Cytotoxic B Cells in Relapsing-Remitting Multiple Sclerosis Patients

Background

Emerging evidence of antibody-independent functions, as well as the clinical efficacy of anti-CD20 depleting therapies, helped to reassess the contribution of B cells during multiple sclerosis (MS) pathogenesis.

Objective

To investigate whether CD19^{B cells may share expression of the serine-protease granzyme-B (GzmB), resembling classical cytotoxic CD8}^{T lymphocytes, in the peripheral blood from relapsing-remitting MS (RRMS) patients.}

Methods

In this study, 104 RRMS patients during different treatments and 58 healthy donors were included. CD8, CD19, Runx3, and GzmB expression was assessed by flow cytometry analyses.

Results

RRMS patients during fingolimod (FTY) and natalizumab (NTZ) treatment showed increased percentage of circulating CD8^GzmB^{T lymphocytes when compared to healthy volunteers. An increase in circulating CD19}^GzmB^{B cells was observed in RRMS patients during FTY and NTZ therapies when compared to glatiramer (GA), untreated RRMS patients, and healthy donors but not when compared to interferon-β (IFN). Moreover, regarding Runx3, the transcriptional factor classically associated with cytotoxicity in CD8}^{T lymphocytes, the expression of GzmB was significantly higher in CD19}^Runx3^{-expressing B cells when compared to CD19}^Runx3^{counterparts in RRMS patients.}

Conclusions

CD19^{B cells may exhibit cytotoxic behavior resembling CD8}^{T lymphocytes in MS patients during different treatments. In the future, monitoring “cytotoxic” subsets might become an accessible marker for investigating MS pathophysiology and even for the development of new therapeutic interventions.}

^{Autoimmune Research Laboratory, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil,}

^{Neuroimmunology Unit, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil,}

^{Department of Neurology, University of Campinas, Campinas, Brazil,}

^{Department of Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, United States,}

^{MS Clinic of Santa Casa de São Paulo (CATEM), Irmandade da Santa Casa de Misericordia de São Paulo, São Paulo, Brazil,}

^{National Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM), Rio de Janeiro, Brazil,}

^{Experimental Medicine Research Cluster (EMRC), São Paulo, Brazil,}

^{Corresponding author.}

Edited by: Luisa María Villar, Ramón y Cajal University Hospital, Spain

Reviewed by: Miriam Laura Fichtner, Yale Medicine, United States; Barbara M.P. Willekens, Antwerp University Hospital, Belgium

*Correspondence: Vinícius O. Boldrini, moc.liamtoh@inirdlob_iv; Alessandro S. Farias, rb.pmacinu@sairafsa; Leonilda M. B. Santos, rb.pmacinu@adlinoel

This article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology

Edited by: Luisa María Villar, Ramón y Cajal University Hospital, Spain

Reviewed by: Miriam Laura Fichtner, Yale Medicine, United States; Barbara M.P. Willekens, Antwerp University Hospital, Belgium

Received 2021 Jul 30; Accepted 2022 Jan 13.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Background

Objective

Methods

In this study, 104 RRMS patients during different treatments and 58 healthy donors were included. CD8, CD19, Runx3, and GzmB expression was assessed by flow cytometry analyses.

Results

Conclusions

Keywords: cytotoxicity, granzyme B, neuroinflammation, neurodegeneration, MS treatment

Abstract

All data are represented in median (max – min values).

*Not all patients were tested for oligoclonal bands (Tested: n = 90; 66% OCB positive in the CSF).

CSF, Cerebrospinal Fluid; OCBs, Oligoclonal Bands; EDSS, Expanded Disease Scale Status.

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