ORIGINAL RESEARCH article
Front. Immunol.
Sec. Multiple Sclerosis and Neuroimmunology
Reduced CD40 expression in B cell subsets of individuals with radiologically isolated syndrome
Provisionally accepted
Christian Keller1Kerstin Stein1Andreu Vilaseca2
Luisa María Villar3
Gary Álvarez Bravo4
Maria Protopapa5Josef Shin5
Nicolas Fissolo2Jose Enrique Martínez-Rodríguez6
Quiroga-Varela A.4
Alexis García Sarreón4Lucía Gutiérrez2
Luciana Midaglia2Xavier Montalban2
Jan D Lünemann1
Manuel Comabella2*- 1Universitat Munster, Münster, Germany
- 2Hospital Universitari Vall d'Hebron, Barcelona, Spain
- 3Hospital Universitario Ramon y Cajal, Madrid, Spain
- 4Hospital Universitari de Girona Doctor Josep Trueta, Girona, Spain
- 5Johannes Gutenberg Universitat Mainz, Mainz, Germany
- 6Institut Hospital del Mar d'Investigacions Mediques, Barcelona, Spain
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Abstract Introduction: B cells play a central role in multiple sclerosis (MS) pathogenesis, yet their activation profiles during the earliest disease stages remain incompletely characterized. We aimed to investigate the expression of the activation markers CD40 and CD71 across peripheral B-cell subsets in individuals with radiologically isolated syndrome (RIS), and compare them to those with clinically isolated syndrome or MS (CIS/MS) and healthy controls (HC). Methods: Peripheral blood cells from individuals with RIS (n=21), CIS/MS (n=15), and HC (n=15) were analyzed by flow cytometry. CD40 and CD71 expression was assessed across major B-cell subsets. Epstein-Barr virus (EBV) serologies were measured to explore associations with activation marker expression. Results: CD40 expression was reduced on transitional, naïve, and memory B-cell subsets in RIS compared to CIS/MS and HC (p<0.001). CD71 expression remained stable across groups. CD40 expression was preserved in plasmablasts and regulatory B cells. No significant associations were observed between CD40 levels and EBV antibody titers. Discussion: In this cross-sectional cohort, CD40 expression was lower on transitional, naïve, and memory B-cell subsets in RIS compared to CIS/MS and HC, whereas plasmablasts and regulatory B cells were comparable. This pattern is consistent with an altered costimulatory state in early, asymptomatic disease and warrants longitudinal studies to determine its clinical relevance.
Keywords: Multiple Sclerosis, B cells, Radiologically isolated syndrome, CD40, biomarkers
Received: 05 Aug 2025; Accepted: 18 Nov 2025.
Copyright: © 2025 Keller, Stein, Vilaseca, Villar, Álvarez Bravo, Protopapa, Shin, Fissolo, Martínez-Rodríguez, A., García Sarreón, Gutiérrez, Midaglia, Montalban, Lünemann and Comabella. 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) or licensor 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.
* Correspondence: Manuel Comabella, manuel.comabella@vhir.org
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