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Purpose: The goal of this study was to develop an imaging probe—IRDye-680RD-OX40 mAb—that can be used for noninvasive imaging and optical imaging of rheumatoid arthritis (RA). OX40/OX40 ligand (OX40L) interactions have been shown to exert potent costimulatory effects on T cell activation. Detectable change in T cell activation profiles was observed in early RA. Methods: OX40 expression pattern was analyzed by flow cytometry. N-hydroxysuccinimide (NHS) esters are used to label proteins selectively on free amino groups of OX40 monoclonal antibody (mAb). Characterization of IRDye-680RD-OX40 mAb was measured and a fluorescence spectrum gathered. Cell binding assay was also performed between activated and naïve murine T cells. Longitudinal near-infrared fluorescence (NIRF) imaging of the probe was performed on day 8, day 9, day 10, and day 11 of adjuvant-induced arthritis (AIA) mouse model. Paw thickness and body weight were compared between the OX40 mAb and IgG injection groups. Results: NIRF imaging with IRDye-680RD-OX40 mAb revealed strong OX40-positive responses with high specificity. Flow analysis showed that OX40 was specifically expressed on the surface of T cells in RP and spleen of AIA model. The AIA group was significantly differentiated from the control group at all time points with imaging monitoring. The region of interest (ROI) was in line with ex vivo imaging and biodistribution study. This study highlights the potential utility of the OX40 NIRF imaging as a new strategy for RA prediction and T cell monitoring. Conclusion: The results provide evidence that IRDye-680RD-OX40 mAb detects organized T cells activation in early RA. The optical probe was capable of detection of RA pathogenesis. It identified transcriptional responses to RA that mediate its immune functions. Thus, it may be an ideal probe for RA imaging. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) is one kind of important epigenetic modification pattern which is extensively involved in immune regulation. The development and progression of autoimmune diseases are closely related to immune dysregulation. Considering that rheumatoid arthritis (RA) is a typical autoimmune disease, the m6A process might be one of the important regulatory mechanisms in the pathogenesis of RA. In this study, we identified five differentially expressed m6A regulators in normal and RA samples from the GEO database. With these five regulators, we constructed the nomogram, and it could accurately identify the risk of RA morbidity. Next, we identified 121 differentially expressed genes (DEGs) between normal and RA samples, of which 36 DEGs were co-expressed with these five m6A regulators. We noted that these DEGs were highly enriched in multiple immunoregulatory signaling pathways, such as cytokine-mediated immune cell chemotaxis, adhesion, and activation. To further characterize the heterogeneity of immunological features, we clustered the RA samples into two subtypes. The C2 subtype has higher infiltration levels of pro-inflammatory cells and activity of pro-inflammatory signaling pathways. Thus, the inflammatory response might be more vigorous in the C2 subtype. Next, we constructed the m6Asig system with the SVM machine learning algorithms and least absolute shrinkage and selection operator (LASSO) regression. The m6Asig could accurately distinguish the C1 and C2 subtypes, which indicated that the m6Asig could be a potential biomarker for the inflammatory activity of RA. Finally, by comparing the information from the CellMiner, TTD, and DrugBank databases, we determined 25 drugs. The targets of these drugs were positively correlated with m6Asig. To be clarified, the above findings were derived from bioinformatics and statistical analyses, and further experimental validation still requires. In summary, this study further revealed the m6A and immunoregulation mechanisms in RA pathogenesis. Also, the m6Asig could be a novel biomarker with potential applicability in the clinical management of RA. [ABSTRACT FROM AUTHOR]

Ultrasound can be used to objectively diagnose and evaluate disease activity in patients with rheumatoid arthritis (RA). We aimed to determine the value of a new automated hand ultrasound (AHUS) scanning device and a simplified 3-joint ultrasound scoring system (US3) in detecting synovitis in RA. We compared AHUS and traditional ultrasound (US) scanning in detecting synovial hyperplasia (SH), joint effusion, bone erosion and power Doppler (PD) synovitis in 49 patients. In addition, we compared the value of US3 (in which 3 proximal interphalangeal [PIP] and/or metacarpophalangeal [MCP] joints with the highest scores for swelling and tenderness were evaluated) with the 22-joint ultrasound scoring system (US22) in 26 patients. Almost perfect κ coefficients (0.86-0.937) were obtained between AHUS and traditional US in detecting SH, joint effusion, bone erosion and PD synovitis (p < 0.001). The intra-class correlation coefficient (ICC) between AHUS and traditional US was 0.955-0.995. Of the US3 findings in AHUS, SH synovitis and PD synovitis were positively correlated with DAS28-CRP (adjusted R2 = 0.421, p < 0.0001; adjusted R2 = 0.365, p < 0.0001). US3 was highly correlated with US22 in detecting SH and PD synovitis (R = 0.792, p < 0.01; R = 0.948, p < 0.01). Compared with US22, a more significant correlation was identified between US3 scores and most clinical and laboratory values. In conclusion, AHUS performed comparably to traditional US in detecting synovitis in RA, and US3 was highly consistent with US22 in assessing synovitis and was positively correlated with RA disease activity. [ABSTRACT FROM AUTHOR]

Irisin is a hormone-like factor secreted by muscle cells and produced by cleavage of the membrane protein fibronectin type III domain protein 5 (FNDC5), which exerts anti-inflammatory and anti-proliferative effects. However, the effects and the underlying mechanisms of irisin in rheumatoid arthritis (RA) are still unclear. Collagen-induced arthritis (CIA) model was induced in DBA/1 mice and then treated with irisin. Arthritis index, paw thickness, weight, number of affected paws, serum inflammatory factors and related pathological tests were measured. RA fibroblast-like synoviocytes (RA-FLSs) were pretreated with IL-1β and irisin, and the migration, proliferation, invasion, oxidative stress and mitochondrial related function of RA-FLSs were detected. Irisin significantly improved arthritis symptoms in CIA mice, as indicated by reduced arthritis index, alleviated paw thickness, decreased the number of affected paws and inhibited release of inflammatory factors. Irisin alleviated joint destruction, FLSs proliferation and the expression of YES-associated protein (YAP) and mitochondrial dynamic related protein 1 (Drp1) in the FLSs of CIA mice. In vitro experiment, irisin inhibited the proliferation, migration and invasion of RA-FLSs and improved oxidative stress induced by IL-1β, thereby restraining the pathogenic transformation of RA-FLSs. Mechanically, irisin suppressed the nuclear translocation of YAP, in turn, could reduce the synthesis of Drp1 protein and inhibit the mitochondrial fission of RA-FLSs, which was reversed by YAP agonists. Therefore, irisin has a protective effect on RA. Irisin inhibits the proliferation, migration, invasion and inflammatory response of RA-FLSs by inhibiting the YAP-Drp1 signaling pathway, which implies a potential therapeutic effect on RA. [ABSTRACT FROM AUTHOR]