Suppression of autoimmune disease and of massive lymphadenopathy in MRL/Mp-lpr/lpr mice lacking tyrosine kinase Fyn (p59fyn).
MRL/Mp-lpr/lpr (MRL/lpr) mice suffer from a generalized autoimmune disease that includes autoantibody production and glomerulonephritis and develop massive lymphadenopathy characterized by an expanded population of CD4- CD8- B220+ T cells that is derived from autoreactive T cells in the periphery. Some of us previously reported that these atypical T cells overexpressed a gene for tyrosine kinase p59fyn (Fyn). To define the role of Fyn in the renal disease and lymphadenopathy in MRL/lpr mice, we have generated Fyn-deficient MRL/lpr mice whose fyn gene is replaced by the gene for beta-galactosidase. Fyn-deficient MRL/lpr mice developed markedly limited disease and lived more than twice as long as the conventional MRL/lpr mice. In the mutant mice, the production of IgG3 anti-DNA autoantibody was significantly (p < 0.005%) reduced, and glomerular deposits of IgG3 and C3 were remarkably diminished. Ag receptor-mediated proliferative responses of Fyn-deficient splenic T cells were markedly impaired. The mutant mice showed delayed accumulation of the atypical CD4- CD8- B220+ T cells that exhibited a significantly lower activity of ZAP-70 compared with those in the conventional MRL/lpr mice. These data demonstrated that Fyn is involved as a positive regulator in the disease of MRL/lpr mice. Fyn provides a signal for both the expansion of autoreactive T cells and the production of IgG3 anti-DNA autoantibody by B cells. Thus, manipulation of Fyn may improve systemic autoimmune disease in humans.
Takahashi
T
T
Department of Molecular Immunology, Center for Basic Research, The Kitasato Institute, Tokyo, Japan.
Yagi
T
T
Kakinuma
S
S
Kurokawa
A
A
Okada
T
T
Takatsu
K
K
Aizawa
S
S
Katagiri
T
T
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000235:genetics; D001327:Autoimmune Diseases / Q000235:genetics / Q000517:prevention & control*; D002455:Cell Division; D003433:Crosses, Genetic; D004247:DNA / Q000276:immunology; D005260:Female; D005921:Glomerulonephritis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D008136:Longevity / Q000235:genetics; D008213:Lymphocyte Activation; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051076:Proto-Oncogene Proteins c-fyn; D011961:Receptors, Fc / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000473:pathology; D051746:ZAP-70 Protein-Tyrosine Kinase
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D011518:Proto-Oncogene Proteins; D011961:Receptors, Fc; C035311:immunoglobulin M receptor; D004247:DNA; D011505:Protein-Tyrosine Kinases; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051746:ZAP-70 Protein-Tyrosine Kinase; C497262:Zap70 protein, mouse