NOD2调节肠道上皮内淋巴细胞发育分化的机制及肠炎相关性研究

Nod2 is the first detected susceptibility gene for crohn's disease(CD)and its variantion is strongly associated with the onset and progression of CD, but until now, the mechanisms of how abberant NOD2 signaling contributes to increased susceptibility to CD remain unclear.Intestinal intraepithelial lymphocytes (IELs), as the first defense line of intestinal mucosal immunity,play an important role in intestinal homeostasis. Our preliminary results have shown that the number of IELs in Nod2 ko mice decreases significantly, while not decreased in Nod1 ko mice and Nlrp3 ko mice. So, in this study, we will investigate the celluar and molecular mechanisms of how NOD2 and downstream signaling affect the development, differentiation and survival of IELs, and especially the role of gut flora in this process. Furthermore, we will focus on studying whether the loss of IELs in Nod2 ko mice contributes the higher suscetibility of Nod2 ko mice to TNBS-induced colitis. This study is helpful to understand the development and differenation of IELs, and more importantly, will contribute to clarify the mechanisms of how dysfunction of Nod2 signaling afffects the progression of CD and possibly provides new clues and targets for the therapy of CD.

NOD2作为最早发现的克罗恩病（Crohn's disease）易感基因，其基因多态性与该疾病的发生发展有密切的关系，但是到目前为止，NOD2及其信号通路异常影响克罗恩病的机制还不清楚。肠道上皮内淋巴细胞（IELs）作为肠道粘膜免疫的第一道防线，对维持肠道粘膜平衡有着重要作用。我们的初步研究发现IELs的数目在Nod2缺陷小鼠中明显降低，而在其它NOD样受体家族蛋白缺陷鼠中(Nod1 ko 和Nlrp3 ko) 没有明显变化。因此本研究将利用Nod2缺陷小鼠研究NOD2通过对肠道共生菌的识别调节IELs发育、分化、存活的细胞和分子机制，并利用结肠炎模型进一步探讨IELs的缺失与NOD2作为克罗恩病易感基因之间的关系。该项研究不仅有助于深入了解IELs的发育分化过程，更有助于阐明NOD2影响克罗恩病发生发展的机制，从而为该疾病的治疗提供新的思路和治疗靶点。

NOD2作为胞内模式识别受体在抵抗胞内菌感染的过程中发挥重要作用，也有报道NOD2功能缺陷与人类克罗恩肠病有密切联系，但是NOD2如何维持肠道粘膜稳态的机制还不清楚。我们的研究工作表明Nod2信号对肠道IEL特别是对其中代表天然免疫功能的细胞亚群的数目具有特异的显著的调节作用，而且主要影响这些细胞在肠道中的增殖和凋亡（自稳）过程。进一步的机制研究表明主要是造血来源的巨噬细胞或者树突状细胞上的Nod2信号通过识别肠道共生菌群维持肠道IEL细胞的自稳；Nod2信号的缺陷会导致肠道局部IL-15表达量的下降，基于肠道微环境IL-15对肠道IEL中天然免疫细胞亚群的存活和稳态具有至关重要的作用，肠道局部IL-15的下降会导致肠道IEL细胞数目下降，IEL细胞数目的减少削弱了局部的免疫防御功能，致使肠炎的发生。该项研究不仅有助于深入了解IEL的发育分化和稳态维持过程，也提示IEL缺失导致的肠道天然免疫功能低下可能是导致携带NOD2突变体的人群易发克罗恩的潜在原因，从而为该疾病的治疗提供新的思路。