Interaction of environment and genetics in the predisposition to inflammatory art

描述(由申请人提供)： 炎症性关节炎是一种高度衰弱的慢性免疫性疾病，会导致关节疼痛和进行性破坏。大多数关节炎综合征被认为是病因不明的多基因疾病。一种流行的理论是，在遗传易感性的背景下，环境微生物触发先天免疫以诱发炎症性疾病。到目前为止，研究的优势集中在关节炎的适应性和T细胞反应上，对导致关节炎的T细胞在诱发疾病中激活之前的先天信号知之甚少。最近发现的一种基因nod揭示了与关节炎有关的遗传学的重要见解。单个碱基对变化I NOD2会导致一种名为Blau综合征的疾病100%显性，患者会患上关节炎，并伴有眼睛和皮肤的炎症。NOD2属于模式识别受体(PRRs)的节点样受体(NLR)家族，是宿主抵御微生物病原体的重要方面，因此表明微生物感知与慢性炎症性疾病之间存在有趣的联系。为了探索NOD2在关节炎中的作用，我们选择使用遗传敏感的SKG小鼠品系中的疾病模型，因为它们会患上一种慢性的T细胞介导的关节炎，这是由暴露在微生物触发因素下诱导的。在SKG小鼠中，一种自发的点突变扰乱了T细胞受体信号，导致正负选择受损，并增加了自身反应性T细胞的产生。虽然SKG小鼠的关节炎与异常的T细胞反应有关，但它的启动依赖于激活C型凝集素受体(CLR)的先天免疫机制，C型凝集素受体是一类已知参与宿主防御真菌和分枝杆菌感染的PRR。我们将NOD2 KO小鼠与SKG小鼠进行杂交，发现NOD2表达不足的SKG小鼠出现了由可激活CLR Dectin-1的Curdlan引发的关节炎加重形式。提出的三个目标与这一应用的核心假设有关：NOD2是通过调节微生物激活CLRs引发的免疫反应来决定关节炎易感性的重要决定因素。我们将：1)确定NOD2的表达如何影响由curdlan引发的SKG小鼠关节炎的发生和发展，包括NOD2的表达如何影响关节内的炎症反应；2)阐明NOD2缺乏对关节致炎T细胞效应和调控反应的有害影响；3)确定CARD9通路是否在SKG小鼠关节炎的诱导过程中是必不可少的，并勾勒出NOD2表达调控的关节炎中心附近的CLR。我们已经确定了一种与T细胞依赖型疾病有关的先天性免疫受体，这可能是揭示一种强大的机制的重要线索，这种机制已经进化出来，可以保护关节免受炎症的侵袭。如果要全面了解先天性免疫受体(如CLR)在关节炎中的作用，了解该受体所利用的信号机制以及与NOD2合作的影响是一个需要解决的重要问题。拟议的研究结果深入了解这些先天免疫途径的运作机制，可能会为开发治疗BLAU综合征以及潜在的其他自体炎症和关节炎疾病开辟新的途径。

DESCRIPTION (provided by applicant): Inflammatory arthritis is a highly debilitating and chronic immunological disease that results in pain and progressive destruction of the joints. Most arthritic syndromes are presumed polygenetic diseases with unknown etiologies. A prevailing theory is that in the context of genetic predisposition, environmental microbes trigger innate immunity in order to induce inflammatory disease. The preponderance of research to date has focused on adaptive and T cell responses in arthritis, with little being understood of what innate signals precede the activation of arthritis-causing T cells in the induction of disease. A recently identified gene NOD has unveiled important insight into the genetics involved in arthritis. A single base-pair change i NOD2 results in 100% penetrance of a disease called Blau syndrome wherein patients develop arthritis that is accompanied by inflammation of the eyes and skin. NOD2 belongs to the NOD-like receptor (NLR) family of pattern recognition receptors (PRRs) and is an important aspect of host defense against microbial pathogens, thereby suggesting an intriguing connection between microbial sensing and chronic inflammatory disease. To explore the role of NOD2 in arthritis, we chose to use disease modeled in the genetically susceptible SKG mouse strain because they develop a chronic, T cell-mediated arthritis that is induced by exposure to microbial triggers. In SKG mice, a spontaneous point mutation that perturbs T cell receptor signaling results in impaired positive and negative selection and enhanced production of autoreactive T cells. While arthritis in SKG mice is related to aberrant T cell responses, its initiation depends on innate immune mechanisms that activate the C- type lectin receptors (CLR), a class of PRRs known to be involved in host defense against fungal and mycobacterial infections. We crossed the NOD2 KO mice to the SKG mice and discovered that SKG mice deficient in NOD2 expression developed an exacerbated form of arthritis triggered by curdlan, which activates the CLR, Dectin-1. The three aims proposed relate to the hypothesis central of this application: NOD2 is an important determinant of arthritis susceptibility through regulation of immunological responses triggered by microbial activation of CLRs. We will: 1) Define how NOD2 expression influences the onset and development of arthritis triggered by curdlan in SKG mice, which includes how NOD2 expression influences inflammatory responses within the joint; 2) Elucidate the deleterious effects of NOD2-deficiency on arthritogenic T cell effector and regulatory responses that are involved in arthritis; 3) Determine whether the CARD9 pathway is essential for induction of arthritis in SKG mice and delineate the proximal CLRs central to arthritis regulated by NOD2 expression. That we have identified an innate immune receptor involved in a T cell- dependent disease may be an important clue into a powerful mechanism that has evolved to protect the joint from inflammation. Understanding the signaling mechanisms utilized by innate immune receptors such as CLRs and the effects of collaboration with NOD2, is an important question that needs to be addressed if the role of this receptor in arthritis is to be fuly understood. Results of the proposed studies delving into the mechanisms through which these innate immune pathways operate could open up new avenues for development of therapies for Blau syndrome and potentially also for other autoinflammatory, arthritic conditions.