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 non-response to anti-IL-17 therapy?
IntroductionAccumulating evidence suggests an important role for interleukin (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 are highly variable between patients and across different diseases. The objective was to determine the variability in expression of IL-17A, IL-17F and their receptors IL-17RA and IL-17RC in synovium of patients with arthritis.MethodsSynovial biopsies were obtained from patients with RA (n¿=¿11), PsA (n¿=¿15) and inflammatory osteoarthritis (OA, n¿=¿14). For comparison, synovium from non-inflamed knee joints (n¿=¿7) were included obtained from controls. Frozen sections were stained for IL-17A, IL-17F, IL-17RA and IL-17RC, and evaluated by digital image analysis. To determine which cells in the synovium express IL-17A and IL-17F, double stainings with CD4, CD8, CD15, CD68, CD163, CD31, Von Willebrand Factor (vWF), peripheral lymph node addressin (PNAd), lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1), mast cell tryptase (MCT) and RAR-Related Orphan Receptor gamma t (ROR¿(t)) were performed and evaluated by confocal microscopy.ResultsIL-17A, IL-17F, IL-17RA and IL-17RC were abundantly expressed in synovial tissues of all patient groups. Whereas IL-17RA was mostly present 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 non-inflamed control tissues. The expression of IL-17A, IL-17F and their receptors was similar in the different patient groups, but highly variable between patients. CD4 and CD8 positive cells co-expressed IL-17A and few cells co-expressed IL-17F. IL-17A and IL-17F were not expressed by CD15 positive 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 ROR¿(t). Colocalization between ROR¿(t) and IL-17A and IL-17F indicates local IL-17 production.ConclusionsIncreased expression of IL-17A is not restricted to synovial tissues of RA and PsA patients but also observed in inflammatory OA. The heterogeneous expression levels may explain non-response to anti-IL17 therapy in subsets of patients.