Lyme disease is a multisystem infectious and inflammatory disease caused by the tick-borne spirochete Borrelia burgdorferi. Stage 3 disease in humans includes a relapsing and sometimes chronic arthritis, which most commonly involves the knee joint and which may lead to erosive joint damage. Histologic features of Lyme arthritis are similar to those of rheumatoid arthritis and include synovial lining cell hyperplasia, hyperplasia of synovial tissue with villous formation, and an inflammatory infiltrate of mononuclear cells, including lymphocytes, plasma cells, and some macrophages. Understanding of the pathogenesis and pathologic changes in Lyme arthritis in humans has been hampered by the difficulty in obtaining synovial tissue and the rarity of synovial samples from patients with early disease. Although animal models of disease have been available, most do not offer good correlation with human disease, and it has been difficult to produce lesions in mice, a species in which the immune system has been well studied. A model of Lyme disease in laboratory mice injected with B. burgdorferi has recently been published in which C3H/He mice develop florid arthritis. BALB/c mice injected via this route develop mild arthritis. However, more florid arthritis is induced in BALB/c mice infected via the bite of infected Ixodes dammini ticks. These two models allow for the careful histologic study of inflamed synovial tissue at specific time intervals post infection. The early events and temporal sequence of events in inflammatory arthritis can thus be determined and compared in mice of different genetic backgrounds. First, the early inflammatory cell migration into joints will be studied via immunohistochemical techniques. Cytokine gene expression will be studied via in situ hybridization and via immunohistochemistry, to identify both mRNA and protein. The temporal events involved in the induction of the metalloproteinases collagenase and stromelysin will be determined by comparison of metalloproteinase mRNA expression with inflammatory cell migration and cytokine expression. The expression of the adhesion molecules LFA-1 and ICAM-1 and ICAM-2 will also be studied. Because persistence of antigens may be the cause of chronic arthritis, Borrelial antigens will be sought via immunoperoxidase and silver strain, and serial synovial cultures will be performed. Finally, the studies outlined will be performed in parallel in two different mouse strains, and compared with the intent of identifying pathogenetic differences between strains.

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Brigham and Women's Hospital
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