Association between levels of synovial anti-citrullinated peptide antibodies and neutrophil response in patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by the presence of anti-citrullinated peptide antibodies (ACPAs) and neutrophils infiltrating the synovial fluid (SF) of the affected joints. The aim of this work was to analyze whether the presence of ACPAs in SF is associated with neutrophil infiltration and with their phenotype in the inflamed joints of RA patients. We found that in the presence of ACPAs, the number of synovial neutrophils correlated with severe disease activity. The SF were divided according to synovial ACPA levels in negative- (<25 U/mL), low- (25-200 U/mL) and high level (˃200 U/mL; ACPAhigh ). We observed that IL-6, IL-17, and IL-8 were significantly elevated in ACPAhigh SF and that IL-8 levels correlated positively with neutrophil counts and with worse clinical manifestations. Additionally, in vitro incubation of neutrophils with ACPAhigh SF resulted in an increased ROS production and extracellular DNA release compared to neutrophils incubated with ACPA-negative SF. These exacerbated effector functions were associated with a fraction of ICAM-1-positive neutrophils, which were induced by ACPAhigh SF. Likewise, in in vivo, we could also detect this subset among neutrophils present in ACPAhigh SF. In conclusion, the data presented here shed light on the role of SF-ACPAs as inductors of a proinflammatory profile in neutrophils.

Association between IL-17 and IgA in the joints of patients with inflammatory arthropathies.

BACKGROUND: Hyperactive secretion and pathogenic effects of interleukin (IL)-17 and IgA have been detected in different arthropathies. Recent evidence has revealed that TH17 cytokines regulate mucosal IgA secretion. However, it is unknown whether and how IL-17 mediates synovial IgA production. Here we aim to investigate the connection of synovial IL-17 with IgA production in the joint. In this study we included synovial fluids (SF) from patients with rheumatoid arthritis (RA; n = 66), spondyloarthritis (SpA; n = 18) and osteoarthritis (OA; n = 36). The levels of IL-17, IL-6, transforming growth factor (TGF)-ß1, B-cell-activating factor of the TNF family (BAFF) and anti-lipopolyssacharide (LPS) immunoglobulin (Ig)A were investigated by enzyme-linked immunosorbent assay (ELISA). Total IgA was measured by radial immunodiffusion assay. Synovial fluid-derived mononuclear cells (SFMC) were stimulated with bacterial antigens or SF-conditioned media, and cytokines and IgA were analyzed in the supernatants. RESULTS: IL-17, IL-6 and TGF-ß1 were increased in SF from both RA and SpA compared with OA patients. Concentration of IL-17 correlated with the disease activity score (DAS)-28, IL-6 and anti-LPS IgA levels. Bacterial-stimulated SFMCs from RA and SpA patients secreted higher IL-17 than vehicle-stimulated SFMCs. Conditioned media with SF containing IL-17 induced anti-LPS IgA production by SFMCs which was independent of IL-6 activity. Concentrations of synovial TGF-ß1 and BAFF correlated with anti-LPS and total IgA levels, respectively. Blockade of IL-17 decreased the production of TGF-ß1 and anti-LPS IgA by SF-stimulated SFMCs. CONCLUSIONS: This study reports a connection between IL-17 and IgA secretion in the joint. In addition, it demonstrates that enterobacterial antigens trigger synovial IL-17 production, and that TGF-ß1 and BAFF may mediate the effect of IL-17 on IgA production. This circuit may contribute to the pathogenesis of inflammatory joint diseases.

Histological and mast cells evaluation after application of botulinum toxin type a in masseter muscles of rats.

Background: Botulinum Toxin Type A (BTX-A) has been largely used to reduce muscle strength of masseter and temporal muscles by producing a temporary weakening of their activity. This study aimed to evaluate the histological changes and the number of mast cells after the injection of BTX-A. Material and Methods: In the masseter muscle of rats in the periods of 1, 7, 15, and 30 days. These muscles were stained with hematoxylin and eosin (H&E) and toluidine blue (TBO). The presence or absence of an inflammatory process and necrosis were analyzed by H&E in all area of the slide at 10X magnification. The number of mast cells was evaluated by counting 10 "hotspots" in the intra-muscular region on TBO-stained slides, 400X magnification. Statistical analysis was performed through two-way analysis of variance and Tukey's test. Results: As a result, the inflammatory process and necrosis were not observed in any periods studied in both groups Regarding mast cells, there was no statistically significant increase in their quantity in the study group when compared to the control group in the evaluation periods of 7 days and 15 days. However, these mast cells increased significantly during the periods of 1 and 30 days. Conclusions: This study showed that even in the absence of an inflammatory process, there was an increase in the number of mast cells in the first 24 hours after the application of BTX-A, with a subsequent balance between the numbers of mast cells at 7 and 15 days, and again an increase after 30 days. Key words:Botulinum toxins type A, mast cells, masseter muscle.

S100A8 alarmin supports IL-6 and metalloproteinase-9 production by fibroblasts in the synovial microenvironment of peripheral spondyloarthritis.

Introduction: Spondyloarthritis (SpA) is a common autoinflammatory disease. S100A8/ S100A9 alarmin is strongly expressed in the synovial sublining layers of psoriatic arthritis. S100A8/ S100A9 is the most abundant protein in rheumatoid arthritis synovial fluid (SF) and has a key role in promoting IL-6 expression in fibroblast-like synoviocytes (FLS). The molecular mechanisms and the role of S100-alarmins in the synovial microenvironment of SpA have never been demonstrated. Methods and Results: Here, we confirm the effect of the synovial microenvironment of peripheral SpA on interleukin-6 (IL-6) and metalloproteinase (MMP)-9 production by FLS. MMP-9 expression and activity were detected, which were reduced in the presence of anti-IL-6R. Analyzing cell signaling mechanisms, we found that stimulation with IL-6 co-triggered MMP-9 and IL-10 secretion. MMP-9 secretion depended on JNK and p38 MAPKs, whereas IL-10 secretion was dependent on the JAK pathway as a potential feedback mechanism controlling IL-6-induced MMP-9 expression. Using a proteomic approach, we identified S100A8 in the peripheral SpA SF. This presence was confirmed by immunoblotting. S100A8 increased the IL-6 secretion via ERK and p38 MAPK pathways. Furthermore, anti-S100A8/A9 reduced both IL-6 and MMP-9 production induced by SpA SF in FLS. Discussion: Our data reveal a marked relationship between S100A8 alarmin with IL-6 and MMP-9 secretion by FLS in the real synovial microenvironment of peripheral SpA. These results identify a mechanism linking S100A8 to the pathogenesis of peripheral SpA.

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