Inflammatory Arthritis: Mechanistic Insights into Initiation and Progression

类风湿关节炎(RA)的发病机制尚不完全清楚。 在与类风湿性关节炎相关的遗传标记中，FLIP已被确定为类风湿性关节炎的危险等位基因。翻转是 在防止死亡受体介导的细胞凋亡中起重要作用，并已被证明是保护 树突状细胞(DC)和巨噬细胞由Fas介导的细胞死亡。我们最近研究了在体内的作用。 通过删除CD11c中的Flip，在表达CD11c的细胞中翻转，如细胞DC和巨噬细胞的子集 产生CD11c-Flip-KO或HuPo小鼠的细胞。HuPo小鼠发展为自发性、炎症性、腐蚀性 关节炎，与滑膜关节成分的自身抗体有关，类似于类风湿关节炎。一批 观察表明，从HuPo老鼠得到的洞察力将有助于我们理解 类风湿关节炎的发病机制。正如在类风湿性关节炎患者中观察到的那样，HuPo小鼠有轻微的淋巴细胞减少。进一步 RA患者关节内Treg活性降低，循环Treg的数量可能是 减少，与疾病活跃度成反比。HuPo小鼠表现出胸腺细胞减少 外周移居，RA患者表现出近期胸腺移行细胞的缺乏，这一点 对周边地区的特雷格人的产生很重要。在HuPo小鼠中，Flt3L在慢性阻塞性肺疾病患者中升高 RA，提示RA患者DC相对减少。根据数据，很明显，胡宝 关节炎是由一种复杂的机制来调节的，这种机制定义了引发关节炎的机制 而活宝关节炎的进展将为类风湿关节炎的发病机制提供新的认识。 基于初步数据，我们提出了一个新的假设，即CD11c滑膜组织的减少- 驻留巨噬细胞是引发HuPo小鼠关节炎的关键。减少，但不是没有特雷格 允许扩增自身反应性T细胞和释放的针对软骨自身抗原的自身抗体 由于巨噬细胞介导的炎症，共同促进了疾病的进展。此外，我们 假设树突状细胞百分比的降低是由CD8α树突状细胞减少和减少所介导的 基础IL-2。这一假设将以三个具体目标进行检验： 1)明确先天性免疫在HuPo小鼠中的作用，确定循环单核细胞、组织- 常驻巨噬细胞和单核细胞来源的巨噬细胞在关节炎的发生和发展中的作用。 2)确定导致疾病发生和/或发展的适应性免疫机制 利用缺乏T细胞或B细胞的小鼠，确定T细胞自身反应、自身抗原- 关节成分的特异性T细胞和自身抗体与关节炎的临床病程有关。 3)明确导致HuPo小鼠Tregs减少的机制，并确定治疗方法 增加Tregs和预防或改善关节炎的方法。

The mechanisms contributing to the pathogenesis of rheumatoid arthritis (RA) are incompletely understood. Among the genetic markers associated with RA, FLIP has recently been identified as a RA risk allele. FLIP is important in preventing death receptor mediated apoptosis and has been shown to be critical to protect dendritic cells (DCs) and macrophages from Fas-mediated cell death. We recently examined the in vivo role of Flip in CD11c-expressing cells such as cells DCs and a subset of macrophages, by deleting Flip in CD11c+ cells generating CD11c-Flip-KO or HUPO mice. HUPO mice develop spontaneous, inflammatory, erosive arthritis, associated with autoantibodies to constituents of the synovial joints, resembling RA. A number of observations suggest that the insights derived from the HUPO mouse will inform our understanding of the pathogenesis of RA. As observed in patients with RA, the HUPO mice are mildly lymphopenic. Further patients with RA exhibit reduced Treg activity within the joints and the number of circulating Tregs may be reduced, inversely correlating with disease activity. HUPO mice exhibit a reduction of thymocytes available for emigration to the periphery, and patients with RA demonstrate a deficiency of recent thymic emigrants, which are important for the generation of Tregs in the periphery. As in HUPO mice, Flt3L is increased in patients with RA, suggesting a relative reduction of DCs in patients with RA. Based on the data, it is clear that HUPO arthritis is mediated by a complex mechanism, and that defining the mechanisms responsible for the initiation and progression of HUPO arthritis will provide insights into the pathogenesis of RA. Based on preliminary data, we propose the novel hypothesis that a reduction of CD11c+ synovial tissue- resident macrophages is critical for initiating the arthritis in HUPO mice. Reduction, but not absence of Tregs permits expansion of autoreactive T cells and autoantibodies directed against cartilage autoantigens released due to macrophage-mediated inflammation, which together promote disease progression. Further, we hypothesize that the reduction of the percent of Tregs is mediated by diminished CD8α+ DCs and decreased basal IL-2. This hypothesis will be tested with 3 specific aims: 1) Define the role of innate immunity in HUPO mice identifying the role of circulating monocytes, tissue- resident macrophages and monocyte derived macrophages in the initiation and progression of arthritis. 2) Define the adaptive immune mechanisms responsible for the initiation and/or progression of disease employing mice deficient in T cells or B cells, defining the association of T cell autoreactivity, autoantigen- specific T cells and autoantibodies to joint constituents with the clinical course of the arthritis. 3) Define the mechanisms responsible for the reduction of Tregs in HUPO mice, and identify therapeutic approaches that will increase Tregs and prevent or ameliorate the arthritis.