Cytotoxic B Cells in Relapsing-Remitting Multiple Sclerosis Patients.

Vinícius O Boldrini,Carlos Otávio Brandão,Irene Santos,Raphael P S Quintiliano,Leonilda M B Santos,Alfredo Damasceno,Alessandro S Farias,Ana M Marques,Breno Ferrari,Marília Andrade,Carla R A V Stella,Rafael P D Carneiro,Ana Leda F Longhini,Adriel S Moraes

doi:10.3389/fimmu.2022.750660

Abstract

BackgroundEmerging 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.ObjectiveTo 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.MethodsIn 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.ResultsRRMS 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.ConclusionsCD19+ 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.

Highlights

Multiple sclerosis (MS) is an autoimmune-mediated demyelinating disease of the central nervous system (CNS)
Flow cytometry analysis of Peripheral blood mononuclear cells (PBMCs) (Figure 1A) showed no differences in the percentage of circulating CD8+ T lymphocytes from relapsing-remitting MS (RRMS) patients when compared to healthy donors
The expression of GzmB was significantly higher in CD8+ T lymphocytes from patients treated with FTY (43.2, mean; 95% CI) (p = 0.0163) and NTZ (40.5, mean; 95% CI) (p = 0.0048) vs. healthy donors, but not in treated RRMS patients during first-line immunomodulatory therapies, Glatiramer Acetate (GA) and IFN (26.8 and 25.5, means; 95% CI) nor in untreated RRMS patients (31.9, mean; 95% CI) vs. healthy donors, respectively (Figure 1E)

Summary

Introduction

Multiple sclerosis (MS) is an autoimmune-mediated demyelinating disease of the central nervous system (CNS). On the other hand, regarding progressive MS courses, the CSF from secondary progressive MS (SPMS) patients showed in vitro neurotoxicity due to the expression of GzmB [16] and cytotoxic CD8+CD57+ T lymphocytes seem to be present in inflamed meninges in these patients with rapidly progressive disease [4]. These findings reinforce that cytotoxic mechanisms derived from CD8+ T lymphocytes are pivotal drivers of CNS damage during MS [12, 17, 18]. Objective: To investigate whether CD19+ B cells may share expression of the serineprotease granzyme-B (GzmB), resembling classical cytotoxic CD8+ T lymphocytes, in the peripheral blood from relapsing-remitting MS (RRMS) patients

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Conclusion