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Synovial tissues of inflamed joints contain cells expressing high levels of Fas and Fas ligand (FasL). Although Fas stimulation is typically associated with cell death, it can also transmit stimulatory signals to certain cell types. Among these are dendritic cells and macrophages, which are abundant in inflamed synovium. To better assess the role of FasL in the pathogenesis of Lyme arthritis, we evaluated the response to<jats:italic>B. burgdorferi<\/jats:italic>infection in C3H\/HeJ<jats:italic>gld<\/jats:italic>mice that bear a nonfunctional mutation in FasL. Compared to wild-type C3H<jats:sup>+\/+<\/jats:sup>mice, C3H<jats:italic>gld<\/jats:italic>mice had a similar bacterial burden and antibody response 2 weeks and 4 weeks following infection, but they manifested a significantly reduced<jats:italic>Borrelia-<\/jats:italic>specific cytokine response. In addition, C3H<jats:italic>gld<\/jats:italic>mice developed a greatly reduced incidence and severity of arthritis. 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