Regulation and function of mucosal IgA immune responses to mycobiota in the gut.

摘要 免疫球蛋白A（伊加）主要分泌在粘膜表面，并覆盖一小部分肠粘膜。 细菌微生物群在健康和疾病中，分泌型伊加（sIgA）结合影响肠道免疫， 通过交联管腔中的微生物群来保持体内平衡以防止对肠上皮的侵入， 穿梭结合的微生物到次级淋巴组织，并直接调节微生物代谢活性。 除了在无菌小鼠中可检测到的“天然”多反应性伊加外，sIgA主要是肠道定植 依赖。免疫原性肠道细菌及其特异性伊加表位的鉴定， 阐明了我们对胃肠平衡机制的理解，以及生态失调如何驱动 肠道病理学与此同时，肠道菌群中真菌成分的潜在参与 （真菌生物群）在这些过程中的作用在很大程度上是未知的。直到最近，肠道真菌才被认为是 导致炎症性疾病相关事件的因素或对治疗的反应， 关于抗真菌粘膜抗体应答的发展、其特异性和 肠道中的诱导机制。在最近的研究中，我们发现Dectin-1基因的多态性 CLEC 7A或Fractalkine受体基因CX 3CR 1与抗真菌免疫缺陷相关， 炎症性肠病（IBD）患者，特别是后者导致肠道真菌过度生长， 抗真菌抗体显著降低。在初步研究中，我们意外地发现了一系列广泛的 sIgA抗体针对的真菌生物。菌丝的形成是许多细菌使用的主要机制。 二型真菌入侵并在宿主体内生存。值得注意的是，我们发现， 损伤和炎症依赖于作为sIgA靶的菌丝产生的毒力因子。这些 初步数据支持抗真菌sIgA抗体应答是由抗真菌抗体诱导的总体假设。 特异性肠道菌群物种，并通过以下方式对抗真菌产生的因子，从而在粘膜免疫中发挥关键作用： 避免真菌与肠上皮的直接接触，以防止肠屏障损伤和相关的肠 炎症我们将在深度测序的辅助下，在体外和体内模型中研究这一假设 和计算平台，以及转基因真菌菌株。我们将检测IgA反应性肠道 真菌生物群和真菌形态型参与抗真菌sIgA抗体的诱导，并将利用 几个模型系统来定义抗真菌sIgA在肠道中的功能作用。

Abstract Immunoglobulin A (IgA) is prominently secreted at mucosal surfaces and coats a fraction of the intestinal bacterial microbiota. In health and disease, secretory IgA (sIgA) binding influences intestinal immunity and homeostasis by crosslinking microbiota in the lumen to prevent encroachment on the intestinal epithelium, shuttling bound microbes to secondary lymphoid tissues, and directly modulating microbial metabolic activity. Aside from the “natural” polyreactive IgA detectable in germ-free mice, sIgA is predominantly gut colonization dependent. The identification of immunogenic commensal bacteria and their specific IgA epitopes have further elucidated our understanding of the mechanisms governing gastrointestinal balance and how dysbiosis can drive intestinal pathologies. Meanwhile, the potential involvement of the fungal component of the gut microbiota (mycobiota) in these processes is largely unknown. Only recently have intestinal fungi been recognized as a factor contributing to events associated with inflammatory disease or response to therapy prompting multiple questions regarding the development of antifungal mucosal antibody responses, their specificity, and mechanisms of induction in the gut. In recent work, we have shown that polymorphisms in the Dectin-1 gene (CLEC7A) or the fractalkine receptor gene CX3CR1 are associated with defects in antifungal immunity in Inflammatory Bowel Disease (IBD) patients, and notably the latter leading to gut fungal overgrowth and substantial decrease of antifungal antibodies. In preliminary studies we unexpectedly identified a broad range of fungal organisms that were targeted by sIgA antibodies. Hyphal formation is a primary mechanism used by many dimorphic fungi to invade and survive within their hosts. Notably we found that mycobiota aggravated intestinal damage and inflammation is dependent upon hyphae-produced virulence factors that are targets of sIgA. These preliminary data support the overall hypothesis that antifungal sIgA antibody responses are naturally induced by specific gut mycobiota species and act against fungi-produced factors to play a key role in mucosal immunity by averting direct contact of fungi with the intestinal epithelium to prevent intestinal barrier damage and related gut inflammation. We will investigate this hypothesis both in vitro and in in vivo models, aided by deep sequencing and computational platforms, and genetically modified fungal strains. We will determine IgA-reactive gut mycobiota and fungal morphotypes involved in the induction of antifungal sIgA antibodies and will make use of several model systems to define the functional role of antifungal sIgA in gut.