Pathogenesis of Borrelia burgdorferi induced arthritis

描述(由申请人提供)：关节炎是一种晚期表现 莱姆病。如果不治疗，莱姆关节炎可能会导致 严重的侵蚀性关节炎。大多数患者使用抗生素后病情好转。 治疗，但有一小部分人将继续患有持续性关节炎。 无论这种治疗后关节炎的原因是不是由于 有机体或自身免疫性疾病是一个激烈争论的领域。这些机制由 哪种伯氏杆菌能引起软骨退化一直不是很好 学习。与其他导致感染性关节炎的细菌不同，伯氏杆菌 不分泌任何能够消化细胞外基质蛋白的酶 那家大麻店。基质金属蛋白酶(MMPs)是一种能够 消化人体软骨的多种成分。我们找到了证据 莱姆关节炎患者的滑液中MMPs升高。 初治和顽固性疾病患者基质金属蛋白酶的诱导模式 显著不同，表明它们可能通过不同的方式发生 机械装置。我们发现伯氏杆菌能刺激基质金属蛋白酶的诱导。 软骨细胞的形态与未经治疗的莱姆病患者相似 关节炎，但与抗生素治疗后的患者不同。 伯氏杆菌的存在会导致软骨外植体的降解 体外培养。基质金属蛋白酶抑制剂可以阻断这种降解。我们的主要假设是 莱姆关节炎患者的软骨侵蚀是通过诱导 在关节炎期间通过接触伯氏杆菌从关节组织中提取MMPs 患者抗生素治疗后是由于不同的MMPs通过 不同的途径(如自身免疫)。 在这项建议中，我们将利用患者的大样本银行 未治疗和治疗后的莱姆关节炎，以充分表征基质金属蛋白酶和 细胞因子在关节中的表达。全面了解MMPProfile，请参阅 这些患者将使我们能够比较 未治疗和治疗后的莱姆关节炎以及其他 关节炎，并试图将特定的MMPs与疾病的表现联系起来。 我们还将把我们的发现与对小鼠关节中MMPs的研究联系起来。 利用莱姆关节炎的小鼠模型，我们将研究其特定的作用。 关节中基质金属蛋白酶产生的细胞类型。然后，确定了MMP 可能与莱姆关节炎相关，我们将检查特定的影响 基质金属蛋白酶抑制剂或基质金属蛋白酶基因基因敲除在小鼠发病过程中的作用 关节炎。最后，我们将确定由B激活的信号通路。 导致致病性MMPs诱导的伯氏杆菌。最近的调查 已经确定了一组受体，命名为Toll样受体(TLRs)， 细菌产品的重要模式识别受体。使用TLR 阻断抗体、显性阴性细胞系和基因敲除小鼠，我们将 剖析导致基质金属蛋白酶诱导的信号通路。 我们相信，对莱姆病中MMPs的研究将带来更好的 了解未经治疗的持续性莱姆关节炎的发病机制。 此外，明确的引发者和优秀的动物模型的存在 疾病允许我们以一种不同的方式来定义基质金属蛋白酶在莱姆关节炎中的作用 对于其他关节炎，如类风湿性关节炎和可能 随后导致了更具体的治疗方法的发展。

DESCRIPTION (provided by the applicant): Arthritis is a late manifestation of Lyme disease. Allowed to progress untreated, Lyme arthritis can result in a severe, erosive arthritis. The majority of patients improve with antibiotic therapy, but a small percentage will continue to have persistent arthritis. Whether the cause of this post-treatment arthritis is due to persistence of the organism or autoimmune disease is an area of intense debate. The mechanisms by which B. burgdorferi can cause cartilage degradation have not been well studied. Unlike other bacteria that cause septic arthritis, B. burgdorferi does not secrete any enzymes capable of digesting extracellular matrix proteins in the joint. Matrix metalloproteinases (MMPs) are host enzymes that are capable of digesting multiple components of human cartilage. We have found evidence that MMPs are elevated in the synovial fluid of patients with Lyme arthritis. The pattern of MMP induction in patients with untreated and persistent disease is significantly different, suggesting that they may occur through different mechanisms. We have found that B. burgdorferi stimulates MMP induction from chondrocytes in a pattern similar to that found in patients with untreated Lyme arthritis, but dissimilar to that seen in patients after antibiotic therapy. The presence of B. burgdorferi results in degradation of cartilage explants in vitro. MMP inhibitors can block this degradation. Our main hypothesis is that cartilage erosions in patients with Lyme arthritis occurs through the induction of MMPs from joint tissue by contact with B. burgdorferi while arthritis in patients post-antibiotic therapy is due to activation of different MMPs through different pathways (e.g. autoimmune). In this proposal, we will take advantage of a large sample bank of patients with untreated and post-treatment Lyme arthritis to fully characterize MMP and cytokine expression in the joints. A full understanding of the MMP profiles in these patients will allow us to make comparisons between patients with untreated and post-treatment Lyme arthritis as well as to patients with other arthritides and attempt to correlate specific MMPs with disease manifestations. We will also correlate our findings with studies of MMPs in the mouse joint. Using the mouse model of Lyme arthritis, we will study the role of specific cell types in MMP production in the joint. Then, having identified MMPs potentially relevant in Lyme arthritis, we will examine the effects of specific MMP inhibitors or genetic knockouts of MMP genes on the course of murine arthritis. Finally, we will determine signaling pathways activated by B. burgdorferi that result in induction of pathogenic MMPs. Recent investigations have identified a group of receptors, designated Toll-like receptors (TLRs), as important pattern recognition receptors for bacterial products. Using TLR blocking antibodies, dominant negative cell lines and knockout mice, we will dissect the signaling pathways that lead to MMP induction. We believe that studies of MMPs in Lyme disease will lead to a better understanding of the pathogenesis of untreated and persistent Lyme arthritis. In addition, the presence of a clear initiator and excellent animal models of disease allow us to define the role of MMPs in Lyme arthritis in a manner not possible for other arthritides such as rheumatoid arthritis and may subsequently lead to the development of more specific therapies.