RHEUMATIC DISEASES IN AN MRL STRAIN OF MICE WITH A DEFICIT IN THE FUNCTIONAL FAS LIGAND

Objective. To characterize Fas antigen expression on the cell surface, and to determine the effect of this expression in rheumatic diseases using a newly established gld-congenic MRL strain of mice (MRL/gld), w hich is defective in its functional Fas ligand (Fas-L). Methods. Flow cytometric analyses of lymphoid cells and macrophages were performed u sing anti-Fas and other cell surface markers, Histopathologic manifest ations were examined using immunochemistry and light and electron micr oscopy, Serum levels of IgG and anti-DNA antibodies were measured by s ingle radial immunodiffusion and enzyme-linked immunosorbent assay, re spectively. Results. MRL/gld mice developed systemic lymphadenopathy w ith an accumulation of Thy1.2+, B220+ and CD4-, CD8- T cells, which bo th express the Fas antigen, Splenic B cells positive for surface IgM a nd/or surface IgD, and resident peritoneal macrophages exhibited lip-r egulated expression of the Fas antigen, at much higher levels than tho se observed in MRL/MpJ.+/+ (MRL/+) mice, Forms of rheumatic disease we re observed in these mice, although not in C3H/HeJ-gld/gld mice, These forms included diffuse glomerulonephritis, granulomatous arteritis, a nd arthritis, and were associated with the infiltration of mononuclear cells expressing the Fas antigen, Serum levels of IgG and anti-DNA an tibodies were significantly increased in MRL/gld mice compared with MR L/+ mice. Conclusion. Rheumatic disease was generated by the gin gene in mice with an MRL background, as it is by the lpr gene, which is a F as deletion mutant, associated with autoimmune traits, Rheumatic disea se in this MRL strain was initiated by an incapacity for Fas/Fas-L-ind uced apoptosis, resulting in the development of autoimmunity and allow ing for a persistent immune response in the affected lesions.