Fingolimod treatment promotes regulatory phenotype and function of B cells.
OBJECTIVE
To evaluate the influence of Fingolimod treatment on B-cell subset composition and function in multiple sclerosis patients and its potential clinical relevance.


METHODS
Subset composition and cytokine production of B cells derived from peripheral blood mononuclear cells from multiple sclerosis patients under Fingolimod treatment, untreated multiple sclerosis patients and healthy controls were analyzed by flow cytometry and ELISA. Migration of lymphocyte subsets across primary human brain microvascular endothelial cells was assessed in an in vitro transmigration assay. Cell numbers and composition of B-cell subsets in cerebrospinal fluid and peripheral blood were determined by flow cytometry. Regulatory B-cell frequencies were correlated with parameters of disease stability.


RESULTS
Within the peripheral B-cell compartment of Fingolimod-treated patients, the proportion of regulatory B cells (CD38(+)CD27(-)CD24(+)CD5(+)) was significantly increased as compared to treatment-naïve multiple sclerosis patients and to healthy controls, and significantly more regulatory B cells produced Interleukin-10. Fingolimod treatment enhanced the capacity of regulatory B cells to transmigrate across brain endothelial cells in an in vitro model of the blood-brain-barrier. In line with these findings, the cerebrospinal fluid/blood ratio of total B cells and regulatory B cells was strongly increased by Fingolimod treatment, and patients exhibited increased regulatory B-cell frequencies in the cerebrospinal fluid. Finally, elevated regulatory B-cell percentages in the periphery significantly correlated with clinical and paraclinical disease stability.


CONCLUSIONS
These data suggest a novel and as yet unrecognized role of Fingolimod in correction of the imbalance between regulatory and effector B-cell functions in multiple sclerosis both by direct effects and indirect partitioning effects on B-cell subpopulations.
Department of Neurology, University of Münster Münster, Germany.
Berit
B
Grützke
Department of Neurology, University of Münster Münster, Germany.
Stephanie
S
Hucke
Department of Neurology, University of Münster Münster, Germany.
Catharina C
CC
Gross
Department of Neurology, University of Münster Münster, Germany.
Martin V B
MV
Herold
Department of Neurology, University of Münster Münster, Germany.
Anita
A
Posevitz-Fejfar
Division of Molecular Neuroimmunology, Department of Neurology, University of Heidelberg Heidelberg, Germany.
Brigitte T
BT
Wildemann
Department of Neurology, University of Düsseldorf Düsseldorf, Germany.
Bernd C
BC
Kieseier
Department of Neurology, University of Düsseldorf Düsseldorf, Germany.
Thomas
T
Dehmel
Department of Neurology, University of Münster Münster, Germany.
Heinz
H
Wiendl
Department of Neurology, University of Münster Münster, Germany.
Luisa
L
Klotz