title: Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis.
abstract: 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 non-inflammatory 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.
authors.affiliation: Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen, 2100, Denmark. jeppe.romme.christensen@rh.regionh.dk
authors.forename: Jeppe
authors.initials: J
authors.lastname: Romme Christensen
authors.forename: Lars
authors.initials: L
authors.lastname: Börnsen
authors.forename: Dan
authors.initials: D
authors.lastname: Hesse
authors.forename: Martin
authors.initials: M
authors.lastname: Krakauer
authors.forename: Per Soelberg
authors.initials: PS
authors.lastname: Sørensen
authors.forename: Helle Bach
authors.initials: HB
authors.lastname: Søndergaard
authors.forename: Finn
authors.initials: F
authors.lastname: Sellebjerg
mesh_terms: D000328:Adult; D001773:Blood Cells / Q000145:classification / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D016207:Cytokines; D012333:RNA, Messenger