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

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.

Is There a Future for Interleukin 17 Blocking Agents in Rheumatoid Arthritis?

“…including adalimumab, rituximab, and tocilizumab 13 . This approach for anti-IL-17 could be supported by data published by van Baarsen, who reported a heterogeneous expression of IL-17 in the synovium 14 . Personalized medicine is at this time a dream, but the validation of synovial tissue predictive markers is one of the most important fields of RA research.…”

Effects of high intensity exhaustive exercise on SOD, MDA, and NO levels in rats with knee osteoarthritis

“…Among these, suspect cell factors primarily included tumor necrosis factor alpha (TNF-α), and interleukin 1 alpha (IL-1α) and 1 beta (IL-1β), among others. IL-1α and IL-1β concentrations have been shown to increase under the pathological conditions of osteoarthritis; this increase improved the fibrinolytic enzyme activity, destroyed the cartilage matrix, and increased the incidence of synovial thickening and bone invasion (van Baarsen et al, 2014). In addition, TNF-α has been demonstrated to have an inhibitory effect on matrix repair, so as to accelerate the degeneration of articular cartilage.…”

Post-Traumatic Arthritis: The Role of Cytokine Levels in Serum and Synovial Fluid

“…Such neutralization of this cytokine or its receptors was shown to decrease arthritis symptoms in a rat model. IL-17 deficiency was also shown to protect the host against arthritis-related collagen damage in a rat model, and IL-17 gene therapy was shown to intensify it (van Baarsen et al, 2014;Zheng et al, 2014). It can be concluded, therefore, that IL-17 in RA patients might cause both inflammation and bone-destruction.…”