Dipeptidyl peptidase I regulates the development of collagen‐induced arthritis

Objective To examine the role of dipeptidyl peptidase I (DPPI), a widely expressed lysosomal cysteine protease, in the development of collagen‐induced arthritis (CIA) in mice. Methods Wild‐type (WT) and DPPI‐deficient (DPPI−/−) mice backcrossed to DBA/1J mice for 10 generations were immunized with bovine type II collagen (CII), and disease susceptibility and severity were assessed over time. Collagen‐specific B cell and T cell responses and the production of proinflammatory cytokines (tumor necrosis factor α, interleukin‐1, and interleukin‐6) were measured. In addition, adoptive transfer of splenocytes from WT, CII‐sensitized mice was performed to evaluate the specific role of DPPI−/− T lymphocytes. Results The majority of DPPI−/− mice were resistant to CIA induction, although clinical disease (i.e., evidence of inflammation and bone erosions) did develop in a small number of DPPI−/− mice. The protection against disease development was not attributable to a defect in the B and T cell response to collagen immunization, because both anticollagen antibody production and T cell proliferation in response to CII were normal. Release of the proinflammatory cytokines was largely unaffected in CII‐stimulated DPPI−/− splenocytes. In addition, when cells isolated from the joints of DPPI−/− mice were stimulated in vitro, they had no intrinsic defect in their ability to release inflammatory cytokines. Last, adoptive transfer of splenocytes from WT, CII‐immunized mice into naive WT and DPPI−/− mice led to development of arthritis in WT mice but not in DPPI−/− mice. Conclusion These results indicate that DPPI regulates a critical step in the development of CIA that is independent of T cell and B cell functions.