Defective fas ligand-mediated apoptosis predisposes to development of a chronic erosive arthritis subsequent to Mycoplasma pulmonis infection

Objective. To determine whether defective T cell apoptosis is associated wi th the development of a chronic arthritis subsequent to mycoplasma infectio n, and to determine whether deletion of T cells can prevent the development of this arthritis. Methods. B6 wild-type (B6-+/+), B6-lpr/lpr, and B6-gld/gld mice were infect ed with Mycoplasma pulmonis. The severity of lymphocytic infiltration and j oint damage was evaluated, and the degree of recovery of viable mycoplasma from the spleen and joints was determined. Antigen-presenting cells derived from Fas mutant lpr mice (lpr-APC) were transfected ex vivo with an adenov irus (Ad) vector to yield lpr-APC expressing high levels of Fas ligand (lpr -APC-AdFasL), which in turn were transferred intraperitoneally into M pulmo nis-infected B6-gld/gld mice. The development of arthritis subsequent to M pulmonis infection and the induction of apoptosis of cells within the synov ial tissue and lymph nodes of lpr-APC-AdFasL-treated B6-gld/gld mice were d etermined. Results. Infection of B6-lpr/lpr and B6-gld/gld mice,with M pulmonis result ed in an acute-phase inflammation of the synovium that later developed into a chronic erosive arthritis. Similar infection of B6-+/+ mice resulted onl y in an acute joint inflammatory response that resolved. Chronic arthritis in B6-gld/gld mice and B6-lpr/lpr was not due to persistent infection, sinc e there were no differences in the rates of clearance of M pulmonis from th e joints of B6-gld/gld or B6-lpr/lpr mice compared with B6-+/+ mice. Treatm ent of infected B6-gld/gld mice with lpr-APC-AdFasL resulted in a significa ntly decreased incidence of chronic arthritis that was associated with a de crease in lymph node T cells, but not with apoptosis of synovial T cells or fibroblasts. Conclusion. Defective Fas/FasL-mediated apoptosis of T cells is an importan t factor that rendered arthritis-resistant B6 mice susceptible to the devel opment of a chronic erosive arthritis subsequent to mycoplasma infection. I n vivo lpr-APC-AdFasL cell-gene therapy is a safe and effective method for inhibiting the development of this arthritis.