title: Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility.
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.
authors.affiliation: INSERM U563 and Pôle des neurosciences, University of Toulouse 3, 31000 Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Couturier
authors.forename: Florence
authors.initials: F
authors.lastname: Bucciarelli
authors.forename: Ramil N
authors.initials: RN
authors.lastname: Nurtdinov
authors.forename: Marc
authors.initials: M
authors.lastname: Debouverie
authors.forename: Christine
authors.initials: C
authors.lastname: Lebrun-Frenay
authors.forename: Gilles
authors.initials: G
authors.lastname: Defer
authors.forename: Thibault
authors.initials: T
authors.lastname: Moreau
authors.forename: Christian
authors.initials: C
authors.lastname: Confavreux
authors.forename: Sandra
authors.initials: S
authors.lastname: Vukusic
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cournu-Rebeix
authors.forename: Robert H
authors.initials: RH
authors.lastname: Goertsches
authors.forename: Uwe K
authors.initials: UK
authors.lastname: Zettl
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.forename: Peter
authors.initials: P
authors.lastname: Rieckmann
authors.forename: Frank
authors.initials: F
authors.lastname: Weber
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Gilles
authors.initials: G
authors.lastname: Edan
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.forename: Lennart T
authors.initials: LT
authors.lastname: Mars
authors.forename: Abdelhadi
authors.initials: A
authors.lastname: Saoudi
authors.forename: Jorge R
authors.initials: JR
authors.lastname: Oksenberg
authors.forename: Michel
authors.initials: M
authors.lastname: Clanet
authors.forename: Roland S
authors.initials: RS
authors.lastname: Liblau
authors.forename: David
authors.initials: D
authors.lastname: Brassat
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D016009:Chi-Square Distribution; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005602:France / Q000453:epidemiology; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D053634:TYK2 Kinase / Q000235:genetics*; D013997:Time Factors; D055815:Young Adult
chemical_list: D016207:Cytokines; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D053634:TYK2 Kinase