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      Differential effects of disease modifying drugs on peripheral blood B cell subsets: A cross sectional study in multiple sclerosis patients treated with interferon-β, glatiramer acetate, dimethyl fumarate, fingolimod or natalizumab

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          Abstract

          Background

          Several disease modifying drugs (DMDs) have been approved for the treatment of multiple sclerosis (MS), however, little is known about their differential impact on peripheral blood (PB) B cell subsets.

          Methods

          We performed a cross sectional study on PB B cells in MS patients treated with interferon-β (n = 25), glatiramer acetate (n = 19), dimethyl fumarate (n = 15), fingolimod (n = 16) or natalizumab (n = 22), untreated MS patients (n = 20), and in patients with non-inflammatory neurological diseases (n = 12). Besides analyzing routine laboratory data, flow cytometry was performed to analyze naïve B cells (CD19+CD20+CD27-IgD+), non-class switched (CD19+CD20+CD27+IgD+) and class-switched memory B cells (CD19+CD20+CD27+IgD-), double negative B cells (CD19+CD20lowCD27-IgD-) and plasmablasts (CD19+CD20lowCD27+CD38++).

          Results

          Treatment associated changes were found for the overall B cell pool as well as for all B cell subsets. Natalizumab increased absolute numbers and percentage of all B cells mainly by expanding the memory B cell pool. Fingolimod decreased absolute numbers of all B cell subsets and the percentage of total B cells. Fingolimod, dimethyl fumarate and interferon-β treatments were associated with an increase in the fraction of naïve B cells while class switched and non-class switched memory B cells showed decreased percentages.

          Conclusion

          Our results highlight differential effects of DMDs on the PB B cell compartment. Across the examined treatments, a decreased percentage of memory B cells was found in dimethyl fumarate, interferon-β and fingolimod treated patients which might contribute to the drugs’ mode of action in MS. Further studies are necessary to decipher the exact role of B cell subsets during MS pathogenesis.

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          Most cited references32

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          B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes.

          Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by autoimmune-mediated demyelination and neurodegeneration. The CNS of patients with MS harbors expanded clones of antigen-experienced B cells that reside in distinct compartments including the meninges, cerebrospinal fluid (CSF), and parenchyma. It is not understood whether this immune infiltrate initiates its development in the CNS or in peripheral tissues. B cells in the CSF can exchange with those in peripheral blood, implying that CNS B cells may have access to lymphoid tissue that may be the specific compartment(s) in which CNS-resident B cells encounter antigen and experience affinity maturation. Paired tissues were used to determine whether the B cells that populate the CNS mature in the draining cervical lymph nodes (CLNs). High-throughput sequencing of the antibody repertoire demonstrated that clonally expanded B cells were present in both compartments. Founding members of clones were more often found in the draining CLNs. More mature clonal members derived from these founders were observed in the draining CLNs and also in the CNS, including lesions. These data provide new evidence that B cells traffic freely across the tissue barrier, with the majority of B cell maturation occurring outside of the CNS in the secondary lymphoid tissue. Our study may aid in further defining the mechanisms of immunomodulatory therapies that either deplete circulating B cells or affect the intrathecal B cell compartment by inhibiting lymphocyte transmigration into the CNS. Copyright © 2014, American Association for the Advancement of Science.
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            Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis

            Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore, it was interestingly to find that current MS-treatments, believed to act via T cell inhibition, including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19 +, CD27 + memory B cells. This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity. Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS. This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.
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              Immune surveillance in multiple sclerosis patients treated with natalizumab.

              Our objective was to test whether natalizumab, an antibody against very late activating antigen (VLA)-4, interferes with central nervous system immune surveillance as assessed by leukocyte cell numbers and cellular phenotypes in cerebrospinal fluid (CSF) and peripheral blood. Cell numbers and cellular phenotypes in CSF and peripheral blood were analyzed in multiple sclerosis (MS) patients treated with natalizumab, untreated MS patients, and patients with other neurological disease (OND). JC virus DNA in the CSF and peripheral blood was quantified by kinetic polymerase chain reaction. CSF leukocyte counts, CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD138(+) plasma cells were significantly lower in natalizumab-treated MS patients compared with OND patients and untreated MS patients. JC virus DNA was not detected in CSF or peripheral blood from natalizumab-treated patients. Six months after cessation of natalizumab therapy, low lymphocyte counts in the CSF persisted. The patient with the highest total leukocyte and CD4(+) and CD8(+)T-cell counts in the CSF experienced a clinical relapse. These data suggest that natalizumab treatment results in a prolonged decrease of lymphocytes in the CSF and are consistent with the hypothesis that natalizumab impairs immune surveillance of the central nervous system.
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                Author and article information

                Contributors
                Role: Formal analysisRole: Writing – original draft
                Role: Data curationRole: Writing – review & editing
                Role: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Writing – review & editing
                Role: Writing – review & editing
                Role: Funding acquisitionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                27 July 2020
                2020
                : 15
                : 7
                : e0235449
                Affiliations
                [1 ] Department of Neurology & Stroke, and Hertie-Institute for Clinical Brain Research, Eberhard-Karls University of Tübingen, Tübingen, Germany
                [2 ] Department of Neurology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
                [3 ] Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
                Institut Cochin, FRANCE
                Author notes

                Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: C.L. Kemmerer: reports no disclosures. V. Pernpeitner: reports no disclosures. C. Ruschil: reports no disclosures. A. Abdelhak: received research funding from the German multiple sclerosis society (DMSG) as well as travel grants from Teva and Novartis all not related to this work. M. Scholl: reports no disclosures. U. Ziemann: UZ has received honoraria from Biogen Idec GmbH, Bayer Vital GmbH, Bristol Myers Squibb GmbH, Pfizer, CorTec GmbH, Medtronic GmbH, and grants from European Research Council, German Research Foundation, German Ministry of Education and Research, Biogen Idec GmbH, Servier, and Janssen Pharmaceuticals NV, all not related to this work. M. Krumbholz: receives financial support from Sanofi-Genzyme, Merck, Novartis, Biogen, Celgene and Roche, not related to this study. B. Hemmer has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare and TG therapeutics; he or his institution have received speaker honoraria from Desitin; holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of MS patients and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. M.C. Kowarik: receives financial support from Merck, Sanofi-Genzyme, Novartis, Biogen, Celgene and Roche, not related to this study. The competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                http://orcid.org/0000-0003-1389-5539
                Article
                PONE-D-20-06004
                10.1371/journal.pone.0235449
                7384624
                32716916
                a7f29ec8-b708-496c-9d89-b2591f8bc08b
                © 2020 Kemmerer et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 March 2020
                : 15 June 2020
                Page count
                Figures: 4, Tables: 1, Pages: 15
                Funding
                The Munich Cluster for Systems Neurology (SyNergy), Munich, Germany is a non-commercial funding program which provided support in the form of salary and research materials for M.C. Kowarik, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Funding of B. Hemmer by SyNergy was not related to this study. The specific roles of the authors are articulated in the ‘author contributions’ section.
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