Differential Effects of Fingolimod and Natalizumab on B Cell Repertoires in Multiple Sclerosis Patients
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ORIGINAL ARTICLE
Differential Effects of Fingolimod and Natalizumab on B Cell Repertoires in Multiple Sclerosis Patients M. C. Kowarik 1,2 & D. Astling 3 & G. Lepennetier 2 & A. Ritchie 4 & B. Hemmer 2,5 & G. P. Owens 4 & Jeffrey L. Bennett 4,6 Accepted: 14 November 2020 # The American Society for Experimental NeuroTherapeutics, Inc. 2020
Abstract 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 (naïve, 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. Key Words Natalizumab . fingolimod . cerebrospinal fluid . B cell migration . B cell maturation . mass sequencing.
Introduction B cells play an important role in the pathophysiology of multiple sclerosis (MS). B cells are detected in MS lesions and
* Jeffrey L. Bennett [email protected] 1
Department of Neurology & Stroke and Hertie-Institute for Clinical Brain Research, Eberhard-Karls University of Tübingen, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany
2
Department of Neurology, Technische Universität München, Ismaninger Str. 22, 81541 Munich, Germany
3
Department of Biochemistry and Molecular Genetics, University of Colorado, 13001 East 17th Place, Aurora, Colorado 80045, USA
4
Department of Neurology, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, Colorado 80045, USA
5
Munich Cluster for Systems Neurology (SyNergy), Feodor-Lynen-Str. 17, 81377 Munich, Germany
6
Department of Ophthalmology, Programs in Neuroscience and Immunology, University of Colorado Anschutz Medical Campus, 12700 East 19th Avenue, Aurora, Colorado 80045, USA
cerebrospinal fluid (CSF), and the persistence of intrathecal oligoclonal immunoglobulin G (IgG) ban
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