The association of Epstein-Barr virus infection with CXCR3+ B-cell development in multiple sclerosis: impact of immunotherapies.

Jamie Van Langelaar,Johnny P.A Samijn,Caroline J.M Luijks,Andrew Bell,Pieter A Van Doorn,Joost Smolders,Menno C Van Zelm,Annet F Wierenga‐Wolf,Theodora A Siepman,Marvin M Van Luijn

doi:10.1002/eji.202048739

Abstract

Epstein–Barr virus (EBV) infection of B cells is associated with increased multiple sclerosis (MS) susceptibility. Recently, we found that CXCR3‐expressing B cells preferentially infiltrate the CNS of MS patients. In chronic virus‐infected mice, these types of B cells are sustained and show increased antiviral responsiveness. How EBV persistence in B cells influences their development remains unclear. First, we analyzed ex vivo B‐cell subsets from MS patients who received autologous bone marrow transplantation (n = 9), which is often accompanied by EBV reactivation. The frequencies of nonclass‐switched and class‐switched memory B cells were reduced at 3–7 months, while only class‐switched B cells returned back to baseline at 24–36 months posttransplantation. At these time points, EBV DNA load positively correlated to the frequency of CXCR3+, and not CXCR4+ or CXCR5+, class‐switched B cells. Second, for CXCR3+ memory B cells trapped within the blood of MS patients treated with natalizumab (anti‐VLA‐4 antibody n = 15), latent EBV infection corresponded to enhanced in vitro formation of anti‐EBNA1 IgG‐secreting plasma cells under GC‐like conditions. These findings imply that EBV persistence in B cells potentiates brain‐homing and antibody‐producing CXCR3+ subsets in MS.

Highlights

The success of anti-CD20 therapy puts forward B cells as important players of autoimmune diseases including multiple sclerosis (MS) [1]
After www.eji-journal.eu purifying these subsets, high Epstein–Barr virus (EBV) copy numbers were measured for class-switched B cells at 3–7 months post-bone marrow transplantation (BMT) (Fig. 1C), at the timeframe in which low numbers of memory B cells are present in the blood
Taking all individual samples into account, we found a positive correlation between EBV load and CXCR3+, but not CXCR4+ or CXCR5+ fractions of class-switched B cells (Fig. 2C and D)

Summary

Introduction

The success of anti-CD20 therapy puts forward B cells as important players of autoimmune diseases including multiple sclerosis (MS) [1]. In MS, one of the hypotheses is that EBV remains latent within pathogenic memory B cells that invade the central nervous system (CNS) [3, 5]. Once in the CNS, pathogenic memory B cells are likely reactivated and further develop into antibody-secreting plasma cells to mediate local inflammation [1]. IL-21 and CD40L are the main triggers of plasma cell differentiation during a GC response [6, 7]. In murine models of autoimmune diseases this response seems to be dysregulated in the presence of IFN-γ [8]

Methods

Results

Conclusion