期刊
JOURNAL OF IMMUNOLOGY
卷 183, 期 12, 页码 8258-8267出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0901784
关键词
-
类别
资金
- National Institutes of Health [R01 AR42527, R01 AR41974, R01 AI44142, U19 AI57266, R01 EY11916, R01 AG15043]
Immune responses to citrullinated neoantigens and clinical efficacy of costimulation blockade indicate a general defect in maintaining T cell tolerance in rheumatoid arthritis (RA). To examine whether TCR threshold calibration contributes to disease pathogenesis, signaling in RA T cells was quantified. RA patients had a selective increase in ERK phosphorylation compared with demographically matched controls due to a mechanism distal of Ras activation. Increased ERK responses included naive and memory CD4 and CD8 T cells and did not correlate with disease activity. The augmented ERK activity delayed SHP-1 recruitment to the TCR synapse and sustained TCR-induced Zap70 and NF-kappa B signaling, facilitating responses to suboptimal stimulation. Increased responsiveness of the ERK pathway was also a characteristic finding in the SKG mouse model of RA where it preceded clinical symptoms. Treatment with subtherapeutic doses of a MEK-1/2 inhibitor delayed arthritis onset and reduced severity, suggesting that increased ERK phosphorylation predisposes for autoimmunity and can be targeted. to prevent disease. The Journal of Immunology, 2009, 183: 8258-8267.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据