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
First Page
243
Last Page
255
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.
Recommended Citation
Layer K,
Lin G,
Nencioni A,
Hu W,
Schmucker A,
Antov AN,
Li X,
Takamatsu S,
Chevassut T,
Dower NA,
Stang SL,
Beier D,
Buhlmann J,
Bronson RT,
Elkon KB,
Stone JC,
Van PL,
Lim B.
Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1. Immunity 2003 Aug; 19(2):243-55.