Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis

Jeppe Romme Christensen,Finn Sellebjerg,Dan Hesse,Helle Bach Søndergaard,Per Soelberg Sørensen,Lars Börnsen,Martin Krakauer

doi:10.1186/1742-2094-9-215

Abstract

BackgroundNumerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce.MethodsWe studied gene expression of a broad panel of cytokines in WB from relapsing-remitting multiple sclerosis (RRMS) patients in remission and healthy controls (HCs). Subsequently we determined the gene expression of the dysregulated cytokines in isolated PBMC subsets (CD4+, CD8+T-cells, NK-cells, B-cells, monocytes and dendritic cells) from RRMS patients and HCs and in CSF-cells from RRMS patients in clinical relapse and non-inflammatory neurological controls (NIND).ResultsRRMS patients had increased expression of IFN-gamma (IFNG), interleukin (IL) 1-beta (IL1B), IL7, IL10, IL12A, IL15, IL23, IL27, lymphotoxin-alpha (LTA) and lymphotoxin-beta (LTB) in WB. In PBMC subsets the main sources of pro-inflammatory cytokines were T- and B-cells, whereas monocytes were the most prominent source of immunoregulatory cytokines. In CSF-cells, RRMS patients had increased expression of IFNG and CD19 and decreased expression of IL10 and CD14 compared to NINDs. CD19 expression correlated with expression of IFNG, IL7, IL12A, IL15 and LTA whereas CD14 expression correlated with IL10 expression.ConclusionsUsing a systematic approach, we show that expression of pro-inflammatory cytokines in peripheral blood primarily originates from T- and B-cells, with an important exception of IFNG which is most strongly expressed by NK-cells. In CSF-cell studies, B-cells appear to be enriched in RRMS and associated with expression of pro-inflammatory cytokines; contrarily, monocytes are relatively scarce in CSF from RRMS patients and are associated with IL10 expression. Thus, our findings suggest a pathogenetic role of B-cells and an immunoregulatory role of monocytes in RRMS.

Highlights

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS)
To relate the findings in peripheral blood to CNS inflammation, we studied gene expression of the dysregulated cytokines in cerebrospinal fluid (CSF)-cells from relapsing-remitting multiple sclerosis (RRMS) patients in relapse, and determined whether it correlated with markers for T, B- and Natural killer cell (NK-cell) and monocytes in the CSF
In the selection of the genes of interest (Table 2), we focused on genes that have been shown to be involved in the pathogenesis of multiple sclerosis (MS), genes involved in the expression of Th1 and Th17 cytokines, and genes expressed in Antigen-presenting cell (APC)

Summary

Introduction

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS). The relation between the peripheral immune system and CNS inflammation in RRMS is underscored by the efficacy of treatment with the monoclonal antibodies natalizumab [3] and rituximab [4], which exert their effect on peripheral immune cells, but have a major impact on disease activity, cell numbers, levels of cytokines and markers of tissue damage in CSF [5,6,7]. Numerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce

Methods

Results

Discussion

Conclusion