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.
INTERPRETATION: 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.