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  • Title: Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility.
    Author: Couturier N, Bucciarelli F, Nurtdinov RN, Debouverie M, Lebrun-Frenay C, Defer G, Moreau T, Confavreux C, Vukusic S, Cournu-Rebeix I, Goertsches RH, Zettl UK, Comabella M, Montalban X, Rieckmann P, Weber F, Müller-Myhsok B, Edan G, Fontaine B, Mars LT, Saoudi A, Oksenberg JR, Clanet M, Liblau RS, Brassat D.
    Journal: Brain; 2011 Mar; 134(Pt 3):693-703. PubMed ID: 21354972.
    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.
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