ERK-dependent T cell receptor threshold calibration in rheumatoid arthritis.

Abstract

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.

• Authors: Karnail Singh, Pratima Deshpande, Sergey Pryshchep, Inés Colmegna, Vladimir Liarski, Cornelia M Weyand, Jörg J Goronzy
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 183 Issue 12 Pg. 8258-67 (Dec 15 2009) ISSN: 1550-6606 [Electronic] United States
• PMID: 20007589 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Receptors, Antigen, T-Cell
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Arthritis, Experimental (enzymology, immunology, metabolism)
• Arthritis, Rheumatoid (enzymology, immunology, metabolism, pathology)
• Calibration (standards)
• Disease Models, Animal
• Extracellular Signal-Regulated MAP Kinases (metabolism, physiology)
• Female
• Humans
• JNK Mitogen-Activated Protein Kinases (biosynthesis, metabolism, physiology)
• Lymphocyte Activation (immunology)
• Male
• Mice
• Mice, Inbred BALB C
• Middle Aged
• Phosphorylation (immunology)
• Receptors, Antigen, T-Cell (biosynthesis, metabolism, physiology)
• Signal Transduction (immunology)
• T-Lymphocyte Subsets (enzymology, immunology, metabolism, pathology)