drug by injection can cause anaphylaxis and even death. Great care should be taken to avoid giving a drug to patients with a past history of allergy to that drug or one that is closely related structurally. Penicillin acts as a hapten; 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 penicillin-modified self peptides can provoke a TH2 response in some individuals. These TH2 cells then activate penicillin-binding B cells to produce IgE antibody to 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 penicillinmodified proteins can cross-link IgE molecules on the mast cells and cause anaphylaxis.
The dose and route of allergen administration determine the type of IgE-mediated allergic reaction that results.
There are two main anatomical distributions of mast cells: those associated with vascularized connective tissues, called connective tissue mast cells, and those found in submucosal layers of the gut and respiratory tract, called mucosal mast cells. In an allergic individual, all of these are loaded with IgE directed against specific allergens. The overall response to an allergen then depends on which mast cells are activated. Allergen in the bloodstream activates connective tissue mast cells throughout the body, resulting in the systemic release of histamine and other mediators. Subcutaneous administration of allergen activates only local connective tissue mast cells, leading to a local inflammatory reaction. Inhaled allergen, penetrating across epithelia, activates mainly mucosal mast cells, causing smooth muscle contraction in the lower airways; this leads to bronchoconstriction and difficulty in expelling inhaled air. Mucosal mast-cell activation also increases the local secretion of mucus by epithelial cells and causes irritation. Similarly, ingested allergen penetrates across gut epithelia, 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 urticaria (hives) when the food allergen reaches the skin.
Allergen inhalation is associated with the development of rhinitis and asthma.
Inhalation is the most common route of allergen entry. Many people have mild allergies to inhaled antigens, manifesting as sneezing and a runny nose. This is called allergic rhinitis, and results from the activation of mucosal mast cells beneath the nasal epithelium by allergens such as pollens that release their protein contents, which can then diffuse across the mucus 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 nose 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 only present during certain seasons of the year. For example, hay fever is caused by a variety of allergens, including certain grass and tree pollens. Autumnal symptoms may be caused by weed pollen, such as that of ragweed. These reactions are annoying but cause little lasting damage.
A more serious syndrome is allergic asthma, which is triggered by allergen-induced activation of submucosal mast cells in the lower airways. This leads within seconds to bronchial constriction and increased secretion of fluid and mucus, making breathing more difficult by trapping inhaled air in the lungs. Patients with allergic asthma ofteeed treatment, and asthmatic attacks can be life-threatening. An important feature of asthma is chronic inflammation of the airways, which is characterized by the continued presence of increased numbers of TH2 lymphocytes, eosinophils, neutrophils, and other leukocytes. Although allergic asthma is initially driven by a response to a specific allergen, the subsequent chronic inflammation seems to be perpetuated even in the apparent absence of further exposure to allergen. The airways become characteristically hyperreactive and factors other than reexposure to antigen can trigger asthma attacks. For example, the airways of asthmatics characteristically show hyperresponsiveness to environmental chemical irritants such as cigarette smoke and sulfur dioxide; viral or, to a lesser extent, bacterial respiratory tract infections can exacerbate the disease by inducing a TH2-dominated local response.
The acute response in allergic asthma leads to TH2-mediated chronic inflammation of the airways.
In sensitized individuals, cross-linking of specific IgE on the surface of mast cells by an inhaled allergen triggers them to secrete inflammatory mediators, causing increased vascular permeability, contraction of bronchial smooth muscle, and increased mucus secretion. There is an influx of inflammatory cells, including eosinophils and TH2 cells, from the blood. Activated mast cells and TH2 cells secrete cytokines that augment eosinophil activation and degranulation, which causes further tissue injury and the entry of more inflammatory cells. The result is chronic inflammation, which can cause irreversible damage to the airways.
Morphological 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 that includes eosinophils, neutrophils, and lymphocytes.
Skin allergy is manifest as urticaria or chronic eczema.
The same dichotomy between immediate and delayed responses is seen in cutaneous allergic responses. The skin forms an effective barrier to the entry of most allergens but it can be breached by local injection of small amounts of allergen, for example by a stinging insect. The entry of allergen into the epidermis or dermis causes a localized allergic reaction. Local mast-cell activation in the skin leads immediately to a local increase in vascular permeability, which causes extravasation of fluid and swelling. Mast-cell activation also stimulates the release of chemicals from local nerve endings by a nerve axon reflex, causing the vasodilation of surrounding cutaneous blood vessels, which causes redness of the surrounding skin. The resulting skin lesion is called a wheal-and-flare reaction. About 8 hours later, a more widespread and sustained edematous response appears in some individuals as a consequence of the latephase response. A disseminated form of the wheal-and-flare reaction, known as urticaria or hives, sometimes appears when ingested allergens enter the bloodstream and reach the skin. Histamine released by mast cells activated by allergen in the skin causes large, itchy, red swellings of the skin.
Allergists take advantage of the immediate response to test for allergy by injecting minute amounts of potential allergens into the epidermal layer of the skin. Although the reaction after the administration of antigen by intraepidermal injection is usually very localized, there is a small risk of inducing systemic anaphylaxis.
Another standard test for allergy is to measure levels of IgE antibody specific for a particular allergen in a sandwich ELISA Although acute urticaria is commonly caused by allergens, the causes of chronic urticaria, in which the urticarial rash can recur over long periods, are less well understood. In up to a third of cases, it seems likely that chronic urticaria is an autoimmune disease caused by autoantibodies against the α chain of
This is an example of a type II hypersensitivity reaction in which an autoantibody against a cellular receptor triggers cellular activation, in this case causing mast-cell degranulation with resulting urticaria.
A more prolonged inflammatory response is sometimes seen in the skin, most often in atopic children. They develop a persistent skin rash called eczema or atopic dermatitis, due to a chronic inflammatory response similar to that seen in the bronchial walls of patients with asthma. The etiology of eczema is not well understood. TH2 cells and IgE are involved, and it usually clears in adolescence, unlike rhinitis and asthma, which can persist throughout life.
Allergy to foods causes symptoms limited to the gut and systemic reactions.
When an allergen is eaten, two types of allergic response are seen. Activation of mucosal mast cells associated with the gastrointestinal tract leads to transepithelial fluid loss and smooth muscle contraction, causing diarrhea and vomiting. For reasons that are not understood, connective tissue mast cells in the dermis and subcutaneous tissues can also be activated after ingestion of allergen, presumably by allergen that has been absorbed into the bloodstream, and this results in urticaria. Urticaria is a common reaction when penicillin is given orally to a patient who already has penicillin-specific IgE antibodies. Ingestion of food allergens can also lead to the development of generalized anaphylaxis, accompanied by cardiovascular collapse and acute asthmatic symptoms. Certain foods, most importantly peanuts, tree nuts, and shellfish, are particularly associated with this type of life-threatening response.
Allergy can be treated by inhibiting either IgE production or the effector pathways activated by crosslinking of cell-surface IgE.
The approaches to the treatment and prevention of allergy are set out. Two treatments are commonly used in clinical practice one is desensitization and the other is blockade of the effector pathways. There are also several approaches still in the experimental stage. In desensitization the aim is to shift the antibody response away from one dominated by IgE toward one dominated by IgG; the latter can bind to the allergen and thus prevent it from activating IgE-mediated effector pathways. Patients are injected with escalating doses of allergen, starting with tiny amounts. This injection schedule gradually diverts the IgE-dominated response, driven by TH2 cells, to one driven by TH1 cells, with the consequent downregulation of IgE production. Recent evidence shows that desensitization is also associated with a reduction in the numbers of late-phase inflammatory cells at the site of the allergic reaction. A potential complication of the desensitization approach is the risk of inducing IgE-mediated allergic responses.
An alternative, and still experimental, approach to desensitization is vaccination with peptides derived from common allergens. This procedure induces T-cell anergy, which is associated with multiple changes in the T-cell phenotype, including downregulation of cytokine production and reduced expression of the CD3:T-cell receptor complex. IgE-mediated responses are not induced by the peptides because IgE, in contrast to T cells, can only recognize the intact antigen. A major difficulty with this approach is that an individual’s responses to peptides are restricted by their MHC class II alleles; therefore, patients with different MHC class II molecules respond to different allergen-derived peptides. As the human population is outbred and expresses a wide variety of MHC class II alleles, the number of peptides required to treat all allergic individuals might be very large.
Another vaccination strategy that shows promise in experimental models of allergy is the use of oligodeoxynucleotides rich in unmethylated cytosine guanine dinucleotides (CpG) as adjuvants for desensitization regimes. These oligonucleotides mimic bacterial DNA sequences known as CpG motifs and strongly promote TH1 responses.
The signaling pathways that enhance the IgE response in allergic disease are also potential targets for therapy.
Inhibitors of IL-4, IL-5, and IL-13 would be predicted to reduce IgE responses, but redundancy between some of the activities of these cytokines might make this approach difficult to implement in practice. A second approach to manipulating the response is to
give cytokines that promote TH1-type responses. IFN-γ, IFN-α, IL-10, IL-12, and TGF-β have each been shown to reduce IL-4-stimulated IgE synthesis in vitro, and IFN-γ and IFN-α have been shown to reduce IgE synthesis in vivo.
Another target for therapeutic intervention might be the high-affinity IgE receptor. An effective competitor for IgE at this receptor could prevent the binding of IgE to the surfaces of mast cells, basophils, and eosinophils. Candidate competitors include humanized anti-IgE monoclonal antibodies, which bind to IgE and block its binding to the receptor, and modified IgE Fc constructs that bind to the receptor but lack variable regions and thus cannot bind antigen. Yet another approach would be to block the recruitment of eosinophils to sites of allergic inflammation. The eotaxin receptor CCR3 is a potential target for this type of therapy. The production of eosinophils in bone marrow and their exit into the circulation might also be reduced by a blockade of IL-5 action.
The mainstays of therapy at present, however, are drugs that treat the symptoms of allergic disease and limit the inflammatory response. Anaphylactic reactions are treated with epinephrine, which stimulates the reformation of endothelial tight junctions, promotes the relaxation of constricted bronchial smooth muscle, and also stimulates the heart. Inhaled bronchodilators that act on β-adrenergic receptors to relax constricted muscle are also used to relieve acute asthma attacks. Antihistamines that block the histamine H1 receptor reduce the urticaria that follows histamine release from mast cells and eosinophils. Relevant H1 receptors include those on blood vessels that cause increased permeability of the vessel wall, and those on unmyelinated nerve fibers that are thought to mediate the itching sensation. In chronic allergic disease it is extremely important to treat and prevent the chronic inflammatory tissue injury. Topical or systemic corticosteroids are used to suppress the chronic inflammatory changes seen in asthma, rhinitis, and eczema. However, what is really needed is a means of converting the T-cell response to the allergenic peptide antigen from predominantly TH2 to predominantly TH1.
Approaches to the treatment of allergy.
Two approaches are in regular clinical use. The first is the injection of specific antigen in desensitization regimes, which are believed to divert the immune response to the allergen from a TH2 to a TH1 type, so that IgG is produced in place of IgE. The second clinically useful approach is the use of specific inhibitors to block the synthesis or effects of inflammatory mediators produced by mast cells.
