The coming-of-age of the hygiene hypothesis

0 The Respiratory Sciences Center, University of Arizona , Tucson, Arizona , USA The hygiene hypothesis, as originally proposed, postulated an inverse relation between the incidence of infectious diseases in early life and the subsequent development of allergies and asthma. New evidence from epidemiological, biological and genetic studies has significantly enlarged the scope of the hypothesis. It now appears probable that environmental 'danger' signals regulate the pattern of immune responses in early life. Microbial burden in general, and not any single acute infectious illness, is the main source of these signals. The latter interact with a sensitive and complex receptor system, and genetic variations in this receptor system may be an important determinant of inherited susceptibility to asthma and allergies. - Introduction There is now convincing evidence indicating that the prevalence of allergic diseases in general, and of asthma in particular, is on the rise in high income societies [1]. Many hypotheses have been proposed to explain these increases, but the most widely discussed and the most controversial is the so-called hygiene hypothesis [2,3]. This hypothesis was first enunciated in quite straightforward terms: the Western lifestyle has succeeded in markedly decreasing the incidence of infections in early life, and these infections may have a protective effect on the subsequent development of allergies. Initially, the hypothesis was mainly based on epidemiologic evidence of an inverse relation between indirect markers of increased infectious burden and prevalence of allergic diseases and allergic sensitization (reviewed in [4]). Concomitant studies on the development of the immune system in early life seemed to provide a biological basis for the hypothesis main postulate. It has been reported that mononuclear cells obtained from cord blood showed markedly decreased cytokine responses to nonspecific stimuli [5]. This included both responses that characterize the T-helper (Th) 1 type (ie IFN-g ) and the Th2 type (ie IL-4). When studied both in cord blood and during the first year of life [6,7], however, Th1-like responses were particularly decreased among children with a family history of allergies and among those who would subsequently become sensitized to aeroallergens. Since IFN-g is known to downregulate Th2-type responses, and these responses are essential for IgE synthesis by B cells, it was suggested that the development of IFN-g responses could be stimulated by exposure to infectious agents postnatally [3,8], and that this could be the mechanism by which these infections protected against the development of allergic diseases. Infectious diseases versus microbial burden Presented in this fashion, the hygiene hypothesis was tested in relation to several infectious diseases. The results were contradictory: whereas markers of a previous infection with foodborne pathogens appeared to be associated with decreased risk of subsequent allergic sensitization, this was not the case for respiratory pathogens [9] or was confined to certain respiratory viruses [10]. Moreover, while some authors reported that contagious diseases such as measles were associated with decreased likelihood of developing allergic conditions [11], other workers were unable to confirm these observations [12]. The finding of an inverse relation between responses to tuberculin test and asthma and allergies in Japan was interpreted by some authors as indicating that infection with Mycobacterium tuberculosis could protect against allergies [13]. Other workers, however, contested that the association was more simply explained by a reduced Th1type response to tuberculin in atopic subjects. But perhaps the greatest challenge to the hygiene hypothesis, expressed simply in terms of an inverse relation between incidence of infectious diseases and allergies, has arisen from studies of children of farmers [1417]. These studies have consistently found that growing up on farms confers significant protection against the development of atopy (as assessed by skin test reactivity to local allergens), allergic rhinitis and (to a lesser extent) asthma. A more detailed analysis of several of these studies showed that the factor that best explained the difference in the prevalence of allergies among children living on farms and those living in the same rural villages but not on a farm was having contact with livestock and poultry [16]. These results suggested that substances produced by farm animals, which could presumably also be abundant in homes located close to these animals quarters, could play a role in the prevention of allergies. In a study by von Mutius et al, dust collected from homes of children living on farms had markedly higher levels of endotoxin than that from homes of children living in the same rural communities but away from animal farms [18]. These findings suggest a broader approach to the understanding of the environmental factors that may influence the development of the immune system and, through this mechanism, decrease the likelihood of the development of allergies. Endotoxins are lipopolysaccharides (LPS) that form part of the outer structure of the cell wall of Gramnegative bacteria. An exquisitely sensitive mechanism that detects the presence of LPS is present in vertebrate immune systems. This receptor system is expressed mainly in antigen presenting cells, and constitutes the first, nonadaptive response to external microbial stimuli. The system in question is in fact made up of pattern-recognition receptors that are capable of detecting the presence of different structures present in Gram-negative and Gram-positive bacteria, mycobacteria, fungi, and even viruses [19]. This receptor system activates a complex intracellular signaling mechanism that will not be discussed in the present article in detail, but that results in the production of a set of cytokines and immune mediators by antigen presenting cells. The finding that exposure to environmental bacterial products, that do not directly cause specific diseases in those exposed, may influence the pattern of immune responses in humans provides an entirely new framework for the understanding of the hygiene hypothesis. The influence of potential infectious agents on the risk of allergies is thus not confined to those that directly produce infectious diseases in humans, but may comprise a much broader set of agents, including those to which the individual is exposed in the home, in schools, in daycare, etc. These agents may act through the respiratory system but also through the intestinal track [9], modulating the development of the immune system during the first years of life. This new set of potential exposures may be very relevant for our understanding of the marked increases in the prevalence of allergies and asthma that have taken place in past decades. The widespread availability of products and practices that promote a (...truncated)