Pathogenic mechanisms in chlamydial reactive arthritis

衣原体反应性关节炎的致病机制

• 批准号: 6942997
• 负责人: JUDITH A. WHITTUM-HUDSON
• 金额: $ 29.8万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6942997
• 关键词: Chlamydia trachomatis; arthritis; bacteria infection mechanism; chlamydial disease; cytokine; disease /disorder etiology; disease /disorder model; host organism interaction; infectious arthritis; inflammation; laboratory mouse; macrophage; sexually transmitted diseases; synovial membrane

DESCRIPTION (provided by applicant): Reactive arthritis (ReA) is a chronic disease characterized by periods of flare alternating with periods of less active inflammation. One criterion of disease classification is a history of prior sexually transmitted or GI infection. Recent data from our collaborative group have shown that a significant number of ReA patients have metabolically active chlamydia in their synovial tissues. To facilitate study of ReA, we developed a murine model of genital chlamydial infection using a human strain of Chlamydia trachomatis to study the inflammatory/immunopathologic mechanisms of joint inflammation. Mice develop ascending genital infection within three weeks. Synovial tissue from knees of these animals exhibits histologic signs of synovitis including increased synovial lining cells, dilated vessels, and foci of mononuclear inflammatory cells, and is PCR positive for chlamydial genes. This model will extend our previous data from a murine ocular chlamydial infection model that demonstrated both dissemination of chlamydia to synovial tissue and development of synovitis.The model will allow us to test mechanisms in chlamydia-associated spondyloarthropathy (ReA) relating to the initiation of synovial inflammation and to determine the roles of local and distant host responses in development of persistent chlamydial infection. Specific molecular, microbiologic and immunologic questions to be asked with the murine model are guided by questions raised by the group's clinical findings from ReA patients: (1) what are the roles of pro-inflammatory and immunologic cytokines produced in synovial tissue during the inflammatory processes? (2) what host cells are infected and where does chlamydial persistence begin? (3) what is the metabolic state of chlamydia in those cells? (4) are persistently infected host cells (presumed mononuclear cells/macrophages) the stimulus for inflammation, or do responses by uninfected host cells to the latter provide the inflammatory stimulus? (5) do the locally produced cytokines determine the establishment of inapparent/persistent chlamydial infection in synovial tissue? The proposed studies in a noninvasive murine model of reactive arthritis will extend our clinical and laboratory findings from patients with chlamydia-associated reactive arthritis, and under controlled experimental conditions, enable us to determine the host cells vs chlamydial components which predispose to development and chronicity of joint inflammation. In the long term, these studies will lead to improved therapies for patients with reactive arthritis and/or indicate requirements to prevent this spondyloarthropathy.

描述（由申请人提供）： 反应性关节炎 (ReA) 是一种慢性疾病，其特征为周期性发作 与炎症不太活跃的时期交替出现。疾病的判断标准之一 分类是既往性传播或胃肠道感染史。 我们合作小组的最新数据表明，大量 ReA 患者的滑膜组织中存在代谢活跃的衣原体。 为了促进 ReA 的研究，我们开发了生殖器衣原体的小鼠模型 使用人类沙眼衣原体菌株来研究感染 关节炎症的炎症/免疫病理学机制。小鼠发育 三周内出现上行生殖器感染。来自膝盖的滑膜组织 这些动物表现出滑膜炎的组织学迹象，包括增加 滑膜衬里细胞、扩张的血管和单核炎症灶 细胞，衣原体基因 PCR 呈阳性。 该模型将扩展我们之前从小鼠眼部衣原体获得的数据 证明衣原体传播到滑膜的感染模型 滑膜炎的组织和发展。该模型将使我们能够测试机制 在衣原体相关性脊柱关节病（ReA）中，与启动有关 滑膜炎症并确定本地和远处宿主的作用 持续性衣原体感染发展中的反应。具体的 向小鼠提出的分子、微生物学和免疫学问题 模型以 ReA 小组临床发现提出的问题为指导 患者：（1）促炎细胞因子和免疫细胞因子的作用是什么 炎症过程中滑膜组织中产生的？ (2)什么主机 细胞被感染，衣原体的持久性从哪里开始？ (3) 什么是 衣原体在那些细胞中的代谢状态如何？ (4)持续感染的宿主 细胞（假定的单核细胞/巨噬细胞）刺激炎症， 或者未感染的宿主细胞对后者的反应提供了炎症 刺激？ (5) 局部产生的细胞因子是否决定建立 滑膜组织中存在不明显/持续的衣原体感染？拟议的 对反应性关节炎的非侵入性小鼠模型的研究将扩展我们的研究 衣原体相关患者的临床和实验室检查结果 反应性关节炎，在受控实验条件下，使我们能够 确定宿主细胞与衣原体成分的关系 关节炎症的发展和慢性化。从长远来看，这些 研究将改善反应性关节炎患者的治疗方法 和/或指出预防这种脊柱关节病的要求。