Additionally, several independent laboratories reported that respiratory viral infections such as influenza could subvert the generation of protective ‘inhalation Poziotinib tolerance’ to aeroallergens (for example) [2,3], a process described originally by our laboratory as the respiratory tract equivalent of oral tolerance (reviewed in [4]). More recently, signals such as enterotoxins from skin-dwelling bacteria

have been invoked as important contributors to the pathogenesis of atopic dermatitis [5]. However, it was also clear from other observations that microbial exposure per se could not be considered in generic terms as ‘pro-atopic’. For example, other microbial-derived agents exemplified by the components of Freund’s adjuvant displayed atopy-antagonistic activity [6], and stimuli derived from normal gut flora were demonstrated to be necessary to facilitate the expression of oral tolerance

to fed allergen [7,8], and also inhalation tolerance to aeroallergen [4]. These observations suggested that microbial-derived stimuli had potential to modulate the aetiology and pathogenesis of atopic diseases in dichotomous ways, their AZD3965 concentration ultimate effects perhaps being context-dependent. A limitation of these ideas was their universal derivation from experimental models, leaving open the question of applicability to corresponding human disease. In order to bridge this conceptual gap, some creative epidemiology was required. While it was not the first observation noting the inverse relationship between risk for allergic disease in humans and microbial exposure/infection frequency, the insightful publication by Richard Strachan in 1989 [9] first articulated this concept Florfenicol in a way that caught the attention of the immunology community, who were focusing upon underlying

sensitization mechanisms. The core observations in the initial Strachan study and subsequent follow-ups pointed to a series of related factors, notably family size, socio-economic class and birth order, as important determinants of allergy risk in the United Kingdom. In particular, the lowest risk was seen in children with multiple older siblings, from relatively poor families [9,10]. These ‘low-risk’ children grew up typically experiencing a relatively high frequency of gastric and respiratory infections contracted from their older siblings, and the concept developed that these robust early microbial exposures helped to educate the immune system in some way to the dangers of inappropriate immune responses against non-pathogenic antigens.