PATHOPHYSIOLOGIC ROLE OF IgE IN ALLERGY AND ASTHMA

TOP ABSTRACT PATHOPHYSIOLOGIC ROLE OF IgE... IgE PHARMACOKINETICS IS IgG IMPLICATED IN... RELATIVE ROLES OF IgE... CONCLUSIONS REFERENCES

Keywords: pathophysiology; asthma; allergy; IgE; allergic cascade

The evidence for a causal relationship between allergens and asthma hinges on epidemiologic findings showing a strong association between specific immunoglobulin E (IgE) antibodies, or total IgE and asthma (1). Burrows and colleagues found a close correlation between serum IgE levels and self-reported asthma (1). In contrast, they found allergic rhinitis to be independent of serum IgE concentration, but associated with cutaneous reactivity to common seasonal aeroallergens in most individuals tested. They concluded that "asthma is almost always associated with some type of IgE-related reaction and therefore has an allergic basis" (1). Numerous epidemiologic studies have shown a highly significant relationship between asthma and sensitization to various allergens (as demonstrated by skin tests or the presence of specific IgE in the serum) (2, 4, 6, 7). In the majority of these studies, the relevant allergens are those found indoors, with the odds ratios (ORs) for asthma among sensitized individuals ranging from 6.2 for cat allergens (4) to as high as 19.7 for house dust mite allergen (2).

These strong associations might appear to support a simple causal relationship, but new data suggest that it may be far more complex. In all studies, sensitization has been associated with asthma; however, there are real questions about the role of current exposure (8). Furthermore, it is clear that a large number of allergic individuals do not develop asthma. Peat and Li recently estimated the magnitude of modifiable risk factors for asthma and found that factors such as breast-feeding for less than 3 mo and parental smoking had relatively small effects (ORs, 1 to 2), whereas in areas with high exposure to house dust mite antigen (i.e., > 10 µg/g), sensitization to mite allergens had a much larger effect (OR > 10) (9).

No studies have yet been conducted on the epidemiology of asthma in which patients are separated on the basis of T-cell responses to specific antigens. However, T-cell immune and inflammatory pathways are thought to play an important role in allergy and asthma symptomatology (Figure 1). CD4⁺ T cells regulate or organize most types of immune responses to foreign proteins by secreting cytokines such as interleukins (IL) and interferons (IFN) and can be categorized into phenotypes (e.g., Th0, Th1, Th2) on the basis of their products. The Th2 class initiates the immediate allergic response by releasing interleukins, primarily IL-4 and IL-5, which induce IgE production, stimulate eosinophilopoiesis, regulate eosinophil functions, and promote the growth of mucosal-type mast cells. In contrast, Th1 cells are primarily involved in classic delayed hypersensitivity and have been proposed to inhibit Th2-driven processes (10).

View larger version (39K): [in this window] [in a new window]   Figure 1.   The traditional model of T-cell differentiation into Th1 or Th2 during human immune responses (immune deviation). DPT = diphtheria, pertussis, and tetanus; MHC = major histocompatibility complex; Eos = eosinophil. *Activated mast cells produce histamine, tryptase, leukotrienes, IL-3, granulocyte-macrophage colony-stimulating factor, TNF-, IL-4, IL-5, and RANTES.

The activation of Th2 and B lymphocytes underlies the process of sensitization to allergens in genetically predisposed individuals. Antigens processed by antigen-presenting cells (APCs) can be recognized by Th2 cells. Interleukins released by activated Th2 cells (e.g., IL-4 and IL-13) enhance production of IgE antibodies. These antibodies, in turn, become attached to other resident cells that possess specific receptors for IgE. A small domain (within Fc 3) of the IgE "constant" region binds to high-affinity (Fc RI) surface receptors on mast cells or basophils or to low-affinity receptors (Fc RII, also known as CD23) on B lymphocytes and eosinophils (11).

The establishment of IgE-bearing cells in the nasal or bronchial mucosa during the sensitization phase sets the stage for their activation during subsequent allergen exposure. When antigen binds to the IgE variable regions of two adjacent antibodies on a mast cell or basophil, their receptors become physically cross-linked (12). The subsequent uptake of calcium ions leads to degranulation and release of proinflammatory mediators such as histamine, tryptase, leukotrienes, and prostaglandins. The mediators released during degranulation are responsible for the symptoms of an immediate allergic reaction. These mast cell mediators can also contribute to late reactions that occur 4 to 8 h after an immediate response. IL-4, produced by mast cells, may also provide a positive feedback to Th2 lymphocytes that sustains their secretion of cytokines (Figure 2) (12, 13).

View larger version (34K): [in this window] [in a new window]   Figure 2.   The release of both preformed and newly generated mediators is triggered by cross-linking of IgE molecules on Fc RI. *Mediators also produced by basophils.  Tryptase can be assayed in serum or secretions as a marker of mast cell degranulation.

At the same time, mast cell-derived mediators cause endothelial cells to upregulate their expression of adhesion molecules for eosinophils, basophils, and lymphocytes. In addition, tryptase may activate proteinase activated receptor-2 (PAR2) on endothelial cells, increasing vascular permeability. These leukocytes are then drawn to the airways during a relatively symptom-free recruitment phase, where they release cytokines and tissue-damaging proteases that contribute to the late-phase response (congestion in allergic rhinitis and renewed bronchoconstriction in asthma). Chronic inflammation eventually produces airway hyperresponsiveness. Specific T cells also generate a memory response, which may contribute to the exacerbation of asthma symptoms on reexposure to certain stimuli (10, 14, 15).

	IgE PHARMACOKINETICS

TOP ABSTRACT PATHOPHYSIOLOGIC ROLE OF IgE... IgE PHARMACOKINETICS IS IgG IMPLICATED IN... RELATIVE ROLES OF IgE... CONCLUSIONS REFERENCES

IgE has a very short half-life (< 1 d) and is present in very low concentrations in the circulation (16), much lower than any other immunoglobulin. In part, this is because some proportion of the circulating amount is continually removed and destroyed in endosomes (in the endosomes IgG is protected by FcRn). IgE is extremely biologically active despite the low concentrations in the circulation. This is because IgE antibodies bind to high-affinity receptors on the surface of mast cells and basophils, so that these cells may be highly sensitive to allergens even when the concentration of IgE in the circulation is very low. In addition, the expression of the high-affinity receptors is upregulated during allergen-induced rhinitis (17), probably by IgE itself (16, 19, 20). Thus, the concentration of circulating IgE does not reflect its true activity. Furthermore, the allergic immune response is comparatively selective, i.e., IgE antibodies are specific to a select group of antigens, rather than a wide range.

The consistency of the allergic response initiated by IgE over time can be attributed both to the long life of IgE-producing B cells and also in part to the stability of mast cells in the skin. In patients with atopic dermatitis, repeated topical application of inhalant allergens to the skin results in eczematous lesions containing high quantities of mast cells (21). If plasma from atopic individuals is injected into nonatopic recipients, they will demonstrate positive responses to allergen skin tests for at least 6 wk, because of the sustained binding of IgE to mast cells. Similarly, purified IgE injected locally into the skin of nonatopic subjects will produce a discrete area of skin reactivity that persists for 2 to 3 wk.

Influence on Mediator Release

Allergic patients produce IgE antibodies specific for foreign antigens, which are harmless to nonallergic individuals. These antibodies bind to IgE-specific receptors on the surface of mucosal and cutaneous mast cells and circulating basophils. Inhaled or ingested allergens cross-link IgE bound to these effector cells, which results in aggregation of the receptors (22). As shown in Figure 2, this cross-linking and aggregation causes the immediate release of preformed mediators such as histamine and, shortly thereafter, the release of newly formed mediators such as arachidonic acid products (e.g., leukotriene D₄, prostaglandin D₂) and cytokines such as tumor necrosis factor- (TNF-), IL-4, and IL-5 (20). As described in the preceding sections, these mediators and cytokines are ultimately responsible for both immediate and late responses (14, 16, 23).

Influence on Cell Recruitment

In nonatopic subjects who receive a passive transfer of serum from an atopic donor or an intradermal injection of purified antibody, a subsequent dermal allergen challenge over 2 d can produce eczematous lesions, including eosinophil recruitment. This is probably accomplished via the IgE bound to mast cells. Although plasma or serum with high IgE concentrations can draw not only eosinophils but also basophils and mononuclear cells to the site of an allergen patch test, other factors must also be involved in basophil recruitment, because basophils were not recruited after infusion of purified IgE and IgG alone (24).

	IS IgG IMPLICATED IN ASTHMA? THE RELEVANCE OF A "MODIFIED Th2 RESPONSE"

TOP ABSTRACT PATHOPHYSIOLOGIC ROLE OF IgE... IgE PHARMACOKINETICS IS IgG IMPLICATED IN... RELATIVE ROLES OF IgE... CONCLUSIONS REFERENCES

Although current theories on preventing the symptoms of allergy and asthma have focused on directing T-cell differentiation away from Th2 and toward Th1 pathways, new evidence challenges this concept. This evidence focuses on several situations where high-dose allergen exposure leads to the production of IgG and IgG₄ without IgE antibodies. The isotype IgG₄ is dependent on the cytokine IL-4 and is a feature of Th2 responses.

Allergy to dog and cat antigens is widely accepted as a cause or aggravator of asthma, but several recent studies on Swedish schoolchildren have revealed an unexpected result: the presence of pets in the home was not among the risk factors for asthma. In fact, having a dog or cat in the home appeared to reduce the risk of asthma (OR = 0.6). This held true even when only allergic asthma was considered (25, 26). Furthermore, it is clear that this is also true for children who are atopic as judged by a positive skin test to another allergen (e.g., pollen) (27).

Other recent population-based research analyzed the effects of allergen exposure and sensitization on the risk of asthma in a cohort of American schoolchildren (Table 1) (4, 7, 28). For house dust mite antigen, greater exposure was correlated with a higher risk of allergy, and the allergic children were more likely to have asthma (OR = 6.9 for asthma among the children with the highest dust mite exposure). In contrast, high exposure to cat allergen was not correlated with the likelihood of specific sensitization, although the risk of asthma was high among those children who were sensitized. In fact, at the highest exposure levels, sensitization was less common than at moderate exposure levels. Further analysis revealed that a large proportion of the nonallergic children with high exposure to cat allergen had made IgG antibodies specific to cat allergen (27).

These findings offered an opportunity to examine immune response to a common inhalant allergen in a population in whom exposure was not correlated with a classic IgE-mediated allergic response. The proportion of IgG in these children that consisted of IgG₄ was found to be the same in the allergic and nonallergic children, confirming that this isotype was not implicated in sensitization. Moreover, multivariable analysis revealed no relationship between IgG and risk of asthma, suggesting very strongly that a "modified" Th2 response involving IgG and IgG₄ but without IgE should be regarded as a form of immunologic tolerance (27).

In summary, the risk of asthma is not increased by dust mite or cat exposure in the absence of sensitization. The only significant independent risk factors for asthma in these studies were sensitization to dust mite or cat (p < 0.001) and total serum IgE over 200 IU/ml (p < 0.01). The presence of IgG specific to cat or dust mite allergen was not significantly associated with asthma risk (27).

These findings suggest a model for immune response to allergens in which IgG and IgG₄ can be produced by certain classes of B cells but do not appear to contribute to disease. By contrast, IgE initiates the allergic response by causing mast cells to release inflammatory mediators and by recruiting eosinophils (Figure 3), although eosinophils may also be recruited by T effector cells. Thus, blocking the effects of IgE is a promising strategy for preventing or ameliorating allergic symptoms. Attempts to shift T-cell differentiation toward Th1 pathways may be less important than shifting immunoglobulin responses from IgE to IgG, as probably occurs with immunotherapy or with naturally developed tolerance to rat allergen, cat allergen, or bee venom (27).

View larger version (22K): [in this window] [in a new window]   Figure 3.   IgE, IgG4, and Th2 cells in the immune response to inhaled allergens. Both IgG4 and IgE are dependent for their expression on IL-4. High exposure can selectively enhance IgG and IgG4. This process is possibly dependent on IL-10 production. VCAM = vascular cell adhesion molecule.

	RELATIVE ROLES OF IgE AND T CELLS IN IMMEDIATE AND LATE-PHASE RESPONSES

TOP ABSTRACT PATHOPHYSIOLOGIC ROLE OF IgE... IgE PHARMACOKINETICS IS IgG IMPLICATED IN... RELATIVE ROLES OF IgE... CONCLUSIONS REFERENCES

Triggering of mast cells by IgE is a convincing explanation for the events immediately following allergen exposure, and it is clear from passive transfer experiments that IgE can mediate histamine release and eosinophil recruitment without the involvement of sensitized T cells. Although mast cells are known to be involved in IgE-dependent late-phase allergic responses and some aspects of chronic allergic inflammation, much remains to be elucidated about this process and the contributory roles of T cells (20).

The role of IgE in the late-phase skin reaction to allergens is strongly supported by the demonstration of the presence of IgE-bound APCs in late cutaneous biopsies (17). Interestingly, recent findings suggest that some features of the late asthmatic response may also be T-cell related and independent of IgE. Haselden and coworkers isolated short overlapping peptides from chain 1 of the cat allergen Fel d I, which did not cross-link IgE, and injected them intradermally in 40 individuals with cat allergy and asthma; nine demonstrated late bronchial reactions but no evidence of any early or late cutaneous response (29).

Summary Regarding the Relevance of IgE Antibodies to Asthma

The evidence that IgE antibodies create a risk of asthma is not new, however several recent developments have strongly reinforced the concept. In all epidemiologic studies the risk factor for asthma is sensitization (i.e., positive skin tests) or IgE antibodies, not IgG antibodies or T-cell responses. Children raised in a home with a cat who have not made IgE antibodies are not at risk for asthma. Furthermore, many of the inflammatory effects of allergen challenge in the skin (i.e., eczema) and eosinophil infiltrate can be passively transferred with IgE antibodies. Finally, treatment with anti-IgE has been shown to improve asthma management significantly.

Many different allergens can contribute to asthma, ranging from dust mites, to pollens, to fungal spores, or fungal colonization. In each case, the antigen is only associated with asthma in subjects who have made an immune response including IgE antibodies (Table 2). However, for many of these allergens, there is evidence for a nonallergic or default pathway. Recent evidence shows that these alternative pathways are distinct depending on the source of allergen exposure. Thus, for trichophyton, the alternative response is delayed hypersensitivity (30, 31). For cat allergen, as we have discussed, the alternative response among children raised in a home with a cat is a modified Th2 response. Similarly, high exposure to rat urine (or bee venom) can produce a modified Th2 response that is not related to asthma. Finally, we have to consider what the alternative response to mite allergen is. In our studies, we have consistently found that nonallergic individuals have little or no IgG antibodies to Der P1, negative skin tests, and poor or no in vitro T-cell responses to mite antigens (32, 33). On the other hand, other researchers have suggested that a Th1 response to mite allergens is established early in life. In our view, the evidence for this Th1 response in nonallergic individuals is not convincing, and, in particular, the evidence that cord blood lymphocyte proliferation represents an in utero immune response to mite allergens is not compelling (34).

	CONCLUSIONS

TOP ABSTRACT PATHOPHYSIOLOGIC ROLE OF IgE... IgE PHARMACOKINETICS IS IgG IMPLICATED IN... RELATIVE ROLES OF IgE... CONCLUSIONS REFERENCES

The epidemiologic findings outlined here strongly suggest that the impact of allergens on asthma is mediated primarily by IgE. By contrast, mechanistic findings derived from studies of allergen avoidance or bronchial provocation cannot define whether the inflammatory responses can be traced to IgE activation of mast cells or to effector T cells. Studies that stratify patients on the basis of IgG response suggest that this immunoglobulin is not a risk factor for asthma. However, the ability of some individuals to develop tolerance to certain allergens after high-dose exposure is probably related to the production of IgG and IgG₄ antibodies without IgE antibodies. In other words, the default immune response is a modified Th2 response rather than a Th1 response and it appears not to be related to asthma. Eosinophil recruitment can also be attributed to IgE, because passive transfer into the skin can sensitize mast cells and produce a delayed eosinophil response. Although IgE is just one player in a highly complex immune response orchestrated by Th2 cells, it is undoubtedly of central importance in both immediate hypersensitivity and the late-phase responses characteristic of allergy and asthma (16, 20). The evidence for a role of allergens in asthma provides a compelling rationale for several forms of treatment. These include allergen avoidance, immunotherapy, and the new approach of directly neutralizing IgE antibodies (23, 35).