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- Title
Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility.
- Authors
Couturier, Nicolas; Bucciarelli, Florence; Nurtdinov, Ramil N; Debouverie, Marc; Lebrun-Frenay, Christine; Defer, Gilles; Moreau, Thibault; Confavreux, Christian; Vukusic, Sandra; Cournu-Rebeix, Isabelle; Goertsches, Robert H; Zettl, Uwe K; Comabella, Manuel; Montalban, Xavier; Rieckmann, Peter; Weber, Frank; Müller-Myhsok, Bertram; Edan, Gilles; Fontaine, Bertrand; Mars, Lennart T; Saoudi, Abdelhadi; Oksenberg, Jorge R; Clanet, Michel; Liblau, Roland S; Brassat, David
- 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 TYK2(GC) genotype with the disease-associated TYK2(GG) 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.
- Publication
Brain : a journal of neurology, 2011, Vol 134, Issue Pt 3, p693
- ISSN
1460-2156
- Publication type
Journal Article
- DOI
10.1093/brain/awr010