Lupus-like kidney disease in mice deficient in the Src family tyrosine kinases Lyn and Fyn

Systemic lupus erythematosus (SLE) is an autoimmune disease whose cause is poorly understood. Mice rendered deficient in specific genes have served as useful animal models in deciphering the genetic control of the disease [1] . We [2] and others [3, 4] previously demonstrated that mice deficient in t he Src family tyrosine kinase Lyn developed a mild lupus-like disease with high survival rates. During the course of investigating the functional inte raction of Src family kinases, we generated a mouse strain deficient in bot h Lyn and Fyn, The double-mutant mice died at relatively young ages and dev eloped a severe lupus-like kidney disease. Unlike the double-mutant mice, s ingle mutants deficient in either Lyn or Fyn lived longer and had distinct subsets of the symptoms found in the former. Lyn deficiency led to high lev els of autoantibody production and glomerulonephritis, as previously report ed [2-4], whereas loss of Fyn contributed to proteinuria by a B and T lymph ocyte-independent mechanism. Our data suggest that the severe kidney diseas e in the double-mutant mice results from a combination of immunological and kidney-intrinsic defect. This new animal model may be informative about th e causes of human SLE.