K-RAS GTPase- and B-RAF kinase-mediated T-cell tolerance defects in rheumatoid arthritis

26Citations
Citations of this article
22Readers
Mendeley users who have this article in their library.

Abstract

Autoantibodies to common autoantigens and neoantigens, such as IgG Fc and citrullinated peptides, are immunological hallmarks of rheumatoid arthritis (RA). We examined whether a failure in maintaining tolerance is mediated by defects in T-cell receptor activation threshold settings. RA T cells responded to stimulation with significantly higher ERK phosphorylation (P < 0.001). Gene expression arrays of ERK pathway members suggested a higher expression of KRAS and BRAF, which was confirmed by quantitative PCR (P = 0.003), Western blot, and flow cytometry (P < 0.01). Partial silencing of KRAS and BRAF lowered activation-induced phosphorylated ERK levels (P < 0.01). In individual cells, levels of these signaling molecules correlated with ERK phosphorylation, attesting that their concentrations are functionally important. In confocal studies, B-RAF/K-RAS clustering was increased in RA T cells 2 min after T-cell receptor stimulation (P < 0.001). Overexpression of B-RAF and K-RAS in normal CD4 T cells amplified polyclonal T-cell proliferation and facilitated responses to citrullinated peptides. We propose that increased expression of B-RAF and K-RAS lowers T-cell activation thresholds in RA T cells, enabling responses to autoantigens.

Cite

CITATION STYLE

APA

Singh, K., Deshpande, P., Li, G., Yu, M., Pryshchep, S., Cavanagh, M., … Goronzy, J. J. (2012). K-RAS GTPase- and B-RAF kinase-mediated T-cell tolerance defects in rheumatoid arthritis. Proceedings of the National Academy of Sciences of the United States of America, 109(25). https://doi.org/10.1073/pnas.1117640109

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free