title: Heterogeneous expression pattern of interleukin 17A (IL-17A), IL-17F and their receptors in synovium of rheumatoid arthritis, psoriatic arthritis and osteoarthritis: possible explanation for nonresponse to anti-IL-17 therapy?
abstract: BACKGROUND
  Accumulating evidence suggests an important role for interleukin 17 (IL-17) in the pathogenesis of several inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Accordingly, clinical trials aimed at blocking IL-17 have been initiated, but clinical results between patients and across different diseases have been highly variable. The objective was to determine the variability in expression of IL-17A, IL-17F and their receptors IL-17RA and IL-17RC in the synovia of patients with arthritis.
  
  
  METHODS
  Synovial biopsies were obtained from patients with RA (n = 11), PsA (n = 15) and inflammatory osteoarthritis (OA, n = 14). For comparison, synovia from noninflamed knee joints (n = 7) obtained from controls were included. Frozen sections were stained for IL-17A, IL-17F, IL-17RA and IL-17RC and evaluated by digital image analysis. We used confocal microscopy to determine which cells in the synovium express IL-17A and IL-17F, double-staining with CD4, CD8, CD15, CD68, CD163, CD31, von Willebrand factor, peripheral lymph node address in, lymphatic vessel endothelial hyaluronan receptor 1, mast cell tryptase and retinoic acid receptor-related orphan receptor γt (RORγt).
  
  
  RESULTS
  IL-17A, IL-17F, IL-17RA and IL-17RC were abundantly expressed in synovial tissues of all patient groups. Whereas IL-17RA was present mostly in the synovial sublining, IL-17RC was abundantly expressed in the intimal lining layer. Digital image analysis showed a significant (P < 0.05) increase of only IL-17A in arthritis patients compared to noninflamed control tissues. The expression of IL-17A, IL-17F and their receptors was similar in the different patient groups, but highly variable between individual patients. CD4+ and CD8+ cells coexpressed IL-17A, and few cells coexpressed IL-17F. IL-17A and IL-17F were not expressed by CD15+ neutrophils. Mast cells were only occasionally positive for IL-17A or IL-17F. Interestingly, IL-17A and IL-17F staining was also observed in macrophages, as well as in blood vessels and lymphatics. This staining probably reflects receptor-bound cytokine staining. Many infiltrated cells were positive for the transcription factor RORγt. Colocalisation between RORγt and IL-17A and IL-17F indicates local IL-17 production.
  
  
  CONCLUSIONS
  Increased expression of IL-17A is not restricted to synovial tissues of RA and PsA patients; it is also observed in inflammatory OA. The heterogeneous expression levels may explain nonresponse to anti-IL-17 therapy in subsets of patients.
authors.forename: Lisa G M
authors.initials: LG
authors.lastname: van Baarsen
authors.forename: Maria C
authors.initials: MC
authors.lastname: Lebre
authors.forename: Dennis
authors.initials: D
authors.lastname: van der Coelen
authors.forename: Saïda
authors.initials: S
authors.lastname: Aarrass
authors.forename: Man W
authors.initials: MW
authors.lastname: Tang
authors.forename: Tamara H
authors.initials: TH
authors.lastname: Ramwadhdoebe
authors.forename: Daniëlle M
authors.initials: DM
authors.lastname: Gerlag
authors.forename: Paul P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use; D015535:Arthritis, Psoriatic / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020381:Interleukin-17 / Q000032:analysis / Q000096:biosynthesis*; D008297:Male; D018613:Microscopy, Confocal; D008875:Middle Aged; D010003:Osteoarthritis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D053722:Receptors, Interleukin-17 / Q000032:analysis / Q000096:biosynthesis; D013583:Synovial Membrane / Q000378:metabolism
chemical_list: D018501:Antirheumatic Agents; C508717:IL17A protein, human; C440021:IL17F protein, human; D020381:Interleukin-17; D053722:Receptors, Interleukin-17