Systemic Inflammation in Progressive Multiple Sclerosis Involves Follicular T-Helper, Th17- and Activated B-Cells and Correlates with Progression

Jeppe Romme Christensen,Fredrik Piehl,Mohsen Khademi,Tomas Olsson,Per Soelberg Sørensen,Finn Sellebjerg,Rikke Ratzer,Lars Börnsen,Lionel G Filion

doi:10.1371/journal.pone.0057820

Abstract

Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4+ and CD8+T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. Flow cytometry studies revealed increased frequencies of ICOS+TFH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 TFH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 TFH-cells. The Th17-subset, interleukin-23-receptor+CD4+T-cells, was significantly increased in PPMS and SPMS. In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN+ and CD83+B-cells in SPMS. ICOS+TFH-cells and DC-SIGN+B-cells correlated with disease progression in SPMS patients. Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4+T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of TFH-cell and plasmablast markers. In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS. The increased frequencies of Th17-cells, activated TFH- and B-cells parallel findings from pathology studies which, along with the correlation between activated TFH- and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS.

Highlights

Progressive multiple sclerosis (MS) is characterized by steady progression of neurological disability without remission
Analysis of Th1- and Th17-phenotypes showed that SPMS and PPMS patients had an increased frequency of IL23-receptor (IL23R)+CD4+T-cells, presumably Th17-cells [35], in blood compared to healthy controls (HC) (Figure 1H–I)
Previous studies have indicated the presence of systemic and intrathecal inflammation in progressive MS, but it is unclear to what extent systemic inflammation mirrors intrathecal inflammation and whether systemic inflammation contributes to intrathecal inflammation and disease progression

Summary

Introduction

Progressive multiple sclerosis (MS) is characterized by steady progression of neurological disability without remission. A low rate of relapses and gadolinium-enhancing lesions, pronounced atrophy and limited efficacy of treatment has supported a view where axonal loss independent of inflammation is thought to be the substrate for disease progression [4]. This view was challenged by recent pathology studies, which indicate that in progressive MS CNS inflammation is abundant and correlates with axonal damage and disease progression [5,6]. ELFs are associated with more rapid disease progression, cortical lesions, meningeal and white matter inflammation, atrophy and neuronal loss [9,10]. Monocytes and dendritic cells have been implicated in MS immunopathology [12,13,14]

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