Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis

被引:69
作者
Christensen, Jeppe Romme [1 ]
Bornsen, Lars [1 ]
Hesse, Dan [1 ]
Krakauer, Martin [1 ]
Sorensen, Per Soelberg [1 ]
Sondergaard, Helle Bach [1 ]
Sellebjerg, Finn [1 ]
机构
[1] Copenhagen Univ Hosp, Rigshosp, Danish Multiple Sclerosis Ctr, Dept Neurol, DK-2100 Copenhagen, Denmark
基金
英国医学研究理事会;
关键词
Relapsing-remitting multiple sclerosis; Immunology; Cytokines; Blood; Cerebrospinal fluid cells; Real-time PCR; MESSENGER-RNA EXPRESSION; TUMOR-NECROSIS-FACTOR; FLUID MONONUCLEAR-CELLS; CEREBROSPINAL-FLUID; INTERFERON-BETA; B-CELLS; DENDRITIC CELLS; FACTOR-ALPHA; CD80; B7-1; T-CELLS;
D O I
10.1186/1742-2094-9-215
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background: 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: We 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 noninflammatory neurological controls (NIND). Results: RRMS 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. Conclusions: Using 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.
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页数:12
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