Differential effects of FTY720 on the B cell compartment in a mouse model of multiple sclerosis

Background: mp4-induced experimental autoimmune encephalomyelitis (eae) is a mouse model of multiple sclerosis (ms),which enables targeted research on b cells,currently much discussed protagonists in ms pathogenesis. here,we used this model to study the impact of the s1p1 receptor modulator fty720 (fingolimod) on the autoreactive b cell and antibody response both in the periphery and the central nervous system (cns). methods: mp4-immunized mice were treated orally with fty720 for 30 days at the peak of disease or 50 days after eae onset. the subsequent disease course was monitored and the mp4-specific b cell/antibody response was measured by elispot and elisa. rna sequencing was performed to determine any effects on b cell-relevant gene expression. s1p1 receptor expression by peripheral t and b cells,b cell subset distribution in the spleen and b cell infiltration into the cns were studied by flow cytometry. the formation of b cell aggregates and of tertiary lymphoid organs (tlos) was evaluated by histology and immunohistochemistry. potential direct effects of fty720 on b cell aggregation were studied in vitro. results: fty720 significantly attenuated clinical eae when treatment was initiated at the peak of eae. while there was a significant reduction in the number of t cells in the blood after fty720 treatment,b cells were only slightly diminished. yet,there was evidence for the modulation of b cell receptor-mediated signaling upon fty720 treatment. in addition,we detected a significant increase in the percentage of b220+ b cells in the spleen both in acute and chronic eae. whereas acute treatment completely abrogated b cell aggregate formation in the cns,the numbers of infiltrating b cells and plasma cells were comparable between vehicle- and fty720-treated mice. in addition,there was no effect on already developed aggregates in chronic eae. in vitro b cell aggregation assays suggested the absence of a direct effect of fty720 on b cell aggregation. however,fty720 impacted the evolution of b cell aggregates into tlos. conclusions: the data suggest differential effects of fty720 on the b cell compartment in mp4-induced eae. © 2017 the author(s).