Purpose Osteoarthritis (OA) is a common and heterogeneous arthritic disorder. Patients suffer pain and their joints are characterized by articular cartilage loss and osteophyte formation. Risk factors for OA include age and obesity with inflammation identified as a key mediator of disease pathogenesis. Interleukin-17A (IL-17) is a pro-inflammatory cytokine that has been implicated in inflammatory diseases such as rheumatoid arthritis. IL-17 can upregulate expression of inflammatory cytokines and adipocytokines. The aim of this study was to evaluate IL-17 levels in the synovial fluid of patients with end-stage knee and hip OA in relation to inflammation- and pain-related cytokines and adipocytokines in synovial fluid and serum, and clinical and radiographic disease parameters. Methods This is a cross-sectional study of 152 patients undergoing total hip and knee arthroplasty for OA. IL-17, IL-6, leptin, adiponectin, visfatin, resistin, C-C Motif Chemokine Ligand 2 (CCL2), C-C Motif Chemokine Ligand 7 (CCL7) and nerve growth factor (NGF) protein levels were measured in synovial fluid and serum using enzyme-linked immunosorbent assay (ELISA). Baseline characteristics included age, sex, body mass index, co-morbidities, pain and function, and radiographic analyses (OA features, K&L grade, minimal joint space width). Results 14 patients (9.2%) had detectable IL-17 in synovial fluid. These patients had significantly higher median concentrations of IL-6, leptin, resistin, CCL7 and NGF. Osteophytes, sclerosis and minimum joint space width were significantly reduced in patients with detectable IL-17 in synovial fluid. No differences were found in pain, function and comorbidities. IL-17 concentrations in synovial fluid and serum were moderately correlated (r = 0.482). Conclusion The presence of IL-17 in the synovial fluid therefore identifies a substantial subset of primary end-stage OA patients with distinct biological and clinical features. Stratification of patients on the basis of IL-17 may identify those responsive to therapeutic targeting.
Objective Monosodium urate monohydrate (MSU) crystal–induced interleukin‐1β (IL‐1β) secretion is a critical factor in the pathogenesis of gout. However, without costimulation by a proIL‐1β–inducing factor, MSU crystals alone are insufficient to induce IL‐1β secretion. The responsible costimulatory factors that act as a priming endogenous signal in vivo are not yet known. We undertook this study to analyze the costimulatory properties of myeloid‐related protein 8 (MRP‐8) and MRP‐14 (endogenous Toll‐like receptor 4 [TLR‐4] agonists) in MSU crystal–induced IL‐1β secretion and their relevance in gout. Methods MRP‐8/MRP‐14 was measured in paired serum and synovial fluid samples by enzyme‐linked immunosorbent assay (ELISA) and localized in synovial tissue from gout patients by immunohistochemistry. Serum levels were correlated with disease activity, and MSU crystal–induced release of MRPs from human phagocytes was measured. Costimulatory effects of MRP‐8 and MRP‐14 on MSU crystal–induced IL‐1β secretion from phagocytes were analyzed in vitro by ELISA, Western blotting, and polymerase chain reaction. The impact of MRP was tested in vivo in a murine MSU crystal–induced peritonitis model. Results MRP‐8/MRP‐14 levels were elevated in the synovium, tophi, and serum of patients with gout and correlated with disease activity. MRP‐8/MRP‐14 was released by MSU crystal–activated phagocytes and increased MSU crystal–induced IL‐1β secretion in a TLR‐4–dependent manner. Targeted deletion of MRP‐14 in mice led to a moderately reduced response of MSU crystal–induced inflammation in vivo. Conclusion MRP‐8 and MRP‐14, which are highly expressed in gout, are enhancers of MSU crystal–induced IL‐1β secretion in vitro and in vivo. These endogenous TLR‐4 ligands released by activated phagocytes contribute to the maintenance of inflammation in gout.
Among the rheumatoid factors (RFs), monospecific and polyspecific types can be distinguished. However the molecular basis responsible for their different specificity is not well understood. In a previous report, we have shown that the binding of the majority of the polyspecific antibodies is salt-sensitive. No binding to IgG was observed under high ionic strength (0.3-0.5 M NaCl). This salt-sensitivity was only observed for 18% of the monospecific RFs. Here, we have analyzed 14 RFs representing the 3 different groups (6 salt-insensitive monospecific, 4 salt-sensitive monospecific and 4 salt-sensitive polyspecific RFs). By analysis of the amino acid composition and the distribution of polar and non-polar residues of their heavy chain complementarity-determining region 3 (H-CDR3) in relation to mono/polyspecifieity, salt-sensitivity and reactivity against human IgG subclasses, we have identified common structural features responsible for their different binding properties. Salt-sensitive RFs (mono as well as polyspecific antibodies) were characterized by long H-CDR3′s (15.3 ± 2.7) that contained large numbers of hydrophilic residues such as arginine and serine, while salt-insensitive RFs had more hydrophobic H-CDR3′s of smaller length (11.3 ± 2.4). In addition, for the monospecific RFs, remarkably similar hydrophilicity H-CDR3 profiles were found that were correlated with their specificity for IgG subclasses. These observations confirm the importance of the H-CDR3 for the binding of RFs to IgG. Furthermore, on the basis of their shorter H-CDR3′s and their rather unique H-CDR3 hydrophilicity profiles, it is likely that the majority of the monospecific RFs should be considered as a group of RFs that is independent of the polyspecific RF repertoire.
Background and objectives Interleukin 33 (IL-33) is the most recently discovered member of the IL-1 family of cytokines. Recent evidence in human and mouse suggests a role for IL-33 and its receptor T1/ST2 in arthritis. In this study, the authors quantified IL-33 levels in serum and synovial fluid (SF), and assessed synovial IL-33 expression levels and pattern in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or osteoarthritis (OA). Materials and methods IL-33 and sST2 levels were assessed by ELISA in serum and SF samples of patients with RA (serum, n=11; SF, n=10), PsA (serum, n=9; SF, n=9) and OA (serum, n=9; SF, n=7). IL-33 mRNA expression levels were quantified by RT-qPCR in synovial biopsies obtained from patients with RA (n=10), PsA (n=10), and OA (n=8). IL-33 protein expression pattern was examined by immunohistochemistry (IHC) in synovial tissue from patients with RA (n=8), PsA (n=7) and OA (n=4). Results Serum and SF IL-33 levels tended to be higher in RA than in OA patients, and serum IL-33 concentrations were significantly higher in RA than in PsA. Interestingly, IL-33 was not detectable in any of the PsA samples tested. In matched serum-SF samples of RA patients (n=10), the authors observed comparable concentrations of IL-33 in SF and in serum. There was a wide variation of synovial tissue IL-33 mRNA levels within each disease group. IL-33 mRNA levels were not significantly different between the groups and a similar IL-33 protein expression pattern was observed by IHC in RA, PsA and OA synovium. In all pathologies, strong nuclear expression of IL-33 was observed in endothelial cells. In addition, IL-33 expression was observed in a subset of RA, PsA and OA patients in the nucleus of cells morphologically consistent with synovial fibroblasts. Conclusions This study confirms increased circulating IL-33 levels in RA. In addition, the authors report that IL-33 is undetectable in the serum or SF of PsA patients. Local expression of IL-33 in the synovium was observed at similar variable levels in RA, PsA and OA, suggesting that inflamed joints do not represent the primary source of elevated serum and SF levels of IL-33 in RA.
Interleukin 33 (IL-33) is the most recently discovered member of the IL-1 family of cytokines. Recent evidence in human and mouse suggests a role for IL-33 and its receptor T1/ST2 in arthritis. In this study, the authors quantified IL-33 levels in serum and synovial fluid (SF), and assessed synovial IL-33 expression levels and pattern in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) or osteoarthritis (OA).
Materials and methods
IL-33 and sST2 levels were assessed by ELISA in serum and SF samples of patients with RA (serum, n=11; SF, n=10), PsA (serum, n=9; SF, n=9) and OA (serum, n=9; SF, n=7). IL-33 mRNA expression levels were quantified by RT-qPCR in synovial biopsies obtained from patients with RA (n=10), PsA (n=10), and OA (n=8). IL-33 protein expression pattern was examined by immunohistochemistry (IHC) in synovial tissue from patients with RA (n=8), PsA (n=7) and OA (n=4).
Results
Serum and SF IL-33 levels tended to be higher in RA than in OA patients, and serum IL-33 concentrations were significantly higher in RA than in PsA. Interestingly, IL-33 was not detectable in any of the PsA samples tested. In matched serum-SF samples of RA patients (n=10), the authors observed comparable concentrations of IL-33 in SF and in serum. There was a wide variation of synovial tissue IL-33 mRNA levels within each disease group. IL-33 mRNA levels were not significantly different between the groups and a similar IL-33 protein expression pattern was observed by IHC in RA, PsA and OA synovium. In all pathologies, strong nuclear expression of IL-33 was observed in endothelial cells. In addition, IL-33 expression was observed in a subset of RA, PsA and OA patients in the nucleus of cells morphologically consistent with synovial fibroblasts.
Conclusions
This study confirms increased circulating IL-33 levels in RA. In addition, the authors report that IL-33 is undetectable in the serum or SF of PsA patients. Local expression of IL-33 in the synovium was observed at similar variable levels in RA, PsA and OA, suggesting that inflamed joints do not represent the primary source of elevated serum and SF levels of IL-33 in RA.
