Control of high-affinity IgE responses to animal venoms by skin innate type 2 immunity

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Understanding how innate type 2 responses of tissues are induced and how these local tissue responses instruct systemic adaptive type 2 responses is a key question in biomedical research. Skin tissue mounts important type 2 responses upon exposure to venoms e.g. through bites of reptiles or insect stings. These type 2 responses can provide innate and adaptive, IgE-mediated protection, even resistance, against venom toxicity, but on the other hand, frequently lead to life-threatening allergic sensitization. Molecular mechanisms and cellular interplay triggered by venoms to induce local type 2 immunity are unclear, as are the signals from venom-exposed skin that instruct adaptive type 2 immunity in the skin-draining lymph node (LN). How these type 2 responses, while in principle protective, frequently go awry to cause anaphylaxis, is a related important question.We hypothesize that the immediate tissue response to the venom and subsequent activation of dermal and LN type 2 cells instructs amounts and affinity of the anti-venom IgE produced and thereby determines the beneficial or potentially fatal outcome. Despite considerable progress in understanding germinal center responses that produce high-affinity IgE through sequential class switching via hypermutated IgG1, the control of this process exerted by the tissue 2 type response remains elusive. To understand instruction of high-affinity anti-venom IgE responses by the innate tissue response starting at the site of venom injection, we will investigate how venom affects skin-resident DCs as well as migratory and LN-resident DC populations in the LN draining the injection site. We will probe the requirement for individual cell types and innate signaling pathways for protective high-affinity anti-venom IgE responses. We will address the key question of how low- and high-affinity IgE responses correlate with resistance or anaphylaxis. Extensively relying on interactions with other FOR groups, we will address the following specific tasks: (1) Quantify affinity and kinetics of affinity maturation of IgE elicited by venoms or venom components in comparison to protease allergens and helminth antigens; (2) determine signals activated in DCs in skin injected with venoms that induce high-affinity IgE. Specifically identify signals which depend on, or are independent of IL-33/ST2 and/or mast cells; (3) determine signals activated by venom injection in DCs, mast cells and macrophages of skin-draining LNs; (4) elucidate innate pathways and cell types required for high-affinity IgE responses; (5) determine how development of resistance versus anaphylaxis depends on high- or low-affinity IgE production. Collectively, our work will elucidate the nature of the skin type 2 response pattern to venoms and the communication of this response to the germinal center and will reveal key features of the “resistance versus anaphylaxis decision”.