Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility
N. Couturier
(1)
,
F. Bucciarelli
(1)
,
R. Nurtdinov
(1)
,
M. Debouverie
(2)
,
C. Lebrun-Frenay
(3)
,
G. Defer
(4)
,
T. Moreau
(5)
,
C. Confavreux
(6, 7)
,
S. Vukusic
(7, 6)
,
I. Cournu-Rebeix
(8, 9)
,
R. Goertsches
(10)
,
U. Zettl
(10)
,
M. Comabella
(11)
,
X. Montalban
(11)
,
P. Rieckmann
(12)
,
F. Weber
(13)
,
B. Muller-Myhsok
(13)
,
G. Edan
(14, 15)
,
B. Fontaine
(8)
,
L. Mars
(1)
,
Abdelhadi Saoudi
(1)
,
J. Oksenberg
(16)
,
M. Clanet
(1)
,
R. Liblau
(1)
,
D. Brassat
(1)
1
CPTP -
Centre de Physiopathologie Toulouse Purpan
2 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
3 CHU Nice - Centre Hospitalier Universitaire de Nice
4 Service de Neurologie [CHU Caen]
5 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
6 Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL]
7 Neuro-oncologie et neuro-inflammation
8 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
9 NPS - Neuroscience Paris Seine
10 University of Rostock
11 Vall d'Hebron University Hospital [Barcelona]
12 Neurologische Klinik Bamberg
13 Max Planck Institute of Psychiatry
14 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
15 CIC-P 0203 INSERM - Unité d’Investigation Neurologique [CHU Rennes]
16 UC San Francisco - University of California [San Francisco]
2 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
3 CHU Nice - Centre Hospitalier Universitaire de Nice
4 Service de Neurologie [CHU Caen]
5 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
6 Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL]
7 Neuro-oncologie et neuro-inflammation
8 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
9 NPS - Neuroscience Paris Seine
10 University of Rostock
11 Vall d'Hebron University Hospital [Barcelona]
12 Neurologische Klinik Bamberg
13 Max Planck Institute of Psychiatry
14 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
15 CIC-P 0203 INSERM - Unité d’Investigation Neurologique [CHU Rennes]
16 UC San Francisco - University of California [San Francisco]
Résumé
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.