There is a strong familial component to asthma, eczema, and rhino-conjunctivitis, the so-called atopic cluster. While this argues for a genetic component to asthma, the rapid increase in the prevalence of asthma means that something in the environment must be responsible. The current consensus is that environmental factors act on genetically susceptible individuals, stimulating the production of specific IgE antibodies against otherwise harmless environmental antigens, such as pollen, house dust mite, and animal dander proteins. Not everyone who develops IgE antibodies will go on to experience clinical symptoms. Indeed, only half of the people with detectable levels of antibody against grass pollen will have any sort of hay fever. Nevertheless, the more IgE antibody someone has, the more likely they are to have associated clinical symptoms. Usually, there is a progression of allergic disease, sometimes termed the allergic march, in which children first suffer with atopic eczema, then they get allergic rhinitis, and afterwards they may progress to develop asthma. But this pattern is certainly not universal, and many children who develop asthma have not had significant eczema or rhinitis. Intriguingly, genetic analysis of asthma and eczema have implicated different chromosomal loci, suggesting that whether an atopic individual develops asthma may depend on the susceptibility of the target organ rather than simply be a consequence of allergic sensitization.
Following extensive research into risk factors for the development of asthma and atopy, it has now been established conclusively that allergic sensitization to common environmental allergens (house dust mites, cockroach, domestic animals, etc.) is a major risk factor for the development of childhood asthma (1-3). The tendency to produce IgE antibodies is regulated by T lymphocytes. Naive B lymphocytes capable of recognizing allergenic proteins start life with a full complement of immunoglobulin heavy-chain genes. When they first encounter the antigenic determinant that they recognize, they differentiate into two cell types: antibody-producing cells that produce IgM antibodies and antigen-specific memory cells. Upon subsequent exposure, the memory cells are triggered to produce a secondary response that consists of higher affinity antibodies than the initial (primary) response. Depending on the context of this secondary stimulation, the memory cells switch over from producing IgM antibodies towards IgG, IgA, or IgE antibodies (4,5). In order to make an IgE response, T cells must recognize the antigen and interact with the B cell to provide ''T-cell help,'' which comprises two signals: a direct contact with ligands on the memory B-cell surface and a signal delivered by soluble mediators (cyto-kines) (4). The contact signal for IgE switching is an interaction between
CD40 and its ligand, while the soluble signal is delivered by either IL-4 or IL-13 (5). This process is partly controlled by the context in which the aller-genic antigen is encountered, and partly by genetic predisposition, with some individuals being more likely to develop allergic antibody responses than others, despite similar levels of allergen exposure (5,6). In individuals predisposed to making IgE responses, their T cells may be skewed towards production of the cytokines IL-4 and IL-5 (the so-called Th2 phenotype), which, respectively, facilitate memory B cells to switch over to make IgE (5) and promote eosinophilic inflammation (7). Th2-type cytokines have also been implicated directly in the pathogenesis of asthma: IL-4 activates vascular endothelial cells and stimulates mucus production, while IL-13 has multiple actions on epithelium, smooth muscle, and fibroblasts, which may alter airways structure and responsiveness (8,9). Thus, the association between Th2 cytokines and asthma is complex, and may not simply be attributable to the effect of IL-4 on IgE switching (10).
When sensitized individuals are exposed to relevant allergens they may develop clinical symptoms, including rhinitis and asthma. However, by no means all sensitized individuals will have clinical symptoms. Many population studies have shown that for every patient with allergic symptoms there is at least one individual who remains asymptomatic despite being sensitized (as judgedby allergy skin tests). Moreover, the relationship between sensitization and symptoms is not simple. Data from Australia has shown a doubling in the proportion of patients reporting asthma and hay fever between 1971 and 1981, without any change in the proportion of patients with positive skin tests to grass pollen or house dust mite (11). The implication is that the likelihood of the sensitization being translated into symptoms has increased, although this increase could also reflect increased willingness to label symptoms as being due to asthma or hay fever.
Conversely, although patients with seasonal allergic rhinitis will almost always be sensitized to seasonal airborne allergens, up to half of adult patients with clinical asthma have no evidence of specific allergic sensitization. These observations call for some caution in postulating a link between allergic sensitization and disease: if patients can have asthma without any evidence of allergy, then presumably the mechanisms operating in these patients might also apply in some patients who happen to be sensitized. In other words, allergy is not necessarily responsible for asthma in all asthmatic patients who show skin-test sensitization.
In summary, the link between allergy and asthma is well established and the majority of patients with asthma have evidence of IgE-mediated hypersensitivity to airborne allergens (12). This is especially true of children with asthma, among whom over 85% will show positive skin tests to one or more airborne allergens (13). While IgE-mediated allergy is clearly an important risk factor for the development of asthma, it is less clear how important allergic triggers are in exacerbations of the disease or in the maintenance of ongoing asthma. In children, most exacerbations of asthma correspond with episodes of viral upper respiratory tract infection (14), while in adults about 50% of exacerbations are associated with rhinovirus infection (15). Anecdotally, exposure to cats or horses can trigger severe acute episodes of asthma, but the role of pollens in triggering acute episodes seems less certain. Asthma admissions to U.K. hospitals are actually lower during the grass pollen hay fever season than in the three months preceding or following the hay fever season (16), although epidemics of acute asthma associated with thunderstorms are probably triggered by inhalation of fragmented pollen grains (17).
Before embarking on allergen-specific therapies for asthma, we therefore need to be confident that allergy is important in the individual patient. We do not know for sure whether IgE-mediated allergy, viral infection, and occupational sensitization are alternative triggers for some final common pathway that presents clinically as asthma. We know that there are similar histological pictures in allergic, non-allergic, and occupational asthma (18-22), and also in children (23), suggesting that at least part of the inflammatory process in asthma is independent of allergy. Understanding these points will be critical in determining whether we should pursue better forms of immunotherapy for asthma, or look elsewhere for a solution.
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