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

Karnail Singh, Pratima Deshpande, Guangjin Li, Mingcan Yu, Sergey Pryshchep, Mary Cavanagh, Cornelia M. Weyand, Jörg J. Goronzy

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E1629-E1637
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number25
DOIs
StatePublished - Jun 19 2012

ASJC Scopus subject areas

  • General

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