Title

Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1.

Document Type

Article

Publication Date

2003

Keywords

Autoimmune-Diseases, Autoimmunity, B-Lymphocytes, CD4-Positive-T-Lymphocytes, Cell-Division, Cytokines, DNA-Binding-Proteins, Immunologic-Memory, Lupus-Erythematosus-Systemic, Lymphocyte-Activation, MAP-Kinase-Signaling-System, Mice, Mice-Mutant-Strains, Mutation, Phenotype, Self-Tolerance, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S

JAX Source

Immunity 2003 Aug; 19(2):243-55.

Abstract

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 RasGRP1lag 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 RasGRP1lag mice and were resistant to activation-induced cell death. RasGRP1lag 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.