We recently hypothesized that T helper 17 (Th17) cells and their associated cytokines are involved in the development of arthritis following infection with Borrelia burgdorferi. Here, we show that interleukin-23 (IL-23), a survival factor for Th17 cells, is required for the induction of arthritis in mice vaccinated with B. burgdorferi strain 297 and challenged with "Borrelia bissettii." When Borrelia-vaccinated and -challenged mice were given antibodies to the p19 subunit of IL-23, they failed to develop the histopathological changes observed in untreated vaccinated and challenged mice. In addition, viable B. bissettii organisms stimulated the secretion of IL-17 from Borrelia-immune lymph node cells during in vitro culture. When anti-IL-23 p19 antibody was included in cultures of B. bissettii organisms and Borrelia-immune lymph node cells, the production of IL-17 was reduced to levels observed in cultures containing immune cells alone. Taken together, these results support the hypothesis that Th17 cell-associated cytokines are involved in the development of Borrelia-mediated arthritis. These findings provide insight into previously overlooked immune mechanisms responsible for the development of Lyme arthritis.The development of severe, destructive arthritis in animals vaccinated and challenged with Borrelia species (12, 29) is dependent upon the production of Borrelia-specific CD4 ϩ T lymphocytes (28) and their cytokines. Recently, we showed that the proinflammatory cytokine interleukin-17 (IL-17) plays a major role in the induction of arthritis following Borrelia vaccination and challenge. Borrelia-vaccinated and -challenged mice given antibodies to IL-17 or to the IL-17 receptor failed to develop the histopathological changes observed in isotype control antibody-treated mice (10,38). Taken together, these findings suggested that IL-17-producing CD4 ϩ T cells augment the development of arthritis during the adaptive immune response to Borrelia infection.Although naïve T cells respond to Borrelia infection, their differentiation into T helper 1 (Th1) and Th2 cells is promoted by IL-12 and IL-4, respectively. In the Borrelia vaccination and challenge model of arthritis, a different pathway of T-cell activation occurs because of the existence of memory T cells. It is known that a subset of activated, or memory, T cells distinct from Th1 and Th2 cells, Th17 cells, can produce IL-17 (42). Differentiation into Th17 cells relies on transforming growth factor ␤ and inflammatory cytokines such as 31,46), while the survival and propagation of Th17 cells are dependent on IL-23 (8). IL-23 is produced by activated dendritic cells and macrophages (7,25) and is known to stimulate the release of IL-17 from activated CD4 ϩ T cells (1). IL-23 is also required for the development of collagen-induced arthritis, and its absence correlates with a reduction in Th17 cells (14, 35) and mRNA encoding IL-17 (35). Therefore, we hypothesized that IL-23 plays a significant role in the IL-17-mediated development of arthritis in Borrelia-vacci...

We showed previously that interleukin-17 (IL-17) plays a significant role in the induction of arthritis associated with Borrelia vaccination and challenge. Little information, however, is available about the chain of immunologic events that leads to the release of IL-17. The production of IL-17 has been linked to stimulation of memory cells by IL-15. Therefore, we hypothesized that IL-15 is involved in the induction of arthritis associated with Borrelia vaccination and infection of mice. Here we present evidence that treatment of Borrelia-vaccinated and -infected mice with anti-IL-15 antibody prevents swelling of the hind paws. More importantly, both anti-IL-15 antibody-and recombinant IL-15 receptor alpha-treated Borrelia-vaccinated and -infected mice were free of major histopathologic indications of arthritis, including hyperplasia, hypertrophy, and vilus formation of the synovium. Similarly, the synovial space and perisynovium were free of inflammatory cells. By contrast, the synovium of nontreated Borrelia-vaccinated and -infected mice had overt hyperplasia, hypertrophy, and vilus formation. Moreover, the synovial space and perisynovium were infiltrated with neutrophils, macrophages, and lymphocytes. Finally, we show that recombinant IL-15 stimulates the release of IL-17 from lymph node cells obtained near the arthritic site. These results suggest that IL-15 plays a major role in orchestrating IL-17 induction of arthritis associated with Borrelia-vaccinated and -infected mice.

Considerable effort has been made to elucidate the mechanism of Lyme arthritis. We focused on p19, a cell cycle-regulating molecule, because it is known to inhibit cell cycle division of T lymphocytes which may be responsible for the induction of arthritis. We show that anti-p19 antibody treatment enhances the inflammatory response normally detected at the tibiotarsal joints of Borrelia burgdorferi-vaccinated and Borrelia bissettiichallenged mice. Specifically, anti-p19 antibody treatment augmented the severity of inflammation within the synovial and subsynovial tissue. Moreover, treatment with anti-p19 antibody caused severe erosion of cartilage and bone with ankle joint destruction. In addition, anti-p19 antibody treatment of Borrelia-vaccinated and -challenged mice enhanced the borreliacidal antibody response, especially against the vaccine isolate. The novel activities of anti-p19 antibody show that p19 may be an important therapeutic site for the treatment of Lyme arthritis.