The hygiene hypothesis postulating the paradoxical protective role of infections on immune-mediateddiseases including atopy (i.e. atopic dermatitis, rhinitis, asthma) and more recently autoimmune diseases hasbeen the matter of extensive investigation. The aim of the present project is to validate this hypothesisintegrating epidemiological and experimental studies.We will review in a meta-analysis published studies of direct and indirect markers of infections and atopicdiseases, and conduct a case-control study to analyse the association between infections and atopy usingatopic dermatitis as a prototypic model. This epidemiological study will assess the occurrence of differentinfections and other risk factors related to the incidence of atopic dermatitis in children under age five inItaly (300 cases and 600 controls).This epidemiological study will be supported by experimental approaches addressing mechanistic questionsraised by the hygiene hypothesis. Experimental models will include induction of acute and chronicbronchoconstriction/asthma, atopic dermatitis. In addition the project will aim at devising new mouse modelsof atopy. The nature of infections providing protection against allergic diseases will be investigated tocharacterise the difference at the molecular level between protective and non protective pathogens or theirderivatives. The underlying immune mechanisms notably homeostasis imbalance, antigenic competition,stimulation of regulatory immune cells and Toll-like receptor involvement will be analysed. In addition todeveloping integrated in vivo models, including the use of transgenic animals, efforts will be focussed on thestudy of available synthetic pathogen-derived compounds showing a protective activity to better approachtheir cellular and molecular mode of action. These studies may pave the way to novel and safe therapies thatcould advantageously substitute for the “protective” immune stimulation induced by major infections.