Skin damage signals mediate allergic sensitization to spatially unlinked antigen

Our current understanding of immunity to pathogens suggests that anatomic coupling of antigens with danger signals is a required feature for the formation of immune memory. However, in the context of pathogen-independent inflammation, the stringency of this anatomical coupling is unclear. Here, we demonstrate that multiple modes of skin injury were sufficient to induce a humoral response to antigens introduced in the gut. Skin damage induced a narrow subset of endocrine cytokines that were necessary and sufficient for the priming of antigens introduced at various distal tissues. Thus, in addition to “local priming” of antigen entering through damaged skin, there also exists another paradigm of “remote priming” where anatomical coupling is not essential because of the dissemination of damage-associated intermediaries. Our findings have implications for understanding the fundamental mechanisms of the formation of humoral memory with wide implications for diseases such as food allergy and in vaccinology.