Proinflammatory phenotype of B10 and B10pro cells elicited by TNF-α in rheumatoid arthritis.

OBJECTIVES: B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases. METHODS: The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α-/- and B cell-specific SHIP-1-/- mouse disease model studies. RESULTS: TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α-/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells. CONCLUSIONS: TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.

Combination of scavenger receptor-A with anti-cyclic citrullinated peptide antibody for the diagnosis of rheumatoid arthritis.

OBJECTIVES: The routine biomarkers for rheumatoid arthritis (RA), including anticyclic citrullinated peptide antibody (anti-CCP), rheumatoid factor (RF), immunoglobulin M (IgM), erythrocyte sedimentation rate (ESR), and C-reaction protein (CRP) have limited sensitivity and specificity. Scavenger receptor-A (SR-A) is a novel RA biomarker identified by our group recently, especially for seronegative RA. Here, we performed a large-scale multicentre study to further assess the diagnostic value of SR-A in combination with other biomarkers for RA. METHODS: The performance of SR-A in combination with other biomarkers for RA diagnosis was first revealed by a pilot study, and was further elucidated by a large-scale multicentre study. A total of 1129 individuals from 3 cohorts were recruited in the study, including RA patients, healthy controls, and patients with other common rheumatic diseases. Diagnostic properties were evaluated by the covariate-adjusted receiver-operating characteristic (AROC) curve, sensitivity, specificity and clinical association, respectively. RESULTS: Large-scale multicentre analysis showed that SR-A and anti-CCP dual combination was the optimal method for RA diagnosis, increasing the sensitivity of anti-CCP by 13% (87% vs 74%) while maintaining a specificity of 90%. In early RA patients, SR-A and anti-CCP dual combination also showed promising diagnostic value, increasing the sensitivity of anti-CCP by 7% (79% vs 72%) while maintaining a specificity of 94%. Moreover, SR-A and anti-CCP dual combination was correlated with ESR, IgM, and autoantibodies of RA patients, further revealing its clinical significance. CONCLUSION: SR-A and anti-CCP dual combination could potentially improve early diagnosis of RA, thus improving the prognosis and reducing mortality.

Profiling analysis of 17ß-estradiol-regulated lncRNAs in mouse thymic epithelial cells.

Thymus is the primary organ for T cell differentiation and maturation. Many studies have demonstrated that estrogen plays a crucial role in thymic epithelial cell (TEC) proliferation during thymic involution. LncRNAs are involved in various biological processes; however, estrogen-mediated lncRNA expression in TECs has not been yet reported. To address this question, the mouse medullary thymic epithelial cell line 1 (MTEC1) was treated with 17ß-estradiol (E2). By using CCK8 assay and flow cytometry, we found that E2 was able to inhibit viability and proliferation of MTEC1 cells. The expression profiles of lncRNAs in MTEC1 cells with or without E2 treatment were then measured by RNA-Seq, and a total of 962 lncRNAs and 2,469 mRNAs were shown to be differentially expressed. The reliability of RNA-Seq was confirmed by quantitative RT-PCR. Correlation analysis was conducted to investigate the potential function of lncRNAs. According to gene ontology (GO) analysis, differentially expressed lncRNAs were mainly related to cell proliferation, cell cycle and cell apoptosis. KEGG pathway analysis indicated that these lncRNAs were associated with several pathways, namely immunological activity, metabolism and cytokine-cytokine receptor interaction. In conclusion, our study provided a novel direction for studying the relationship between lncRNAs and E2 in the thymus.

Electrical and Physical Characteristics of WO3/Ag/WO3 Sandwich Structure Fabricated with Magnetic-Control Sputtering Metrology †.

In this work, three layers of transparent conductive films of WO3/Ag/WO3 (WAW) were deposited on a glass substrate by radio frequency (RF) magnetron sputtering. The thicknesses of WO3 (around 50~60 nm) and Ag (10~20 nm) films were mainly the changeable factors to achieve the optimal transparent conductivity attempting to replace the indium tin oxide (ITO) in cost consideration. The prepared films were cardinally subjected to physical and electrical characteristic analyses by means of X-ray diffraction analysis (XRD), field-emission scanning electron microscope (FE-SEM), and Keithley 4200 semiconductor parameter analyzer. The experimental results show as the thickness of the Ag layer increases from 10 nm to 20 nm, the resistance becomes smaller. While the thickness of the WO3 layer increases from 50 nm to 60 nm, its electrical resistance becomes larger.

Soluble CD24 is an inflammatory biomarker in early and seronegative rheumatoid arthritis.

Introduction: Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease characterized by autoantibody production, joint inflammation and bone destruction. Nearly 1/3 of RA patients with the active disease also exhibit a normal range of ESR and CRP. Here we assessed the performance and clinical significance of soluble CD24 (sCD24) as a biomarker of disease activity in RA.Methods: A total of 269 RA patients, 59 primary Sjogren's syndrome (SS) patients, 81 systematic lupus erythematosus (SLE) patients, 76 osteoarthritis (OA) patients and 97 healthy individuals (HC) were included in this study. Soluble CD24 in sera were detected by ELISA. Therefore, the concentration of sCD24 was analyzed in RA patients with different disease activity statuses.Results: The sCD24 was significantly increased in RA (2970 pg/mL), compared to other rheumatic diseases (380-520 pg/mL) and healthy individuals (320 pg/mL). Moreover, sCD24 was elevated in 66.67% of early RA and 61.11% of seronegative RA patients. In addition, sCD24 was significantly correlated with the disease duration and inflammatory indicators.Conclusion: The sCD24 could be an inflammatory biomarker in RA patients, especially in early and seronegative patients.

B cell subsets in adult-onset Still's disease: potential candidates for disease pathogenesis and immunophenotyping.

BACKGROUND: Adult-onset Still's disease (AOSD) is a systemic autoinflammatory disorder of unknown etiology. B cells are critical participants in different rheumatic diseases, and their roles in AOSD are rarely investigated. This study aimed to unveil the B cell subset features in AOSD and provide evidence for B cell-based diagnosis and targeted therapies of AOSD. METHODS: B cell subsets in the peripheral blood of AOSD patients and healthy controls (HCs) were detected by flow cytometry. Firstly, the frequencies of B cell subsets were compared. Then, the correlation analysis was performed to explore the correlation between B cell subsets and clinical manifestations in AOSD. Finally, unbiased hierarchical clustering was performed to divide AOSD patients into three groups with different B cell subset features, and the clinical characteristics of the three groups were compared. RESULTS: The frequencies of B cell subsets were altered in AOSD patients. Disease-promoting subsets (such as naïve B cells, double negative B cells (DN B cells), and plasmablasts) increased, and potential regulatory subsets (such as unswitched memory B cells (UM B cells) and CD24hiCD27+ B cells (B10 cells)) decreased in the peripheral blood of AOSD patients. In addition, the altered B cell subsets in AOSD correlated with the clinical and immunological features, such as immune cells, coagulation features, and liver enzymes. Intriguingly, AOSD patients could be divided into three groups with distinct B cell immunophenotyping: group 1 (naïve B cells-dominant), group 2 (CD27+ memory B cells-dominant), and group 3 (precursors of autoantibody-producing plasma cells-dominant). Moreover, these three group patients demonstrated differential manifestations, including immune cells, liver or myocardial enzymes, coagulation features, and systemic score. CONCLUSIONS: B cell subsets are significantly altered in AOSD patients, potentially contributing to the disease pathogenesis. These findings would inspire B cell-based diagnosis and targeted therapies for this refractory disease.

Graphene Nanosheet-Wrapped Mesoporous La0.8Ce0.2Fe0.5Mn0.5O3 Perovskite Oxide Composite for Improved Oxygen Reaction Electro-Kinetics and Li-O2 Battery Application.

A novel design and synthesis methodology is the most important consideration in the development of a superior electrocatalyst for improving the kinetics of oxygen electrode reactions, such as the oxygen reduction reaction (ORR) and the oxygen evolution reaction (OER) in Li-O2 battery application. Herein, we demonstrate a glycine-assisted hydrothermal and probe sonication method for the synthesis of a mesoporous spherical La0.8Ce0.2Fe0.5Mn0.5O3 perovskite particle and embedded graphene nanosheet (LCFM(8255)-gly/GNS) composite and evaluate its bifunctional ORR/OER kinetics in Li-O2 battery application. The physicochemical characterization confirms that the as-formed LCFM(8255)-gly perovskite catalyst has a highly crystalline structure and mesoporous morphology with a large specific surface area. The LCFM(8255)-gly/GNS composite hybrid structure exhibits an improved onset potential and high current density toward ORR/OER in both aqueous and non-aqueous electrolytes. The LCFM(8255)-gly/GNS composite cathode (ca. 8475 mAh g-1) delivers a higher discharge capacity than the La0.5Ce0.5Fe0.5Mn0.5O3-gly/GNS cathode (ca. 5796 mAh g-1) in a Li-O2 battery at a current density of 100 mA g-1. Our results revealed that the composite's high electrochemical activity comes from the synergism of highly abundant oxygen vacancies and redox-active sites due to the Ce and Fe dopant in LaMnO3 and the excellent charge transfer characteristics of the graphene materials. The as-developed cathode catalyst performed appreciable cycle stability up to 55 cycles at a limited capacity of 1000 mAh g-1 based on conventional glass fiber separators.