Analyses of the role of the TNF family member LIGHT (TNFSF14) in mucosal immune regulation

肠道免疫系统受到严格调节，提供对共生微生物群及其产物以及饮食抗原的耐受性，同时保留对入侵病原体发起有效免疫反应的能力。即使在今天，这个精心平衡的系统的监管机制的细节也没有得到很好的理解。然而，该系统失调的后果在炎症性肠病中是明显的，其中粘膜免疫系统的持续激活导致慢性炎症。肿瘤坏死因子（TNF）家族细胞因子在基本免疫过程中起着重要作用。其成员之一LIGHT （TNFSF14）已被证明可引起多种自身免疫性综合征，包括当其在T细胞上组成性表达时引起肠道炎症。相反，在结肠炎小鼠模型中，非t细胞上的LIGHT表达具有抗炎作用，因为光照不足大大加速了疾病的发作和严重程度。有趣的是，人类编码LIGHT的基因映射到IBD的易感性位点。本实验将研究LIGHT表达在维持粘膜免疫耐受中的作用，这意味着LIGHT可能是治疗炎症性肠病的新靶点。

The intestinal immune system is tightly regulated providing tolerance against the commensal microbiota and its products as well as against dietary antigens while retaining the ability to launch an effective immune response against invading pathogens. The details of the regulatory mechanisms of this carefully balanced system are not well understood even today. The consequences of dysregulation of this system however, are obvious in inflammatory bowel diseases, where constant activation of the mucosal immune system leads to chronic inflammation. The tumor necrosis factor (TNF) family of cytokines plays important roles in fundamental immunological processes. One of its members, LIGHT (TNFSF14), has been shown to cause a variety of autoimmune syndromes, including intestinal inflammation when it was constitutively expressed on T cells. In contrast, in a mouse model of colitis, LIGHT expression on non-T cells is anti-inflammatory, because LIGHT-deficiency greatly accelerated disease onset and severity. Interestingly, the human gene encoding for LIGHT maps to a susceptibility locus for IBD. The experiments in this proposal will investigate the role of LIGHT expression in the maintenance of mucosal immune tolerance, which implicates LIGHT as a putative new target for the treatment of inflammatory bowel diseases.