New perspectives on the initiation of allergic immune responses at barrier sites

Although allergies exert a devastating global impact and often lack effective treatment strategies, our knowledge on the mechanisms that initiate and propagate type-2 immune responses remain enigmatic. Recent advances have highlighted additional roles for epithelial cells (e.g. tuft cells) and sensory neurons as initiators and amplifiers of type-2 immune responses. In response to protease activity of allergens, Toll-like receptor stimulation or cellular damage, these type-2 sentinels can release cytokines, alarmins or neuropeptides capable of (i) activating and expanding innate immune cells, (ii) polarizing T helper type-2 cells and (iii) promoting allergic inflammation. Overexpression of these type-2 immune mediators has been associated with allergic disorders and together with their disease promoting role in experimental model systems have paved the way for the generation of new biologics. The aim of this review is to provide a concise view on recent developments in the field and to discuss these findings in the context of allergic inflammation.