Differential Effects of Fingolimod and Natalizumab on B Cell Repertoires in Multiple Sclerosis Patients

Natalizumab and fingolimod are effective multiple sclerosis (MS) therapies that disrupt lymphocyte migration but have differential effects on B cell maturation and trafficking. We investigated their effects on peripheral blood (PB) and cerebrospinal fluid (CSF) B cell repertoires using next-generation deep sequencing. Paired CSF and PB B cell subsets (naive, CD27(+) memory, and CD27(-)IgD(-) double-negative B cells and plasmablasts) were collected by applying flow cytometry at baseline and after 6 months of treatment and their respective heavy-chain variable region repertoires assessed by Illumina MiSeq. Treatment with fingolimod contracted, whereas natalizumab expanded circulating PB B cells. CSF B cell numbers remained stable following fingolimod treatment but decreased with natalizumab therapy. Clonal overlap between CSF and PB B cells was reduced with natalizumab treatment but remained stable with fingolimod therapy. Lineage analyses of pre- and posttreatment CSF B cell repertoires revealed large, clonally expanded B cell clusters in natalizumab-treated MS patients but no intrathecal clonal expansion following fingolimod therapy. Our findings suggest that natalizumab diminishes the exchange of peripheral and intrathecal B cells without impacting intrathecal clonal expansion. In contrast, fingolimod treatment fails to alter blood-brain barrier B cell exchange but diminishes intrathecal clonal expansion. Sphingosine-1 phosphate receptor inhibition may alter intrathecal B cell biology in MS.

Automated summary

Natalizumab and fingolimod have differential effects on B cell populations in multiple sclerosis, with fingolimod treatment contracting peripheral blood B cells while natalizumab treatment expands them. The clonal overlap between CSF and PB B cells is reduced with natalizumab but remains stable with fingolimod therapy. These findings suggest that the two therapies have distinct impacts on the exchange and clonal expansion of B cells in MS patients.