Ligation of TLR7 promotes joint inflammation and bone loss in RA.

描述(由申请人提供)： 在美国，有250万人患有类风湿关节炎(RA)。类风湿关节炎是一种慢性炎症性自身免疫性疾病，始于青年至中年，如果不治疗可能会导致关节完全破坏。目前类风湿性关节炎尚无治愈方法，高达40%的类风湿关节炎患者因缺乏疗效或耐受性而对抗肿瘤坏死因子药物或其他生物治疗无效，因此迫切需要新的治疗靶点。研究发现，采用新的治疗方法可以使所有患有类风湿关节炎的现役和退役军人和退伍军人以及他们的家人和朋友受益。通过识别调节类风湿性关节炎滑膜炎症和骨侵蚀的级联反应，有效和改进的治疗将使现役人员能够更长时间地服役，并将缓解退伍军人的关节疼痛和残疾。随着疾病活动性的降低，RA滑膜CD68+巨噬细胞的数量减少，因此髓系细胞的数量与放射性骨损伤、关节疼痛和炎症密切相关。然而，促使类风湿关节炎髓系细胞分化为促炎巨噬细胞或成熟的侵蚀破骨细胞的机制尚不清楚。为了解决这一关键问题，通过微阵列分析，与正常髓系细胞相比，确定了类风湿关节炎中高度调控的基因。在对芯片数据的验证中，我们发现TLR7基因在RA滑液和RA外周血髓系细胞中的表达水平高于正常外周血髓系细胞。我们在RA滑液中发现了一种新的TLR7内源性配体，并证明该配体能够将新招募的NA�Ve髓样细胞转化为炎性巨噬细胞表型。我们还发现破骨细胞的成熟过程与TLR7表达的增加有关，并且对TLR7内源性配体的增强反应可以促进完全成熟的RA破骨细胞的分化。根据支持的数据，我们假设通过TLR7结扎，NA�ve RA髓系细胞重塑为促炎巨噬细胞和成熟的破骨细胞。因此，破坏TLR7与其内源性配体的结合将通过失调炎性巨噬细胞和成熟破骨细胞的发育来缓解RA和实验性关节炎。我们首次发现了一种新的TLR7内源性配体，并建议确定这种内源性配体与TLR7的连接在RA发病中的起源和潜在机制，以及这一系列事件是如何与炎症RA网络相互联系的。最后，我们将证明阻断TLR7与其内源性配体的连接是否可以作为RA的一个有前景的新治疗靶点。

DESCRIPTION (provided by applicant): In the United States, 2.5 million people have rheumatoid arthritis (RA). RA is a chronic inflammatory autoimmune disorder that starts in the young to middle adult years and may lead to complete joint destruction if untreated. There is no cure for RA at present and up to 40% of RA patients do not respond to anti-TNF agents or other biological treatments due to lack of efficacy or intolerability therefore novel treatment targets are urgently needed. Findings that lea to novel treatments can benefit all active and retired military and VA members with RA, as well as their families and friends who may suffer from RA. Effective and improved treatments through identification of cascades that modulate RA synovial inflammation and bone erosion will allow active duty members to remain longer in service and will also relieve joint pain and disability in retired Veterans. The quantity of RA synovial CD68+ macrophages is reduced in positive response to therapy concurrent with reduction in disease activity therefore the number of myeloid cells closely correlates with radiological bone damage, joint pain and inflammation. Yet, the mechanism that drives RA myeloid cell differentiation to proinflammatory macrophages or mature bone eroding osteoclasts is undefined. To address this vital issue, highly modulated genes were identified in RA compared to normal myeloid cells employing microarray analysis. In validation of the microarray data, we found that TLR7 is one of the most highly upregulated genes in RA synovial fluid and RA peripheral blood myeloid cells compared to normal peripheral blood myeloid cells. We discovered a novel TLR7 endogenous ligand in RA synovial fluid and documented that this ligand is strongly capable of transforming the newly recruited na�ve myeloid cells into inflammatory macrophage phenotype. We also found that the osteoclast maturation process is associated with increased TLR7 expression and that the enhanced response to TLR7 endogenous ligand can provoke differentiation of fully mature RA osteoclasts. Based on the supportive data, we hypothesize that the na�ve RA myeloid cells are remodeled to proinflammatory macrophages and mature osteoclasts through TLR7 ligation. Therefore disruption of TLR7 binding to its endogenous ligand will resolve RA and experimental arthritis by dysregulating the development of inflammatory macrophages and mature osteoclasts. We uncover for the first time, a novel TLR7 endogenous ligand, and propose to determine the origination and the underlying mechanism by which ligation of this endogenous ligand to TLR7 contributes to RA pathogenesis and how this cascade of events is interconnected to the inflammatory RA network. Finally we will document whether interruption in TLR7 ligation to its endogenous ligand can be used as a promising new therapeutic target in RA.