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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
12
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pubmed:dateCreated |
2009-12-16
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pubmed:abstractText |
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-kappaB 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.
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pubmed:grant |
http://linkedlifedata.com/resource/pubmed/grant/R01 AG015043-11,
http://linkedlifedata.com/resource/pubmed/grant/R01 AI044142-10,
http://linkedlifedata.com/resource/pubmed/grant/R01 AI44142,
http://linkedlifedata.com/resource/pubmed/grant/R01 AR041974-14,
http://linkedlifedata.com/resource/pubmed/grant/R01 AR042527-15,
http://linkedlifedata.com/resource/pubmed/grant/R01 AR41974,
http://linkedlifedata.com/resource/pubmed/grant/R01 EY011916-08,
http://linkedlifedata.com/resource/pubmed/grant/R01 EY11916,
http://linkedlifedata.com/resource/pubmed/grant/R01AG15043,
http://linkedlifedata.com/resource/pubmed/grant/R01AR42527,
http://linkedlifedata.com/resource/pubmed/grant/U19 AI057266-068181,
http://linkedlifedata.com/resource/pubmed/grant/U19 AI57266
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-10878393,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-10922071,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-11056669,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-11323282,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-11369787,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-12393721,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-12577055,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-12748655,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-1280847,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-12878725,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-12932282,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-14614165,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-14647385,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-14745016,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-15084263,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-15142260,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-15208781,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-15642146,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-15674368,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-15790350,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-15797492,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-15914087,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-16231973,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-16273109,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-16447223,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-16461343,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-16585962,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-16697661,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-16731003,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-16932728,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-17283063,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-17382377,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-17974596,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-18173373,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-18209096,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-18287017,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-18388522,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-19007421,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-19255426,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-19451263,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-8619093,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-8621791,
http://linkedlifedata.com/resource/pubmed/commentcorrection/20007589-9826720
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
AIM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Dec
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pubmed:issn |
1550-6606
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
15
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pubmed:volume |
183
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
8258-67
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pubmed:dateRevised |
2011-1-5
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pubmed:meshHeading |
pubmed-meshheading:20007589-Humans,
pubmed-meshheading:20007589-Animals,
pubmed-meshheading:20007589-Mice,
pubmed-meshheading:20007589-Arthritis, Rheumatoid,
pubmed-meshheading:20007589-Phosphorylation,
pubmed-meshheading:20007589-Female,
pubmed-meshheading:20007589-Male,
pubmed-meshheading:20007589-Calibration,
pubmed-meshheading:20007589-Middle Aged,
pubmed-meshheading:20007589-Disease Models, Animal,
pubmed-meshheading:20007589-Lymphocyte Activation,
pubmed-meshheading:20007589-Mice, Inbred BALB C,
pubmed-meshheading:20007589-Signal Transduction,
pubmed-meshheading:20007589-Arthritis, Experimental
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