Back to Basics: T Cellular Control of Nod2 in Uveitis

项目总结： 葡萄膜炎是一组复杂的疾病，加起来约占全球视力发病率的15%。对许多人来说 患者，葡萄膜炎可能是一种慢性终生疾病，治疗方法可能会控制疼痛的炎症，但 不能提供解药。对于一些有风湿性疾病的人来说，葡萄膜炎还伴随着 关节、皮肤或内脏。因此，有一个迫切的，尚未得到满足的需求，以确定葡萄膜炎的关键机制，因为它 重大的相关个人、社会和经济负担。先天免疫，作为第一道防线 对抗微生物病原体，是一种必须严格监管的反应，以避免过度炎症和 组织破坏。这种调节在眼睛中尤其重要，因为眼睛中有多种因素和过程在起作用 共同限制炎症，以保护对视力至关重要的脆弱细胞和组织。身体的感官 环境中潜在的致病微生物通过先天免疫受体，这些受体分为 不同的家族，如Toll样受体(TLRs)或Nod样受体(NLRs)。一个NLR，NOD2，不仅是 作为微生物和外来基序的细胞内传感器，但与非传染性相关 BLAU综合征中的肉芽肿性葡萄膜炎。利用T细胞介导的葡萄膜炎模型，实验性自身免疫 葡萄膜炎(EAU)，NOD2在预防自身免疫性葡萄膜炎中发现了一个意想不到的新作用。是这样的 保护被发现是由CD4+T细胞提供的，并涉及NOD2对致病能力的调节 通过控制细胞因子IL-17的产生来控制CD4+T细胞亚群Th17细胞的功能。基于这些 结果，以及其他关键的初步数据，这项建议旨在系统地探索光谱 NOD2可能影响致病T细胞反应的进化的作用。使用方法论 包括分子、细胞和整个动物的评估，实验将检验中心假设 NOD2是引起葡萄膜炎的自身反应性T细胞的关键免疫调节剂，它由三个部分组成 具体目标：1)深入研究NOD2如何改变CD4+T细胞个体或群体的葡萄膜生成潜力 细胞；2)阐明NOD2在与T细胞受体交叉的T细胞内部操作中的作用 (TCR)信号和T细胞功能；以及3)确定NOD2是否影响T细胞的发育和 葡萄膜生成T细胞的成熟。NOD2在自身免疫性疾病中的作用还有待进一步研究。 完全澄清了。这项研究可能会开辟新的调查途径，最终可能导致 在葡萄膜炎以及其他威胁视力的疾病的治疗干预的新战略中。

PROJECT SUMMARY: Uveitis is a complex set of diseases that together constitute ~15% of visual morbidity worldwide. For many patients, uveitis can be a chronic life-long disease for which therapies may manage painful inflammation, but do not provide a cure. For some with rheumatologic conditions, uveitis is also accompanied by diseases of the joint, skin, or gut. Thus there is an urgent, unmet need to define key mechanisms of uveitis because of its significant associated personal, social, and economic burdens. Innate immunity, as the first line of defense against microbial pathogens, is a response that must be tightly regulated to avoid excessive inflammation and tissue destruction. Such regulation is especially important in the eye, where multiple factors and processes act together to limit inflammation so as to preserve the delicate cells and tissues critical to vision. The body senses potentially pathogenic microbes in the environment via innate immune receptors, which are classified into distinct families such as Toll-like receptors (TLRs) or NOD-like receptors (NLRs). One NLR, Nod2, not only serves as an intracellular sensor of microbial and foreign motifs, but is causally linked to non-infectious granulomatous uveitis in Blau syndrome. Using a model of T cell-mediated uveitis, experimental autoimmune uveitis (EAU), an unexpected novel role was identified for Nod2 in protection against autoimmune uveitis. Such protection was found to be conferred by CD4+ T cells and involved Nod2 modulation of the pathogenic capacity of a subset of CD4+ T cells, Th17 cells, by controlling their production of the cytokine IL-17. Based on these findings, as well as additional key preliminary data, this proposal aims to systematically probe the spectrum of actions by which Nod2 could impact the evolution of disease-causing T cells responses. Using methodologies that encompass molecular, cellular, and whole animal evaluation, experiments will test the central hypothesis that Nod2 is a critical immunomodulator of autoreactive T cells that cause uveitis, and are organized in three Specific Aims: 1) Delve into how Nod2 alters the uveitogenic potential of individual or populations of CD4+ T cells; 2) Elucidate the effects of Nod2 on the internal operations of T cells that intersect with T-cell receptor (TCR) signaling and T cell function; and 3) Determine whether Nod2 influences T cell development and maturation of uveitogenic T cells. The role of Nod2 in autoimmune diseases is an area that has yet to be more fully clarified. This research could potentially open up new avenues of investigation that could ultimately result in novel strategies for therapeutic intervention of uveitis, as well as of other vision-threatening diseases.