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: 6477822
• 负责人: Linden T Hu
• 金额: $ 38.3万
• 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/6477822
• 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， 莱姆病如果不加治疗，莱姆关节炎会导致 严重的侵蚀性关节炎大多数患者在使用抗生素后症状会有所改善 治疗，但一小部分将继续有持续性关节炎。 是否这种治疗后关节炎的原因是由于持续的 生物体或自身免疫性疾病是一个激烈争论的领域。的机制 其中B。burgdorferi可导致软骨退化一直不好 研究了不像其他细菌引起脓毒性关节炎，B。布格多费里群岛 不分泌任何能够消化细胞外基质蛋白的酶 接头。基质金属蛋白酶（MMP）是宿主酶， 消化人体软骨的多种成分我们发现了证据 在莱姆关节炎患者的滑液中MMPs升高。 未治疗和持续性疾病患者MMP诱导模式 是显著不同的，这表明它们可能通过不同的方式发生， 机制等我们发现B. burgdorferi刺激MMP诱导， 软骨细胞的模式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。 B的存在。Burgdorferi导致软骨外植体的降解， 体外MMP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 通过与B接触从关节组织中提取MMPs。Burgdorferi，而关节炎 患者抗生素治疗后是由于不同的MMP激活， 不同的途径（例如自身免疫）。 在这个提议中，我们将利用大量的患者样本库 未治疗和治疗后的莱姆关节炎，以充分表征MMP， 关节中的细胞因子表达。充分了解MMP概况， 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与疾病表现相关联。 我们还将把我们的发现与小鼠关节中MMPs的研究相关联。 使用小鼠莱姆关节炎模型，我们将研究特异性 细胞类型在MMP生产中的联合。然后，在确定了基质金属蛋白酶之后， 潜在相关的莱姆关节炎，我们将研究的影响，具体 MMP抑制剂或MMP基因敲除对小鼠病程的影响 关节炎最后，我们将确定由B激活的信号通路。 导致致病性MMP诱导的伯氏螺旋体。最近的调查 已经鉴定了一组受体，称为Toll样受体（TLR）， 细菌产物的重要模式识别受体。使用TLR 阻断抗体，显性阴性细胞系和敲除小鼠，我们将 剖析导致MMP诱导的信号通路。 我们相信，对基质金属蛋白酶在莱姆病中的研究将导致更好的 了解未经治疗和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良的动物模型， 疾病使我们能够定义MMPs在莱姆关节炎中的作用， 可能用于其他关节炎，如类风湿性关节炎， 随后导致更具体的治疗方法的发展。