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AB0176 P38 MAPK phosphorylation as a rheumatoid arthritis biomarker
  1. M. Lopez-Santalla1,
  2. I. Gonzalez-Alvaro2,
  3. A. Lamana2,
  4. A.M. Ortiz2,
  5. S. Castañeda2,
  6. J.M. Salvador1
  1. 1Immunology and Oncology, Spanish National Research Council (CSIC)
  2. 2Rheumatology, Hospital Universitario de la Princesa, Instituto de Investigaciόn Sanitaria La Princesa, Madrid, Spain

Abstract

Background p38 MAPK plays an important role in inflammatory processes involved in the development of rheumatoid arthritis (RA). In T cells, p38 can be activated through the MAPKK family, by phosphorylation at Thr180-Tyr182 residues, after different types of stress (proinflammatory cytokines, osmotic shock and UV radiation) or by phosphorylation at Tyr323 through tyrosine kinases Lck and Zap70, after T cell receptor (TCR) activation. Gadd45a is a negative regulator of the TCR-mediated p38 phosphorylation on Tyr323. Our group has shown that constitutive activation of Tyr323p38 leads to spontaneous development of autoimmune disease in murine models and that T cells from active RA patients have an increased phosphorylation on Tyr323 compared to T cells from healthy controls, ankylosing spondylitis and RA patients in remission.

Objectives Analysis of p38 phosphorylation and Gadd45a expression in T cells from early arthritis (EA) patients to identify variables associated with disease activity.

Methods We studied 49 patients with EA (42 women). Median age at disease onset was 54 years [p25-p75: 47-63] and disease duration at the inclusion in the register, 4 months (3 - 7). We analyzed the p38 MAPK phosphorylation (at Thr180-Tyr182 and Tyr323) by flow cytometry in T cells purified from peripheral blood samples. We measured the expression level of GADD45a by quantitative RT-PCR adjusted by the expression of β-actin.

Results At the first visit, we observed a significant correlation between pTyr323 levels and the DAS28 value. Patients with a family history of RA had higher levels of pTyr323 (p=0.01), suggesting a genetic component in the pTyr323 hyperactivation. pTyr323 levels were also higher in those cases who met EULAR/ACR 2010 criteria for RA. There wasa decreased expression of Gadd45a mRNA (p<0.05) in T lymphocytes of RA patients compared to T cells from healthy controls.

Conclusions Our results indicate that the phosphorylation status of p38a on Tyr323 can be used to evaluate the inflammatory activity of RA patients. Decreased expression of Gadd45a in T cells from active RA patients can increase the activation of p38a MAPK. Our results suggest that inhibition of this activation pathway is an attractive therapeutic target to modulate the activation of p38 in a specific manner in T cells.

Disclosure of Interest None Declared

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