2012
DOI: 10.1073/pnas.1117640109
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K-RAS GTPase- and B-RAF kinase–mediated T-cell tolerance defects in rheumatoid arthritis

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 … Show more

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Cited by 30 publications
(29 citation statements)
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“…In line with this, it was shown that B-Raf is activated by TCR signaling (4,20,21,55), that B-Raf deficiency in T cells results in developmental defects in the mouse (21), and that B-Raf is critical for TCR-mediated ERK activation in T cells from rheumatoid arthritis patients (56). In this study, we show that, upon TCR stimulation, the inhibitory N-terminal 14-3-3 binding site of B-Raf (S365) was dephosphorylated, and B-Raf was hyperphosphorylated, again showing that B-Raf is a downstream-signaling molecule of the TCR.…”
Section: Discussionmentioning
confidence: 65%
“…In line with this, it was shown that B-Raf is activated by TCR signaling (4,20,21,55), that B-Raf deficiency in T cells results in developmental defects in the mouse (21), and that B-Raf is critical for TCR-mediated ERK activation in T cells from rheumatoid arthritis patients (56). In this study, we show that, upon TCR stimulation, the inhibitory N-terminal 14-3-3 binding site of B-Raf (S365) was dephosphorylated, and B-Raf was hyperphosphorylated, again showing that B-Raf is a downstream-signaling molecule of the TCR.…”
Section: Discussionmentioning
confidence: 65%
“…Specifically, dampened T cell receptor-induced ERK signaling could be attributed to overactivity of DUSP6, which, in turn, increased due to failing repression by miR-181a in aging T cells. CD4 T cells from RA patients are characterized by dysregulated signaling cascades, shifting their threshold to activating signals and possibly removing them from protective tolerance mechanisms [51 ** ]. How abnormalities in signaling pathways, some of which appear to be a consequence of the cellular aging process, are connected to the breakdown of tolerance and the tissue-injurious immunity in rheumatoid arthritis needs further studies [52,53].…”
Section: Rewiring Of the Old T Cellmentioning
confidence: 99%
“…9–14 The magnitude and duration of ERK activation appears to modulate T cell function. Overexpression of RAS or RAF can enhance T cell activation and proliferation and conversely inhibition of RAS blocks T cell activation (10,15,16). This pathway is also important in various T cell functions including the differentiation of T cell subtypes, cytokine signaling, chemotaxis and survival (17,18).…”
Section: Introductionmentioning
confidence: 99%