The Role of Jam-A in Regulating Intestinal Antigen Presenting Cell Function and I

描述(由申请人提供)： 大量的观察表明，炎症性肠病是一个多因素的过程，至少包括三个主要的相互作用因素：环境条件、粘膜免疫功能改变和遗传易感因素。虽然遗传因素和环境很难以可控的方式进行研究，但人们的注意力和研究调查主要集中在了解粘膜免疫反应上，其工作假设是肠道炎症是由于对正常肠道微生物区系的免疫耐受性下降造成的。虽然人们对肠道炎症的发病机制有越来越多的了解，但迫切需要更彻底地了解控制炎症的保护性因素，以便设计更有效的治疗方法。一个重要的挑战仍然是保持对正常共生细菌的耐受性和允许对病原微生物的适当粘膜免疫反应之间的关键平衡的能力。粘膜常驻抗原提呈细胞(APC)，特别是树突状细胞(DC)和巨噬细胞，在这方面很有希望，因为它们可以摄取肠道细菌、病毒和原虫，并诱导不同类型的免疫反应，例如促炎(Th1/Th17)和调节性(Treg/TR1/Th3)T细胞反应。本质上，粘膜APC是位于上皮屏障下方的哨兵，能够启动和协调肠道免疫反应。重要的是，粘膜DC和巨噬细胞的功能与覆盖的肠上皮细胞紧密结合。这一完整的肠层创建了一个关键的半渗透屏障，允许腔液和分子在上皮细胞之间通过，同时严格调节肠道微生物区系的流量。肠道上皮屏障完整性的改变会对肠道疾病的易感性产生深远的影响。虽然在肠道炎症发生之前，肠上皮通透性增加之间存在联系，但关于上皮屏障如何调节固有层下的固有免疫细胞和获得性免疫细胞的了解很少。因此，明确了解JAM-A缺乏引起的肠上皮通透性增加对固有层DC和巨噬细胞功能的影响(特定目标1)，并详细分析JAM-A缺乏对肠道炎症过程中免疫反应的调节(特定目标2)的结果，将是了解和治疗肠道炎症以及粘膜耐受和免疫的重大进展。这项建议的总体目标是对肠上皮屏障通透性增加如何调节固有层抗原提呈细胞在动态平衡和炎症中的功能有一个更深入的基础了解。推动这项研究的中心假说是，肠道上皮屏障“泄漏”会导致肠道固有层巨噬细胞和树突状细胞功能障碍，并导致肠道炎症的发生。

DESCRIPTION (provided by applicant): Numerous observations have suggested that inflammatory bowel disease is a multifactorial process encompassing at least three major interacting elements: environmental conditions, altered mucosal immune function, and genetic susceptibility factors. While genetic factors and the environment are incredibly difficult to investigate in a controlled manner, attention and research investigation has focused on understanding mucosal immune responses with the working hypothesis being that intestinal inflammation results from a breakdown in immune tolerance to normal intestinal microbiota. While there is increasing understanding of the factors that contribute to the pathogenesis of intestinal inflammation, there is an urgent need for more thoroughly understanding protective factors that control inflammation in order to design more efficacious treatments. An important challenge remains the ability to maintain the critical balance between enforcing tolerance to normal commensal bacteria, while allowing for appropriate mucosal immune responses to pathogenic microbes. Mucosal resident antigen presenting cells (APCs), particularly dendritic cells (DCs) and macrophages, hold great promise in this regard because they can uptake enteric bacteria, viruses, and protozoa and induce distinct types of immune responses, for example pro-inflammatory (Th1/Th17) versus regulatory (Treg/Tr1/Th3) T cells responses. In essence, mucosal APCs are sentinels situated just beneath the epithelial barrier and are capable of initiating and orchestrating intestinal immune responses. Importantly, mucosal DC and macrophage function is closely integrated with overlying intestinal epithelial cells. This intact intestinal layer creates a critical, semi-permeable barrier that allows passage of luminal fluid and molecules between epithelial cells while tightly regulating the flux of the enteric microbiota. Alterations in the integrity of the intestinal epithelial barrier can have a profound impact on intestinal disease susceptibility. While there are associations between increased intestinal epithelial permeability predating the onset of intestinal inflammation, little is understood about how the epithelial barrier regulates innate and adaptive immune cells in the underlying lamina propria. Thus, a clear understanding of the consequences of increased intestinal epithelial permeability created by JAM-A deficiency on the function of lamina propria DCs and macrophages (Specific Aim 1) and detailed analysis of the outcome of JAM-A deficiency in regulation of immune responses during intestinal inflammation (Specific Aim 2) would represent major advancements toward the understanding and treatment of intestinal inflammation, as well as mucosal tolerance and immunity. The overall goal of this proposal is to gain a stronger fundamental understanding of how increased intestinal epithelial barrier permeability regulates the function of lamina propria antigen presenting cells in homeostasis and inflammation. The central hypothesis driving this research is that a "leaky" intestinal epithelial barrier leads to dysfunction of intestinal lamina propria macrophages and dendritic cells and the development of intestinal inflammation.