Pathogenic mechanisms in chlamydial reactive arthritis

Wayne State University, Detroit MI

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Abstract

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.