SUPPRESSION OF AUTOIMMUNE-DISEASE AND OF MASSIVE LYMPHADENOPATHY IN MRL MP-LPR/LPR MICE LACKING TYROSINE KINASE FYN (P59(FYN))/

MRL/Mp-lpr/lpr (MRL/lpr) mice suffer from a generalized autoimmune dis ease that includes autoantibody production and glomerulonephritis and develop massive lymphadenopathy characterized by an expanded populatio n of CD4(-)CD8(-)B220(+) T cells that is derived from autoreactive T c ells in the periphery, Some of us previously reported that these atypi cal T cells overexpressed a gene for tyrosine kinase p59(fyn) (Fyn), T o define the role of Fyn in the renal disease and lymphadenopathy in M RL/lpr mice, we have generated Fyn-deficient MRL/lpr mice whose fyn ge ne is replaced by the gene for beta-galactosidase, Fyn-deficient MRL/l pr mice developed markedly limited disease and lived more than twice a s long as the conventional MRL/lpr mice, In the mutant mice, the produ ction of IgG3 anti-DNA autoantibody was significantly (p < 0.005%) red uced, and glomerular deposits of IgG3 and C3 were remarkably diminishe d, Ag receptor-mediated proliferative responses of Fyn-deficient splen ic T cells were markedly impaired, The mutant mice showed delayed accu mulation of the atypical CD4(-)CD8(-)B220(+) T cells that exhibited a significantly lower activity of ZAP-70 compared with those in the conv entional MRL/lpr mice, These data demonstrated that Fyn is involved as a positive regulator in the disease of MRL/lpr mice, Fyn provides a s ignal for both the expansion of autoreactive T cells and the productio n of IgG3 anti-DNA autoantibody by B cells, Thus, manipulation of Fyn may improve systemic autoimmune disease in humans.