title: Prostaglandin E2 synthesizing enzymes in rheumatoid arthritis B cells and the effects of B cell depleting therapy on enzyme expression.
abstract: BACKGROUND
  B cells may play an important role in promoting immune activation in the rheumatoid synovium and can produce prostaglandin E(2) (PGE(2)) when activated. In its turn, PGE(2) formed by cyclooxygenase (COX) and microsomal prostaglandin E(2) synthase 1 (MPGES1) contributes to the rheumatoid arthritis (RA) pathological process. Therapeutic depletion of B cells results in important improvement in controlling disease activity in rheumatoid patients. Therefore we investigated the expression of PGE(2) pathway enzymes in RA B cells and evaluated the effects of B cell depleting therapy on their expression in RA tissue.
  
  
  METHODS
  B cells expressing MPGES1 and COX-2 were identified by flow cytometry in in vitro stimulated and control mononuclear cells isolated from synovial fluid and peripheral blood of RA patients. Synovial biopsies were obtained from 24 RA patients before and at two consecutive time points after rituximab therapy. Expression of MPGES1, COX-1 and COX-2, as well as interleukin (IL)-1β and IL-6, known inducers of MPGES1, was quantified in immunostained biopsy sections using computerized image analysis.
  
  
  RESULTS
  Expression of MPGES1 or COX-2 was significantly upregulated upon stimulation of B cells from blood and synovial fluid while control cells displayed no detectable enzymes. In synovial biopsy sections, the expression of MPGES1, COX-1 or COX-2 was resistant to rituximab therapy at 8 or 16 weeks after start of treatment. Furthermore expression of IL-1β in the synovial tissue remained unchanged, while IL-6 tended to decrease after therapy.
  
  
  CONCLUSIONS
  Therapy with B cell depleting agents, although efficient in achieving good clinical and radiographic response in RA patients, leaves important inflammatory pathways in the rheumatoid synovium essentially unaffected.
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institute, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Karina Roxana
authors.initials: KR
authors.lastname: Gheorghe
authors.forename: Rogier M
authors.initials: RM
authors.lastname: Thurlings
authors.forename: Marie
authors.initials: M
authors.lastname: Westman
authors.forename: Maartje J
authors.initials: MJ
authors.lastname: Boumans
authors.forename: Vivianne
authors.initials: V
authors.lastname: Malmström
authors.forename: Christina
authors.initials: C
authors.lastname: Trollmo
authors.forename: Marina
authors.initials: M
authors.lastname: Korotkova
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
authors.forename: Paul-Peter
authors.initials: PP
authors.lastname: Tak
mesh_terms: D001172:Arthritis, Rheumatoid / Q000201:enzymology / Q000276:immunology / Q000628:therapy; D001402:B-Lymphocytes / Q000201:enzymology* / Q000473:pathology; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000032:analysis; D051546:Cyclooxygenase 2 / Q000032:analysis; D015232:Dinoprostone / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation; D053583:Interleukin-1beta / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D019746:Intramolecular Oxidoreductases / Q000032:analysis; D008212:Lymphocyte Depletion / Q000379:methods*; D000071876:Prostaglandin-E Synthases; D013583:Synovial Membrane / Q000473:pathology
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone