Education of lung epithelial cells as an alternative explanation for the protective effect of infectious pressure on development of allergy and asthma.
There is an epidemic of allergy and asthma in the Western industrialized world, with up to 30% of children showing reactivity to common inhaled and food allergens. The reason for the increase in these Th2-associated diseases is currently unclear. The hygiene hypothesis of allergy states that lifestyle changes leading to less "infectious pressure" in the first year of life are associated with more allergy. Conversely, growing up on a farm (with high environmental endotoxin exposure) or amongst older siblings strongly protects against allergy. The immunological explanation has been that less infections, normally cleared by Th1 cells, lead to a dysbalance in the immune system so that Th2 responses are stimulated. We have obtained preliminary data that endotoxin exposure prior to allergen exposure strongly protects against allergy because lung epithelial cells upregulate TNFAIP3 (A20), a negative regulator of Toll like receptor and IL-1R family signalling. In this project we will address how A20 controls the epithelial threshold for allergen recognition and how this leads to alterations in dendritic cell and T cell activation. We have developed the necessary tools to measure and eliminate A20 selectively in lung epithelial cells. Our epithelium-centered view on regulation of pulmonary immunity offers an entirely new explanation for the effect of infectious pressure on development of allergy and asthma that may one day lead to development of new preventive strategies.