Fc Receptors & Cytokine Balance in Rheumatoid Arthritis

描述（由申请人提供）： 促炎和抗炎细胞因子之间的平衡在确定类风湿性关节炎（RA）的严重程度和进展中的重要作用现已得到充分确立。炎症细胞因子肿瘤坏死因子（TNF）和白细胞介素-1（IL-1）的关键作用已被阻断TNF和IL-1活性的新生物疗法的疗效所证实。RA滑膜炎的特征还在于表达有效的炎性细胞因子IL-10。IL-10的关键活性是抑制TNF和IL-1的产生和活性。然而，很明显，至少在活动性疾病期间，滑膜IL-10不足以抑制TNF和IL-1至滑膜炎减轻或消退的程度。25年前发现RA滑膜中存在自身抗体和免疫复合物，并提出免疫复合物在RA发病机制中的重要作用。最近，有兴趣的体液免疫，免疫复合物，和下游效应途径介导的Fc受体的IgG（Fc？Rs）和补体在RA发病机制中的作用。 在这个应用程序中，我们建议将新出现的想法和证据的重要性，自身抗体和免疫复合物在RA与已建立的范式有关的重要性，亲和亲细胞因子之间的平衡。我们的假设是，连接Fc？RA滑膜中免疫复合物的Rs使细胞因子平衡向促炎细胞因子产生增加的方向转变。这一假设是基于我们的初步数据，Fc？R连接抑制IL-10信号传导、Stat 3活化和生物活性，从而损害IL-10抑制TNF产生的能力。我们已经发现IL-10信号传导在RA滑膜巨噬细胞中被阻断。此外，低水平的IFN 7（激活Statl），如在RA滑膜中发现的那些，调节Fc？TR表达和功能更强烈地抑制IL-10信号传导，伴随着TNF产生的增加。我们建议更好地了解调节RA中IL-10信号传导的分子机制，并成为Fc与IL-10之间串扰的基础。Rs，IL-10和IFN-7将产生洞察RA发病机制，并可能作为新的治疗方法的基础。我们的具体目标是：1.阐明RA中IL-10信号抑制的分子基础和病理生理学意义。2.使用K/BxN血清诱导的关节炎小鼠模型鉴定FcRs调节炎性关节炎中细胞因子平衡的机制。3.表征IFN 7和STAT对免疫复合物诱导的Fc？依赖性关节炎，并探讨其潜在机制。

DESCRIPTION (provided by applicant): An important role for the balance between pro-inflammatory and anti-inflammatory cytokines in determining the severity and progression of rheumatoid arthritis (RA) is now well established. A key role for the inflammatory cytokines tumor necrosis factor (TNF) and interleukin-1 (IL-1) has been confirmed by the efficacy of new biological therapies that block TNF and IL-1 activity. RA synovitis is also characterized by the expression of the potent antiinflammatory cytokine IL-10. A key activity of IL-10 is the suppression of TNF and IL-1 production and activity. However, it is clear that, at least during active disease, synovial IL-10 is insufficient to suppress TNF and IL-1 to the point where synovitis diminishes or resolves. The presence of autoantibodies and immune complexes in RA synovium was discovered over 25 years ago, and a prominent role for immune complexes in RA pathogenesis has been proposed. Recently, there has been a resurgence of interest in the role of humoral immunity, immune complexes, and downstream effector pathways mediated by Fc receptors for IgG (Fc?Rs) and complement in RA pathogenesis. In this application, we propose to link the emerging ideas and evidence on the importance of autoantibodies and immune complexes in RA with the established paradigm concerning the importance of balance between pro- and antiinflammatory cytokines. Our hypothesis is that ligation of Fc?Rs by immune complexes in RA synovium shifts cytokine balance toward increased production of pro-inflammatory cytokines. This hypothesis is based upon our preliminary data that Fc?R ligation suppresses IL-10 signaling, Stat3 activation, and bioactivity, thus compromising the ability of IL-10 to suppress TNF production. We have found that IL-10 signaling is blocked in RA synovial macrophages. In addition, low levels of IFN7 (which activates Statl), such as those found in RA synovium, modulate Fc?TR expression and function to more strongly inhibit IL-10 signaling, with concomitant increases in TNF production. We propose that greater understanding of the molecular mechanisms that regulate IL-10 signaling in RA, and underlie the cross talk between Fc? Rs, IL-10, and IFN 7 will yield insight into RA pathogenesis and may serve as the basis for novel therapeutic approaches. Our specific aims are to: 1. Delineate the molecular basis and pathophysiological significance of the suppression of IL-10 signaling in RA. 2. Identify mechanisms by which FcRs regulate cytokine balance in inflammatory arthritis using the K/BxN serum-induced arthritis murine model. 3. Characterize the effects of IFN7 and STATs on immune complex-induced, Fc?R-dependent arthritis, and explore underlying mechanisms.