title: Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1.
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.
authors.affiliation: Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Katrin
authors.initials: K
authors.lastname: Layer
authors.forename: Guosheng
authors.initials: G
authors.lastname: Lin
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Adam
authors.initials: A
authors.lastname: Schmucker
authors.forename: Andrey N
authors.initials: AN
authors.lastname: Antov
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Li
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takamatsu
authors.forename: Timothy
authors.initials: T
authors.lastname: Chevassut
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Dower
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Stang
authors.forename: David
authors.initials: D
authors.lastname: Beier
authors.forename: Janet
authors.initials: J
authors.lastname: Buhlmann
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Keith B
authors.initials: KB
authors.lastname: Elkon
authors.forename: James C
authors.initials: JC
authors.lastname: Stone
authors.forename: Luk
authors.initials: L
authors.lastname: Van Parijs
authors.forename: Bing
authors.initials: B
authors.lastname: Lim
mesh_terms: D000818:Animals; D017209:Apoptosis; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015551:Autoimmunity / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002455:Cell Division; D016207:Cytokines / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors; D007156:Immunologic Memory; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010641:Phenotype; D017634:Self Tolerance / Q000235:genetics
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse