Autoimmunity as the consequence of a spontaneous mutation in RasGRP1

Katrin Layer, Guosheng Lin, Alessio Nencioni, Wei Hu, Adam Schmucker, Andrey N. Antov, Xiaoyu Li, Satoshi Takamatsu, Timothy Chevassut, Nancy A. Dower, Stacey L. Stang, David Beier, Janet Buhlmann, Roderick T. Bronson, Keith B. Elkon, James C. Stone, Luk Van Parijs, Bing Lim

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)243-255
Number of pages13
JournalImmunity
Volume19
Issue number2
DOIs
Publication statusPublished - Aug 1 2003

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

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  • Cite this

    Layer, K., Lin, G., Nencioni, A., Hu, W., Schmucker, A., Antov, A. N., Li, X., Takamatsu, S., Chevassut, T., Dower, N. A., Stang, S. L., Beier, D., Buhlmann, J., Bronson, R. T., Elkon, K. B., Stone, J. C., Van Parijs, L., & Lim, B. (2003). Autoimmunity as the consequence of a spontaneous mutation in RasGRP1. Immunity, 19(2), 243-255. https://doi.org/10.1016/S1074-7613(03)00209-7