Autoimmunity as the consequence of a spontaneous mutation in Rasgrp1.
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.
Layer
Katrin
K
Center for Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Lin
Guosheng
G
Nencioni
Alessio
A
Hu
Wei
W
Schmucker
Adam
A
Antov
Andrey N
AN
Li
Xiaoyu
X
Takamatsu
Satoshi
S
Chevassut
Timothy
T
Dower
Nancy A
NA
Stang
Stacey L
SL
Beier
David
D
Buhlmann
Janet
J
Bronson
Roderick T
RT
Elkon
Keith B
KB
Stone
James C
JC
Van Parijs
Luk
L
Lim
Bing
B
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
D016207:Cytokines; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse