Pathogenesis of Borrelia burgdorferi induced arthritis

伯氏疏螺旋体诱发关节炎的发病机制

• 批准号: 6625641
• 负责人: Linden T Hu
• 金额: $ 34.35万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6625641
• 关键词: Borrelia; Lyme disease; arthritis; autoimmunity; biological signal transduction; cartilage disorder; cell membrane; clinical research; collagenase; cytokine; enzyme induction /repression; enzyme linked immunosorbent assay; human tissue; laboratory mouse; medical complication; microarray technology; pathologic process; polymerase chain reaction; secondary infection; synovial fluid; tissue /cell culture; toll like receptor

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.

描述（由申请人提供）：关节炎是一种晚期表现 莱姆病。如果不治疗的话，莱姆关节炎可能会导致 严重的糜烂性关节炎。大多数患者使用抗生素后病情有所改善 治疗，但一小部分人将继续患有持续性关节炎。 这种治疗后关节炎的原因是否是由于持续存在的 有机体或自身免疫性疾病是一个争论激烈的领域。其机制由 哪些伯氏疏螺旋体会导致软骨退化尚未得到很好的解决 研究过。与其他引起化脓性关节炎的细菌不同，伯氏疏螺旋体 不分泌任何能够消化细胞外基质蛋白的酶 联合。基质金属蛋白酶 (MMP) 是能够 消化人体软骨的多种成分。我们已经找到证据 莱姆关节炎患者的滑液中 MMP 升高。 未经治疗且持续性疾病患者的 MMP 诱导模式 显着不同，表明它们可能通过不同的方式发生 机制。我们发现伯氏疏螺旋体可刺激 MMP 诱导 软骨细胞的模式与未经治疗的莱姆病患者的模式相似 关节炎，但与抗生素治疗后患者所见的情况不同。 伯氏疏螺旋体的存在导致软骨外植体降解 体外。 MMP 抑制剂可以阻止这种降解。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发生的 当关节炎发生时，通过与伯氏疏螺旋体接触从关节组织中提取 MMP 抗生素治疗后的患者是由于不同 MMP 的激活所致 不同的途径（例如自身免疫）。 在此提案中，我们将利用大量患者样本库 使用未经治疗和治疗后的莱姆关节炎来充分表征 MMP 和 关节中细胞因子的表达。全面了解 MMP 配置文件 这些患者将使我们能够在患者之间进行比较 未经治疗和治疗后的莱姆关节炎以及患有其他疾病的患者 关节炎并尝试将特定 MMP 与疾病表现联系起来。 我们还将把我们的发现与小鼠关节中 MMP 的研究联系起来。 使用莱姆关节炎小鼠模型，我们将研究特定的作用 联合生产 MMP 的细胞类型。然后，确定了 MMP 与莱姆关节炎潜在相关，我们将检查特定的效果 MMP 抑制剂或 MMP 基因基因敲除对小鼠病程的影响 关节炎。最后，我们将确定 B 激活的信号通路。 伯氏杆菌导致致病性 MMP 的诱导。最近的调查 已经鉴定出一组受体，称为 Toll 样受体 (TLR)，如 细菌产物的重要模式识别受体。使用 TLR 阻断抗体、显性失活细胞系和基因敲除小鼠，我们将 剖析导致 MMP 诱导的信号通路。 我们相信，莱姆病中 MMP 的研究将带来更好的结果。 了解未经治疗的持续性莱姆关节炎的发病机制。 此外，存在明确的引发剂和优秀的动物模型 疾病使我们能够以一种不存在的方式定义 MMP 在莱姆关节炎中的作用 可能患有其他关节炎，例如类风湿性关节炎，并且可能 随后导致更具体疗法的开发。