B Lymphocytes in Multiple Sclerosis: Bregs and BTLA/CD272 Expressing-CD19+ Lymphocytes Modulate Disease Severity.

Federica Piancone,Simone Agostini,Laura Mendozzi,Mario Clerici,Domenico Caputo,Francesca La Rosa,Martina Zoppis,Marco Rovaris,Marina Saresella,Ivana Marventano,Renato Longhi

doi:10.1038/srep29699

Abstract

B lymphocytes contribute to the pathogenesis of Multiple Sclerosis (MS) by secreting antibodies and producing cytokines. This latter function was analyzed in myelin olygodendrocyte protein (MOG)-stimulated CD19+ B lymphocytes of 71 MS patients with different disease phenotypes and 40 age-and sex-matched healthy controls (HC). Results showed that: 1) CD19+/TNFα+, CD19+/IL-12+ and CD19+/IFNγ+ lymphocytes are significantly increased in primary progressive (PP) compared to secondary progressive (SP), relapsing-remitting (RR), benign (BE) MS and HC; 2) CD19+/IL-6+ lymphocytes are significantly increased in PP, SP and RR compared to BEMS and HC; and 3) CD19+/IL-13+, CD19+/IL-10+, and CD19+/IL-10+/TGFβ+ (Bregs) B lymphocytes are reduced overall in MS patients compared to HC. B cells expressing BTLA, a receptor whose binding to HVEM inhibits TcR-initiated cytokine production, as well as CD19+/BTLA+/IL-10+ cells were also significantly overall reduced in MS patients compared to HC. Analyses performed in RRMS showed that fingolimod-induced disease remission is associated with a significant increase in Bregs, CD19+/BTLA+, and CD19+/BTLA+/IL-10+ B lymphocytes. B lymphocytes participate to the pathogenesis of MS via the secretion of functionally-diverse cytokines that might play a role in determining disease phenotypes. The impairment of Bregs and CD19+/BTLA+ cells, in particular, could play an important pathogenic role in MS.

Highlights

In experimental allergic encephalomyelitis (EAE), in particular, the most widely investigated animal model of MS, interleukin (IL)-10 producing B cells were shown to have an important immunomodulatory role[7]
Whereas no differences were observed when either unstimulated or non-antigenic-stimulated cells were analyzed, results showed that CD19+cells expressing TNFαwere significantly increased in patients with a diagnosis of either PP, SP and RR multiple sclerosis compared to BEMS individuals and healthy controls (HC), with the highest values being present in PPMS patients
IL-6-expressing CD19+B lymphocytes were significantly increased in patients with a diagnosis of either PP, SP and RR multiple sclerosis compared to BEMS individuals and HC, with the highest values being present in PPMS patients

Summary

Introduction

In experimental allergic encephalomyelitis (EAE), in particular, the most widely investigated animal model of MS, interleukin (IL)-10 producing B cells were shown to have an important immunomodulatory role[7]. In contrast with what is observed with IL-10, the production of pro-inflammatory cytokines by activated B lymphocytes is increased in MS, and lymphotoxin (LT) and tumor necrosis factor alpha (TNFα) were shown to mediate oligodendrocyte toxicity in vitro[13]. This scenario is observed in relapsing-remitting (RR) MS, the most common disease phenotype; in these patients B lymphocytes produce augmented quantities of LT and TNFαand reduced amounts of IL-10 in response to polyclonal stimuli and myelin antigens[9,14,15]. Data indicating a likely role for B cells and BTLA in the pathogenesis of MS led us to analyze the role of B cells, and in particular of BTLA-expressing B lymphocytes in MS patients affected by different disease phenotypes, and in those whose disease remission is pharmacologically-induced

Methods

Results

Conclusion