RETRACTED: Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1 (Retracted Article)

A mouse strain was identified with a recessive genetic lesion, which spontaneously developed a lymphoproliferative autoimmune syndrome exhibiting features of systemic lupus erythematosus. Positional mapping of the disease-associated locus revealed a lesion in Rasgrp1 that prevented the translation of the RasGRP1 protein. T cells from these mice failed to activate Ras or proliferate vigorously following antigen encounter and showed defects in positive selection. Peripheral RasGRP1(lag) T cells spontaneously adopted a memory phenotype and were able to transfer disease to lymphopenic recipient mice. CD4(+) T cells accumulated in the lymphoid tissues of older RasGRP1(lag) mice and were resistant to activation-induced cell death. RasGRP1(lag) B cells were functionally normal, but activated B cells were detected in older mice, as were autoantibodies directed against self-antigens. Our findings indicate that Ras signaling pathways are required to maintain T cell tolerance and to prevent autoimmune disease.