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

了解组织的先天2型反应是如何被诱导的，以及这些局部组织反应如何指导系统的适应性2型反应是生物医学研究的关键问题。皮肤组织在接触毒液时产生重要的2型反应，例如通过爬行动物的叮咬或昆虫的叮咬。这些2型反应可以提供先天的和适应性的，ige介导的保护，甚至抵抗毒液毒性，但另一方面，经常导致危及生命的过敏性致敏。由毒液诱发局部2型免疫的分子机制和细胞相互作用尚不清楚，暴露于毒液的皮肤在皮肤引流淋巴结（LN）中指示适应性2型免疫的信号也不清楚。这些2型反应虽然原则上具有保护作用，但如何经常出错而引起过敏反应，是一个相关的重要问题。我们假设，组织对毒液的直接反应以及随后皮肤和LN 2型细胞的激活指示了产生的抗蛇毒IgE的数量和亲和力，从而决定了有益或潜在致命的结果。尽管在理解生发中心反应通过超突变IgG1的顺序类转换产生高亲和力IgE方面取得了相当大的进展，但组织2型反应对这一过程的控制仍然难以捉摸。为了了解从注射毒液部位开始的先天组织反应对高亲和力抗蛇毒IgE反应的指导作用，我们将研究蛇毒如何影响皮肤上的DC，以及LN中引流注射部位的迁移和LN上的DC群体。我们将探讨个体细胞类型和先天信号通路对保护性高亲和力抗蛇毒IgE反应的要求。我们将解决低亲和力和高亲和力IgE反应如何与抵抗或过敏反应相关的关键问题。广泛依赖于与其他FOR组的相互作用，我们将解决以下具体任务：(1)量化与蛋白酶过敏原和蠕虫抗原相比，由毒液或毒液成分引起的IgE的亲和力和亲和力成熟动力学；(2)测定注射了能诱导高亲和力IgE的毒液的皮肤dc中激活的信号。特异性识别依赖于或独立于IL-33/ST2和/或肥大细胞的信号；(3)测定蛇毒注射液激活的dc、肥大细胞和巨噬细胞的信号；(4)阐明高亲和力IgE应答所需的先天途径和细胞类型；(5)确定耐药与过敏反应的发展如何取决于高或低亲和力IgE的产生。总的来说，我们的工作将阐明皮肤对毒液的2型反应模式的性质以及这种反应与生发中心的交流，并将揭示“抵抗与过敏反应决定”的关键特征。

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”.