Abstract
IntroductionAccumulating 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.MethodsSynovial 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).ResultsIL-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.ConclusionsIncreased 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0426-z) contains supplementary material, which is available to authorized users.
Highlights
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)
Increased expression of interleukin 17A (IL-17A) is not restricted to synovial tissues of RA and PsA patients; it is observed in inflammatory OA
Th17 cells were originally identified by their expression of the proinflammatory cytokine interleukin 17 (IL-17) and represent a distinct subset of CD4+ cells characterised by the expression of Retinoic acid receptor–related orphan receptor γt (RORγt) [5]
Summary
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). Whereas initial studies focused mainly on type 1 helper T (Th1) cells as having a prominent role in rheumatoid arthritis (RA), subsequent studies suggested that Th17 cells have an important role in this disease. The functional role of this new type of effector helper T cell has been studied extensively in recent years and shows that it has important functions in the response to microbial infection and in promoting and maintaining chronic inflammation and autoimmunity [1]. The most studied family members are IL-17A and IL-17F, which are mainly produced by Th17 cells to protect against extracellular pathogens and fungi and have proinflammatory properties. IL-17 promotes the transcriptional activation of proinflammatory cytokines, hematopoietic cytokines, acute-phase response genes and antimicrobial mediators [6], especially in synergy with other proinflammatory cytokines such as tumour necrosis factor and IL-1β [7,8]. In addition to IL-17RA, IL-17RC is required for signalling in response to IL-17A or IL-17F [10,11]
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