Chapter 190. Allergic Disease and Atopy

A precipitous increase in incidence and prevalence of allergic diseases in the last decades leads to the current estimate that up to 50% of the population of Western societies shows reactivity on skin testing to one or more environmental allergens.1 In some subpopulations, up to one in four children suffer from asthma. One explanation for this dramatic increase in allergic diseases is the “hygiene hypothesis,” which posits that a decrease in the exposure to microbes due to improved hygiene, smaller families, less breastfeeding, more immunizations, and lack of serious childhood infections results in altered immunoregulation and deviation toward an allergic disease-promoting TH2 response. Microbial exposure promotes the production of regulatory T cells involved in maintaining tolerance to allergens (see Chapter 186). Lack of sufficient microbial exposure may result in weakened tolerance and, in the setting of other factors such as genetic predisposition and environmental exposures, result in the promotion of allergic diseases.

Allergic diseases are immunological diseases in that their genesis and manifestations result from the functioning of components of the immune system. Disease pathogenesis is mediated by both innate immune responses, involving mast cells, basophils, eosinophils, and dendritic and Langerhans cells, as well as acquired immune responses involving T and B lymphocytes. Orchestrating the allergic response is the TH2 CD4+ T-helper-cell lineage, which is now appreciated to play a central role in the pathogenesis of allergic diseases. TH2 cells recruit other components of the innate and acquired immune response by virtue of their production of a set of proatopic cytokines, including IL-4, IL-5, IL-10, and IL-13.2 They promote the production of IgE, a key trigger of immediate hypersensitivity reactions, and help sustain chronic allergic inflammation in such diseases as asthma and eczema.

The increased knowledge of allergic diseases and their pathogenesis has stimulated the development of new therapeutic approaches, including desensitization therapy with defined allergen preparations or pharmacologic interventions aimed at depleting IgE or targeting the action of mediators such as leukotrienes.

Allergic disorders develop when individuals with a genetic predisposition are exposed to environmental triggers.3 A unifying attribute of these disorders is atopy, defined as a genetically determined predisposition (and hence tends to be familial) to generate IgE antibodies on exposure to environmental antigens. Subsequent exposure to the offending antigen, or allergen, triggers an immediate hypersensitivity reaction. This is an IgE-mediated tissue response that is characterized by increased vascular permeability, vasodilatation, smooth muscle contraction, and local inflammation. The atopic (or allergic) trait integrates pathways of the acquired immune response, including specialized T helper cells and IgE-producing B cells, as well as components of the innate immune response, including mast cells, eosinophils, basophils, and neutrophils. These pathways are critical to pathogenesis in allergic diseases. In contrast, many adverse reactions to foods or drugs are not allergic in nature in that they proceed independently of the immune system, for example, milk intolerance from lactase. Some immune-mediated reactions are not allergic because they involve non-atopic mechanisms of immune injury, such as a delayed-type hypersensitivity reaction to poison ivy.

IgE production is one feature of a more fundamental specific immune response orchestrated by the TH2 subset of CD4+ T helper cells.2 TH2 cells are critical for promoting acute hypersensitivity responses and maintaining the state of chronic and relapsing eosinophil-predominant inflammation that is characteristic of chronic allergic inflammation. TH2 cells represent a separate lineage of T helper cells that arises from an uncommitted, pluripotent TH0 state. TH0 cells may differentiate toward either the TH1, involved in fighting intracellular pathogens, the proallergic TH2 lineage, the proinflammatory TH17, and the induced or adaptive regulatory T cells, which promote immune tolerance. These different T-cell types are distinguished by their profile of cytokine production. For example, TH2 cells produce a distinct set of cytokines necessary for the allergic response, including IL-4 and IL-13, which promote IgE production; IL-5 and granulocyte-macrophage colony-stimulating factor, which promote eosinophil production in the bone marrow; and IL-10, which promotes B-cell differentiation into plasma cells. In contrast, TH2 cells do not produce IL-2 and interferon-gamma, characteristic of TH1 cells, which reciprocally do not produce TH2-type cytokines. Whereas allergic diseases exhibit dominance of TH2 cytokines, TH1 and TH17 cytokines may also contribute to the pathogenesis of some allergic diseases such as atopic dermatitis.4

Induction of an allergic immune response requires uptake and processing by antigen-presenting cells (APCs), which then present peptide fragments to specific T cells. Among the most efficient APCs are dendritic cells. There is evidence to suggest that dendritic cells are heterogeneous, with a myeloidlike dendritic cell subset more prone to stimulate TH2 differentiation. The quantity and phenotype of dendritic cells appear altered in atopic individuals in a way that promotes TH2 responses. Neighboring cells can influence the outcome of TH-cell differentiation. In particular, mast cells, basophils and natural killer T cells can polarize the local cytokine milieu in ways that favor TH2 responses by virtue of their production of IL-4. Preexisting allergen-specific IgE may favor the induction of TH2 responses, both by activating mast cells and basophils to produce IL-4 and IL-13 and by facilitating B-cell antigen presentation.

The host is typically exposed to very low levels of allergens, small- to medium-sized proteins that are highly soluble and are carried on desiccated particles such as pollen. On contact with the mucosa, they are eluted from their carrier particles. Too large a protein may not easily pass through mucosal surfaces, and proteins that are too small may not be able to cross-link IgE on mast cells. Allergens are frequently enzymatically active. In particular, proteases feature prominently among allergens. Der p I, the major allergen of the house dust mite Dermatophagoides pteronyssinus, is a cysteine protease. Papain, a protease derived from the papaya fruit that is used in both industrial and medicinal applications, is a homolog of Der p I and a well-known allergen in its own right. Another industrial allergen is subtilisin, a protease that was frequently used in some laundry detergents. The reason many allergens are enzymatically active is not clear, but it is possible that the enzymatic activity may potentiate antigen uptake and/or presentation or skew the immune response toward the TH2 lineage.

A critical component of the atopic phenotype is IgE. Its production results from the interaction of antigen-presenting B cells with antigen-specific T helper cells.5 At least two signals are required to shift immunoglobulin production from IgM to IgE, a process called class-switch recombination. The first signal is provided by the TH2 cytokines IL-4 or IL-13, which are the only cytokines that can support IgE production by cultured B cells. A second signal is delivered by the interaction of a B-cell protein termed CD40 with its protein ligand CD40L, which is expressed on the surface of activated TH cells. TH2 cells provide both signals necessary for IgE production. CD4+ TH2 cells are present in respiratory mucosa and regional lymphoid tissues of atopic individuals, where they promote IgE production by interacting with naïve B cells presenting allergen-derived peptide antigens. TH2 cells are critical to the maintenance of the allergic inflammation in atopic diseases such as asthma, and they can mediate the passive transfer of allergic airway responses.

IgE mediates two distinct functions in the host: initiation of the immediate hypersensitivity reaction and promotion of antigen presentation leading to augmented immune responses.5 These functions are mediated by dedicated receptors expressed on immune cells. The first is the high-affinity IgE receptor, or FcεRI, a multimeric receptor expressed on a variety of cells, including mast cells, basophils, dendritic and Langerhans cells, and activated eosinophils and monocytes. FcεRI binds IgE with high affinity, which exceeds by 2 to 4 logs the binding affinities of other immunoglobulin Fc receptors, and with 1:1 stoichiometry. An important consequence of the high-affinity binding of FcεRI to IgE is that in atopic individuals with high IgE levels, virtually all FcεRI molecules are constitutively bound by IgE.

Cross-linking by multivalent allergenic proteins of IgE bound to FcεRI on mast cells, basophils, and activated eosinophils initiates a signal transduction cascade that results in the exocytosis of stored granules and the release of their content. It also results in the de novo synthesis by these cells of cytokines and inflammatory mediators. Because of the very high affinity of allergen–IgE and IgE–FcεRI interactions, FcεRI isoforms expressed on antigen-presenting cells, including dendritic, Langerhans, and activated monocytic cells, allow efficient antigen presentations at very low levels of antigen. The antigen-presenting function of FcεRI is important for potentiation and long-term maintenance of IgE-driven allergic and inflammatory responses. This role may be especially important in chronic allergic inflammatory diseases such as eczema and asthma.

A second IgE receptor, FcεRII or CD23, is expressed on B cells and antigen-presenting cells. Its affinity for IgE, although lower than that of FcεRI, nevertheless is substantial. A major function of FcεRII is to augment cellular and humoral immune responses in settings of recurrent allergen encounters.

Cross-linking of IgE bound to FcεRI on tissue mast cells or on circulating basophils triggers the release of granules containing preformed mediators, including histamine, TNF-α, proteoglycans, and neutral proteases, including tryptase, chymase, and carboxypeptidase. It also results in the rapid de novo synthesis of lipid-derived mediators, including prostaglandin D2, the chief prostaglandin product of mast cells, as well as platelet-activating factor and leukotrienes B4, C4, D4, and E4. The release of these mediators induces an immediate hypersensitivity reaction, which in an atopic individual is seen as the “wheal and flare” skin reaction on scratching of the skin with an allergenic substance. It is characterized by vasodilatation, edema, and smooth muscle contraction. A similar reaction pattern is seen in other tissues such as bronchial airways, where mediator release on allergen inhalation rapidly induces mucosal edema, mucus production, smooth muscle constriction, and reduced airflow. The immediate hypersensitivity reaction is reversible and usually subsides within 2 hours of its initiation.

IgE-induced immediate hypersensitivity reaction is often followed by a late-phase reaction, a second wave of hypersensitivity responses occurring several hours after the acute reaction. The late-phase reaction may manifest as a second wave of decreased airflow in asthmatics or recurrence of sneezing and rhinorrhea in patients with allergic rhinitis 4 to 8 hours after the initial allergen contact. A similar recurrence of clinical symptoms occurs in other allergic diseases as well.

The late-phase reaction arises from the recruitment to the allergen challenge site of an inflammatory cellular infiltrate that includes neutrophils, T lymphocytes, and eosinophils. Eosinophil recruitment plays a central role.

Despite the pivotal functions of IgE in immediate hypersensitivity reactions, there are situations in which mast cell degranulation may proceed by IgE-independent mechanisms.6 For example, the syndrome of active anaphylaxis, with mast cell degranulation and mediator release, can be induced in humans by repeated infusion of IgA-containing blood-derived product (blood, plasma, or immunoglobulin preparations) in individuals who are IgA deficient. Such infusions result in the development by these individuals of IgG (rarely IgE) anti-IgA antibodies.7 On rechallenge with the offending product, IgG/anti-IgA immune complexes are formed that precipitate mast cell degranulation and anaphylaxis by interaction with low-affinity Fc receptors for IgG on mast cells.

An important example of chronic allergic inflammation proceeding by IgE-independent mechanisms involves patients with so-called intrinsic allergic diseases, including asthma and eczema. In contrast to the majority of children and many adults with asthma and eczema in whom evidence of pathogenic immediate hypersensitivity can be demonstrated by skin testing, individuals with intrinsic disease forms lack evidence of IgE-mediated reactions. However, these patients exhibit a pattern of allergic inflammation and TH2 cytokine expression that is very similar to that found in patients with the extrinsic or allergic disease form. These findings are consistent with the notion that whereas IgE is not essential for the development of TH2-driven allergic inflammation, it may lower the threshold for the development of allergic inflammation in response to allergen exposure.

The contribution of non–IgE- and non–immune-dependent mechanisms in the genesis of allergic inflammation is now recognized for diseases such as atopic dermatitis, where defects in the skin barrier function seems to play an important role in disease evolution.8 Mutations that compromise the skin barrier function, including those in the SPINK5 gene (Netherton syndrome) and filaggrin (ichthyosis vulgaris), are associated with the development of allergic skin inflammation. In particular, the incidence of common heterozygous mutations in filaggrin, present in up to 10% of people of European ancestry, rises to up to 40% in patients with atopic dermatitis of the same heritage. Filaggrin mutations are associated with extrinsic (allergy-associated) but not intrinsic (non–allergy-associated) atopic dermatitis and with allergic sensitization, total serum IgE levels, and asthma in those patients, suggesting that they are involved in primary development of allergic sensitization. Other tissue-expressed genes have also been implicated in the pathogenesis of asthma, such as the disintegrin and metalloprotease ADAM33, which plays an important role in airway remodeling. These and other findings indicate a broad role for tissue-expressed gene products in the initiation and propagation of allergic disorders.

The allergic response can be attenuated or even abrogated by measures aimed at modifying its underlying immune mechanisms. Foremost is scrupulous allergen avoidance, which can result not only in symptomatic relief but, if persistent long term, may result in hyposensitization. This has been most successfully demonstrated for dust mite allergy. Furthermore, early life avoidance of a dust mite–rich environment may forestall the development of respiratory allergic diseases such as asthma. Immunotherapy with allergenic extracts is also effective in hyposensitizing the allergic response.

Several therapies target specific components of the allergic response. Antihistamines target the vasoactive effects of the mast cell. They are useful in immediate hypersensitivity reactions but ineffective for the late-phase reaction or chronic allergic inflammation, which is better managed by steroids. The recent development of leukotriene receptor antagonists has provided a valuable steroid-sparing tool to combat the effect of persistent leukotriene production by eosinophils and other inflammatory cells in chronic allergic inflammation.

Novel therapies are being introduced aimed at interrupting key pathways in atopic response. Interruption of signals delivered by IL-4 and IL-13 by using soluble IL-4 receptors is also showing promise in allergic diseases such as asthma. Anti-IgE monoclonal antibodies that block binding of IgE to FcεRI without inducing immediate hypersensitivity reaction or anaphylaxis reduce IgE levels in humans by binding to IgE and removing it by immune complex formation. These antibodies attenuate both the early and late-phase responses to inhaled allergen and reduce the associated increase in eosinophils in sputum.