Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility

Nicolas Couturier, Florence Bucciarelli, Ramil N. Nurtdinov, Marc Debouverie, Christine Lebrun-Frenay, Gilles Defer, Thibault Moreau, Christian Confavreux, Sandra Vukusic, Isabelle Cournu-Rebeix, Robert H. Goertsches, Uwe K. Zettl, Manuel Comabella, Xavier Montalban, Peter Rieckmann, Frank Weber, Bertram Müller-Myhsok, Gilles Edan, Bertrand Fontaine, Lennart T. MarsAbdelhadi Saoudi, Jorge R. Oksenberg, Michel Clanet, Roland S. Liblau, David Brassat*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

92 Citations (Scopus)

Abstract

The tyrosine kinase 2 variant rs34536443 has been established as a genetic risk factor for multiple sclerosis in a variety of populations. However, the functional effect of this variant on disease pathogenesis remains unclear. This study replicated the genetic association of tyrosine kinase 2 with multiple sclerosis in a cohort of 1366 French patients and 1802 controls. Furthermore, we assessed the functional consequences of this polymorphism on human T lymphocytes by comparing the reactivity and cytokine profile of T lymphocytes isolated from individuals expressing the protective TYK2GC genotype with the disease-associated TYK2GG genotype. Our results demonstrate that the protective C allele infers decreased tyrosine kinase 2 activity, and this reduction of activity is associated with a shift in the cytokine profile favouring the secretion of Th2 cytokines. These findings suggest that the rs34536443 variant effect on multiple sclerosis susceptibility might be mediated by deviating T lymphocyte differentiation toward a Th2 phenotype. This impact of tyrosine kinase 2 on effector differentiation is likely to be of wider importance because other autoimmune diseases also have been associated with polymorphisms within tyrosine kinase 2. The modulation of tyrosine kinase 2 activity might therefore represent a new therapeutic approach for the treatment of autoimmune diseases.

Original languageEnglish
Pages (from-to)693-703
Number of pages11
JournalBrain
Volume134
Issue number3
Early online date22 Feb 2011
DOIs
Publication statusPublished - Mar 2011

Keywords

  • autoimmunity
  • multiple sclerosis
  • susceptibility T lymphocyte polarization
  • TYK2

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