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

多发性硬化 酪氨酸激酶 免疫学 自身免疫性疾病 受体酪氨酸激酶 酪氨酸 JAK-STAT信号通路 细胞因子 生物 酪氨酸激酶2 癌症研究 信号转导 血小板源性生长因子受体 受体 遗传学 抗体 生长因子 生物化学
作者
Nicolas Couturier,Florence Bucciarelli,Ramil Nurtdinov,Marc Debouverie,Christine Lebrun‐Frénay,Gilles Defer,T. Moreau,Cyrille B. Confavreux,Sandra Vukusic,Isabelle Cournu‐Rebeix,Robert Goertsches,Uwe K. Zettl,Manuel Comabella,Xavier Montalbán,Peter Rieckmann,Frank Weber,Bertram Müller‐Myhsok,Gilles Edan,Bertrand Fontaine,Lennart T. Mars,Abdelhadi Saoudi,Jorge R. Oksenberg,M. Clanet,Roland Liblau,David Brassat
出处
期刊:Brain [Oxford University Press]
卷期号:134 (3): 693-703 被引量:102
标识
DOI:10.1093/brain/awr010
摘要

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.

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