What drives the allergic march?

The “allergic march”, which refers to the natural history of atopic diseases, is characterized by a typical sequence of sensitization and manifestation of symptoms which appear during a certain age period, persist over years or decades, and often show a tendency for spontaneous remission with age. “Atopy” refers to those allergic conditions which tend to cluster in families, including hay fever, asthma, and eczema, and which are associated with the production of specific IgE antibodies to common environmental allergens. Sensitization may or may not be relevant to the induction of clinical symptoms, which by themselves are characterized by inflammation, corresponding to hyperresponsiveness of the skin or mucous membranes. Epidemiologic studies of atopic diseases have received much attention over the past decade. Cross-sectional studies such as the International Study of Asthma and Allergies in Children (ISAAC) have provided evidence of remarkable differences in the prevalence of certain atopic phenotypes in children aged 6 and 13 years between continents and countries and even within countries ( 1, 2). Sequential cross-sectional studies using a standard questionnaire suggest that the prevalence of some of these phenotypes in defined age groups is truly increasing, and is not simply explicable by an increase in awareness or a change in diagnostic methods ( 3, 4). Longitudinal follow-up studies including cohorts from birth such as the Tucson Study on Asthma (USA) ( 5) or the Multicenter Allergy Study in Germany ( 6, 7) have been designed to clarify the natural history of the disease; to describe associations between phenotypes and genetic, environmental, or lifestyle factors; and to generate hypotheses for causal relationships. Intervention studies have been conducted to assess the role of different environmental factors in the UK ( 8), Germany, The Netherlands, Canada, and Australia. It is to be hoped that these studies will not only contribute to a better understanding of the genetic and environmental factors that regulate early immune responses to allergens and the development of symptoms, but will also lead to more rational strategies for primary and secondary prevention. One of the important implications of the epidemiologic data so far available is that it is obviously useful to disentangle various phenotypes and focus on single manifestations at a certain age window, since different specific phenotypes (clinical symptoms, sensitization, total serum IgE, etc., at a certain age) may be induced or modulated by different genetic, environmental, or lifestyle factors. Although most investigators seem to agree that a complex interaction between genetic and environmental factors regulates the manifestation and development of different atopic features, much of the natural history of atopy and asthma and its determinants is still not well understood. The following general criteria were accepted in order to assess the effect of specific exposures or other lifestyle-related factors that cannot be randomly assigned (randomized) by investigators, as published in a report by the US Department of Health and Education in 1964 ( 9). Strength of an association. The stronger the observed association, the less likely it is that the association is entirely due to various sources of error. Dose-response effect. The observation that the frequency of a disease increases with the dose or level of exposure usually lends support to a causal interpretation. Lack of temporal ambiguity. It is important to demonstrate that the hypothetic causes preceded the occurrence of the disease. Consistency of the findings. All studies dealing with a given relationship produce similar results, so that a causal interpretation is enhanced. Biologic plausibility of the hypothesis. If the hypothetic effect makes sense in the context of current biologic knowledge, we are more likely to accept a causal interpretation. Coherence of the evidence. A causal interpretation is strengthened if the findings do not seriously conflict with our understanding of the natural history of the disease or with other accepted facts about disease occurrence. Specificity of the association. A causal interpretation is suggested if the study factor is found to be associated with only one disease or if the disease is found to be associated with only one factor. There is a hierarchy of evidence that can be extracted from differently designed studies. As far as causal inferences are concerned, cross-sectional surveys and case-control studies are able to generate hypotheses prospective longitudinal cohort studies without intervention are more suggestive in describing a time sequence between potential courses and the health effect controlled longitudinal intervention studies, whenever applicable and acceptable, provide information with the greatest relative weight. Although wide individual variations may be observed, atopic diseases tend to be related to the first decades of life, and obviously require a juvenile immune system. In general, no clinical symptoms are detectable at birth ( Fig. 1), and although the production of IgE antibodies is possible from the 11th week of gestation, no specific sensitization to food or inhalant allergens as measured by elevated serum IgE antibodies can be detected with standard methods. Development of atopic dermatitis (AD), asthma, and allergic rhinoconjunctivitis with age. Data from German Multicenter Atopy Study ( 7). During the first months of life, the first IgE responses to food proteins develop ( Fig. 2a), particularly those to hen's egg and cow's milk ( 10). Even in completely breast-fed infants, high amounts of specific serum IgE antibodies to hen's egg may be detected. It has been proposed that exposure to hen's egg proteins occurs via the mother's milk, but this needs further clarification. Point prevalence of sensitization to food (a), indoor (b), and outdoor (c) allergens in German children. Data from MAS cohort study with estimates for original population-based sample of 4882 children (cutoff level for serum specific IgE 0.7 kU/l) ( 10). Sensitization to environmental allergens from indoor and outdoor sources ( Fig. 2b and c) requires more time and is generally observed between the first and tenth birthdays. The annual incidence of early sensitization depends on the amount of exposure. In a longitudinal birth cohort study in Germany (MAS), a dose-response relationship could be shown between early exposure to cat and mite allergens and the risk of sensitization during the first years of life ( Fig. 3). Early exposure to major allergens of Dermato-phagoides pteronyssinus (Der p 1) and D. farinae (Der f 1) and specific sensitization at ages of 1, 2, and 3 years ( 6). It has been known for many years that atopic diseases run in families. The risk of neonates developing atopic symptoms during the first two decades of life strongly depends on the manifestation of the disease in their parents and siblings. Already at the phenotype level, it is obvious that there is a closer association between specific disorders such as asthma or atopic dermatitis in the child and the same manifestations in parents or siblings than with other atopic manifestations in the family ( 11). These clinical observations already suggest the presence of phenotype-specific genes. Although the role of the family history, which was studied in the 1970s by Kjellmann & Croner ( 21), is undoubtedly strong, the majority of children developing atopic dermatitis or asthma during the first years of life in a country such as Germany had been born into families without any manifestation of atopic disease ( Fig. 4). Therefore, the majority of prospectively affected children will not be identified at birth by family history. Population-based lifetime prevalence of asthma in German children at 5 years of age in relation to parental history of atopy ( 5). During the last two decades, molecular genetic studies have been performed for various allergic diseases including asthma. They were stimulated by the assumption that atopic phenotypes might become preventable once the precise recognition of genetically predisposed children was possible. Various genes predisposing to atopy have since been identified, influencing specific IgE responses to par-ticular allergens, as well as the bronchial tone or bronchial hyperresponsiveness and non-IgE-mediated inflammation. Two approaches are being applied in order to identify genes related to disease: Positional cloning in which the entire genome is screened with a panel of polymorphic DNA markers. This method tries to demonstrate the genetic linkage of a certain phenotype and genetic markers of known chromosomal localization. Examination of candidate genes which are already known to be involved in the pathophysiologic mechanism contributing to a certain phenotype. The role of candidate genes may be assessed by defining polymorphisms within the respective genes and testing for associations with the disease. A linkage of atopy to the chromosomal region 11q13 was first reported by the Oxford group of Cookson et al. in 1989 ( 12, 13). Marsh et al. ( 14) found in Amish families a linkage between total IgE levels and several markers in the 5q23–31 region, which contains genes coding for IL-3, IL-4, IL-5, IL-9, IL-12B, and IL-13 as well as the glucocorticoid receptor and the β2-adrenergic receptor. Barnes et al. ( 15) have recently reported the linkage of asthma and total serum IgE concentrations on chromosome 12q in Afro-Caribbean families. In this region, the genes for interferon-gamma and stem-cell factor are present. In the German MAS cohorts, a linkage was found to high total serum IgE concentrations during the first 3 years of life at D12S 379 ( 16). The human major histocompatibility complex (MHC) includes genes coding for HLA class II molecules, which are involved in the recognition and presentation of exogenous peptides. An HLA influence on specific IgE responses to a minor ragweed antigen (Amb AV) was described already in 1982 by Marsh et al. ( 17). Like the human MHC, the T-cell receptor has become a candidate for studies investigating the linkage between IgE responses and microsatellites from certain regions of one of the chains. From the genetic studies published so far, it can be concluded ( 18, 19) that both asthma and other allergic diseases are genetically heterogeneous disorders each of the atopic phenotypes is probably the result of a polygenic inheritance and a complex inter-action between genes and environmental factors. In contrast to single-gene disorders in asthma and atopic phenotypes, there may be a dissociation of genotype and phenotype, whereby genes may increase the susceptibility but not necessarily lead to full disease expression ( 20). Currently, whole genome screen studies are under way, focusing on different atopic phenotypes, including asthma; if fruitful, these studies will contribute to the identification of individuals at risk, who might become candidates for primary prevention measures, as well as of individuals who may respond to certain therapeutic interventions in the future. An obvious prerequisite for effective primary prevention measures is the ability to predict which individuals will develop atopic disease. Therefore, it would be highly desirable, if no genetic markers are available, to have access to immunologic markers capable of identifying individuals at risk before the process of sensitization has been induced or the disease has become manifest. The production of IgE is known to be largely genetically controlled. Therefore, the measurement of IgE concentrations in cord blood, which was first investigated by Kjellmann & Croner ( 21), was at first thought to be a useful screening test ( 22). Unfortunately, more recent studies have shown that neither the sensitivity, the specificity, nor the predictive value of cord-blood IgE measurements is acceptable for use of this factor as a screening test. Using data from the German MAS study, Edenharter et al. ( 23) were recently able to demonstrate that elevated cord-blood IgE concentrations can predict early sensitization, but not airway or skin symptoms. As far as the prediction of asthma is concerned, eosinophils and their mediators (eosinophil cationic protein [ECP], eosinophil peroxidase, and eosinophil protein X) have been studied in infancy in order to identify individuals who are developing chronic disease. In a Norwegian cohort study, wheezing infants had significantly higher levels of serum ECP than controls ( 24). Whether concentrations of mediators from eosinophils also predict the chronic disease process remains to be shown. Pohunek et al. ( 25) studied eosinophils in bronchial biopsies and suggested that increased numbers of eosinophils are a risk factor for chronic asthma. Recently, several groups have studied the in vitro response of fetal or cord-blood peripheral blood mononuclear cells to allergens or mitogens with respect to later development of atopic disease ( 26–29). It was shown that fetal T cells have the capacity to respond on incubation with allergen, and that there are differences in immune responses between those infants who develop atopic disease later, and those who stay healthy. The risk of developing atopic disease is obviously associated with a reduced capacity to secrete interferon-gamma after PHA stimulation at birth. Martinez et al. were able to demonstrate that low TH1 cytokine production at 12 months was associated with atopic sensitization to inhalant allergens at 6 years of age ( 30). In a small birth cohort study, Prescott et al. measured mononuclear cell-proliferative and cytokine responses to specific allergens every 6 months from birth to 2 years of age. They demonstrated a continuation of fetal allergen-specific TH2 response during infancy, and a decreased capacity for production of the TH1 cytokine interferon-gamma in those children who subsequently developed atopic disease ( 31, 32). From the data published so far, it appears unlikely that immunologic markers obtained during the neonatal period might serve as predictors for atopic disease in the near future. Nevertheless, these observations are leading to a better understanding of the mode of immunodeviations which facilitate the manifestation of atopic disease. As long as we lack genetic and immunologic markers as potential predictors for atopic diseases, primary prevention of atopy will be difficult to achieve. Several groups, including our own, have reported elevated serum IgE antibodies to hen's egg proteins as predictors of subsequent sensitization to aeroallergens and to the development of allergic airway symptoms ( 33, 34). These findings might become important in strategies for secondary prevention, since infantile IgE responses to hen's egg are observed very early, generally during infancy. During the last decade, a of environmental and lifestyle factors have been found to be significantly associated with certain atopic Whether these associations are of biologic needs to be demonstrated by longitudinal intervention studies. The of certain factors has to be particularly since several factors such as or have to be markers of other environmental factor has been studied as as exposure to environmental allergens as a potential risk factor for sensitization and manifestation of atopy and asthma ( From a of cross-sectional studies ( performed in children and in it has become obvious that there is a between particularly in the and Longitudinal studies such as the MAS study in Germany ( have demonstrated that during the first years of life, there is a dose-response relationship between indoor exposure to and cat allergens and the risk of as far as the manifestation of atopic dermatitis ( and asthma is concerned, the is much less studies performed by et al. ( suggest that in children exposure to allergens not only the risk of asthma, but also the time of of the disease. recent by the same suggest that factors other than exposure are important in which children develop asthma ( In a & ( have several environmental factors to be for the incidence and of atopic diseases, particularly asthma. the of the various on the of the that indoor exposure is the environmental factor with by far the on the manifestation of asthma. In recent the that exposure asthma with airway via sensitization has been in several the prevalence of asthma in children has been of exposure ( at in genetically allergic sensitization, the production of specific IgE is differently from the manifestation of disease and airway has been shown to be a cytokine for the process of sensitization, other particularly IL-5, obviously a role in the of ( Fig. 5 a of the role of and early as well as in sensitization and the development of asthma. of hypothetic role of genetic factors and environmental exposure in specific sensitization and development of asthma. 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