Inflammatory Arthritis: Mechanistic Insights into Initiation and Progression

类风湿性关节炎（RA）的发病机制尚不完全清楚。 在与RA相关的遗传标记中，FLIP最近被确定为RA风险等位基因。flip是 在防止死亡受体介导的细胞凋亡中是重要的，并且已经显示对保护 树突状细胞（DC）和巨噬细胞从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+细胞中的Flip，在CD11c表达细胞（如DC细胞和巨噬细胞亚群）中进行Flip 产生CD11c-Flip-KO或HUPO小鼠的细胞。HUPO小鼠出现自发性、炎症性、糜烂性 关节炎，与滑膜关节成分的自身抗体相关，类似于RA。一些 观察表明，来自HUPO小鼠的见解将告知我们对 RA的发病机制。如在RA患者中观察到的，HUPO小鼠是轻度淋巴细胞减少的。进一步 RA患者在关节内表现出Treg活性降低，循环中的Treg数量可能与关节炎的发生有关。 减少，与疾病活动呈负相关。HUPO小鼠表现出胸腺细胞减少， 移民到周边，和RA患者表现出缺乏最近的胸腺移民， 对周边地区的结核病的产生很重要。如在HUPO小鼠中，Flt3L在患有以下疾病的患者中增加： RA，表明RA患者的DC相对减少。根据数据，很明显，HUPO 关节炎是由一个复杂的机制介导的，并定义了负责启动的机制， 和进展的HUPO关节炎将提供深入了解RA的发病机制。 基于初步数据，我们提出了新的假设，即CD11c+滑膜组织的减少- 驻留的巨噬细胞对于引发HUPO小鼠的关节炎至关重要。减少，但并非不存在TdR 允许自身反应性T细胞和针对软骨自身抗原释放的自身抗体的扩增 由于巨噬细胞介导的炎症，它们共同促进疾病进展。我们还 假设TcB百分比的降低是由减少的CD8 α + DCs介导的， 基础IL-2。该假设将通过3个具体目标进行检验： 1)确定先天免疫在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衍生的巨噬细胞在关节炎的发生和发展中的作用。 2)定义导致疾病发生和/或进展的适应性免疫机制 使用T细胞或B细胞缺陷的小鼠，定义T细胞自身反应性、自身抗原- 特异性T细胞和自身抗体与关节炎的临床进程。 3)确定HUPO小鼠中TdR降低的机制，并确定治疗性 这些方法将增加Tibetan并预防或改善关节炎。

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.