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Objective: Accumulating evidence suggests that differentially expressed circular RNAs (circRNAs) play critical roles in immune cells of systemic lupus erythematosus (SLE) patients. Hsa_circ_0000479 has been studied in the field of cancer and infection, whereas seldom studied in autoimmune diseases. The aim of this study was to investigate the role and clinical value of neutrophil hsa_ circ_0000479 in SLE. Methods: The expression levels of hsa_circ_0000479 in both healthy individuals and SLE patients' neutrophils were detected by qPCR and compared with those in peripheral blood mononuclear cells (PBMCs). In addition, the correlation of hsa_circ_0000479 levels in neutrophils with the clinical and immunological features of SLE patients was also analysed. Results: The expression levels of hsa_circ_0000479 in the patients with SLE were significantly higher in neutrophils than that of PBMCs, and also significantly higher than that in healthy controls (HCs). Moreover, the expression levels of hsa_circ_0000479 in neutrophils were negatively associated with absolute neutrophil count and complement 3 (C3), whereas positively correlated with anti-dsDNA and anti-nucleosome antibodies in SLE. In addition, SLE patients with higher levels of hsa_circ_0000479 demonstrated more several clinical manifestations, including Raynaud's phenomenon, alopecia and leucopenia. Conclusions: Hsa_circ_0000479 is up-regulated in neutrophils of SLE patients, and is also associated with several important laboratory indicators and clinical manifestations, suggesting that hsa_circ_0000479 in neutrophils was one of probable factors involved in the pathogenesis of SLE with potential clinical value. [ABSTRACT FROM AUTHOR]

Background: The roles that CD16+ monocyte subset plays in T-cell activation and B-cell response have not been well studied in systemic lupus erythematosus (SLE). Objective: The present study aimed to investigate the distribution of CD16+ monocyte subsets in SLE and explore their possible roles in T-cell activation and B-cell differentiation. Methods: The frequencies of monocyte subsets in the peripheral blood of healthy controls (HCs) and patients with SLE were determined by flow cytometry. Monocyte subsets were sorted and cocultured with CD4+ T cells and CD19+ B cells. Then, T and B cells were collected for different subset detection, while the supernatants were collected for immunoglobulin G, IgA, and IgM or interferon-γ and interleukin-17A detection by enzyme-linked immunosorbent assay. results: Our results showed that CD16+ monocytes exhibited a proinfammatory phenotype with elevated CD80, CD86, HLA-DR, and CX3CR1 expression on the cell surface. It's further demonstrated that CD16+ monocytes from patients and HCs shared different cell-surface marker profles. The CD16+ subset was enriched in SLE and had an exacerbated capacity to promote CD4+ T cell polarization into a Th17 phenotype. Also, CD16+ monocytes had enhanced impacts on CD19+ B cells to differentiate into plasma B cells and regulatory B cells with more Ig production. conclusion: This study demonstrated that CD16+ monocytes, characterized by different cell-surface marker profiles, were enriched and played a critical role in driving the pathogenic T- and B-cell responses in patients with SLE. [ABSTRACT FROM AUTHOR]

Objectives: Although myeloid-derived suppressor cells (MDSCs) have been linked to T cell tolerance, their role in autoimmune rheumatoid arthritis (RA) remains elusive. Here we investigate the potential association of MDSCs with the disease pathogenesis using a preclinical model of RA and specimen collected from patients with RA.Methods: The frequency of MDSCs in blood, lymphoid tissues, inflamed paws or synovial fluid and their association with disease severity, tissue inflammation and the levels of pathogenic T helper (Th) 17 cells were examined in arthritic mice or in patients with RA (n=35) and osteoarthritis (n=15). The MDSCs in arthritic mice were also characterised for their phenotype, inflammation status, T cell suppressive activity and their capacity of pro-Th17 cell differentiation. The involvement of MDSCs in the disease pathology and a Th17 response was examined by adoptive transfer or antibody depletion of MDSCs in arthritic mice or by coculturing mouse or human MDSCs with naïve CD4+ T cells under Th17-polarising conditions.Results: MDSCs significantly expanded in arthritic mice and in patients with RA, which correlated positively with disease severity and an inflammatory Th17 response. While displaying T cell suppressive activity, MDSCs from arthritic mice produced high levels of inflammatory cytokines (eg, interleukin (IL)-1β, TNF-α). Mouse and human MDSCs promoted Th17 cell polarisation ex vivo. Transfer of MDSCs facilitated disease progression, whereas their elimination in arthritic mice ameliorated disease symptoms concomitant with reduction of IL-17A/Th17 cells.Conclusions: Our studies suggest that proinflammatory MDSCs with their capacity to drive Th17 cell differentiation may be a critical pathogenic factor in autoimmune arthritis. [ABSTRACT FROM AUTHOR]

Background: Recently, our research group identified the non-deleted (functional) leucocyte immunoglobulin-like receptor A3 (LILRA3) as a new genetic risk for rheumatoid arthritis.Objectives: To further investigate whether the functional LILRA3 is a new susceptibility factor for other autoimmune diseases-for example, systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS).Methods: The LILRA3 deletion polymorphism and its tagging single nucleotide polymorphism rs103294 were genotyped for 1099 patients with SLE, 403 patients with pSS and 2169 healthy controls. Association analyses were performed in whole dataset or clinical/serological subsets. The impact of LILRA3 on SLE activity and LILRA3 expression was evaluated.Results: The functional LILRA3 conferred high susceptibility to both SLE (p=3.51×10(-7), OR=2.03) and pSS (p=1.40×10(-3), OR=2.32). It was associated with almost all the clinical/serological features in SLE, especially with leucopenia (p=4.09×10(-7), OR=2.19) and thrombocytopenia (p=1.68×10(-5), OR=1.70). In pSS, functional LILRA3 was specifically associated with leucopenia (p=4.39×10(-4), OR=3.25), anti-Ro/SSA-positive subphenotypes (p=4.54×10(-3), OR=2.34) and anti-La/SSB-positive subphenotypes (p=0.012, OR=2.49). Functional LILRA3 conferred higher disease activity in patients with SLE (p=0.044) and higher LILRA3 expression in both SLE (p=5.57×10(-8)) and pSS (p=1.49×10(-7)) than in controls.Conclusions: Functional LILRA3 is a new susceptibility factor for SLE and pSS. It highly predisposes to certain phenotypes such as leucopenia and thrombocytopenia in SLE, and may confer increased disease activity in SLE and a higher risk of leucopenia and autoantibody-positive subphenotypes in pSS. [ABSTRACT FROM AUTHOR]

Objective. To assess the diagnostic value of salivary gland ultrasonography (SGUS) for primary SS (pSS) and to compare the usefulness of two existing SGUS scoring systems. Methods. Ultrasonography examination of major salivary glands was conducted for 105 pSS patients and 41 disease control subjects without SS and 16 healthy control subjects. The imaging features were graded using two different scoring systems (0-16 and 0-48, respectively) obtained from the grades of bilateral parotid and submandibular glands. Receiver operating characteristic curves were used to describe and compare the diagnostic accuracy of the two ultrasonography echostructure scoring systems for pSS. The agreement of diagnosis for pSS between the two scoring systems was determined by /c-statistics. Results. SGUS scores for the pSS group were significantly higher than those for the non-pSS group (P< 0.001). The best score cut-off was 7 in the 0-16 system (80% sensitivity and 93% specificity, respectively), and it was 15 in the 0-48 system (88.6% sensitivity and 84.2% specificity, respectively). Compared with the 0-16 system, combined evaluation of all four glands when using the 0-48 system improved the diagnostic accuracy. Association analysis of both scoring systems showed a positive correlation of SGUS scores with RF and γ-globulin% (P<0.05, overall). Conclusion. SGUS is a feasible method for pSS diagnosis with higher sensitivity using the 0-48 system and better specificity using the 0-16 system. SGUS scores are related to RF and g-globulin%. [ABSTRACT FROM AUTHOR]

Objectives Hyperplasia of synovial fibroblasts, infiltration with lymphocytes and tissue hypoxia are major characteristics of rheumatoid arthritis (RA). Extensive data support a key role for toll-like receptors (TLRs) in RA. Little is known regarding the impact of hypoxia on TLR-induced inflammation in RA. The aim of this study was to reveal the effects of hypoxia and its regulator, hypoxia-inducible factor-1α (HIF-1α), on the inflammatory response of RA synovial fibroblasts (RASF) to TLR ligands. Methods Hypoxia was induced in RASF by incubation with Na2S2O4. TLR3 ligand polyIC, TLR2 ligand peptidoglycan, TLR4 ligand LPS and TLR9 ligand CpG were used to stimulate the cells. Effects of hypoxia on TLR-induced inflammatory mediators were determined by RT-PCR, qPCR and ELISA. Overexpression of HIF-1α as well as knocking-down its expression was used to reveal its fundamental role. RASF-induced inflammatory T cell expansion was determined by flow cytometry analysis of T helper (Th)1/Th17 cells, and IFN-γ/IL-17 production by ELISA after RASF/T cell coculture. Results Hypoxia potentiated the expression of inflammatory cytokines, metalloproteinases and VEGF in RASF stimulated by different TLR ligands, especially polyIC, a synthetic mimic of dsRNA from viruses or apoptotic cells. HIF-1α played a fundamental role in this synergy. Moreover, HIF-1α overexpression enhanced RASF-mediated expansion of inflammatory Th1 and Th17 cells, leading to proinflammatory IFN-γ and IL-17 production. Conclusions Our findings suggest that hypoxia and HIF-1α may function in conjunction with TLR-stimulated innate immune responses to drive inflammation in RA. This pathway may serve as a therapeutic target for the disease. [ABSTRACT FROM AUTHOR]

Objective. To investigate the expression and clinical significance of trans-membrane MerTK (mMer) on circulating CD14+ monocytes/macrophages and soluble MerTK (sMer) levels in plasma in systemic lupus erythematosus (SLE). Method. 108 SLE patients and 42 healthy controls were recruited in this study. The expression of mMer on the surfaces of CD14+ monocytes/macrophages was evaluated by flow cytometry (FCM). The sMer levels were measured by ELISA. Real-time quantitative PCR was applied to evaluate the mRNA levels of MerTK and ADAM17. Results. Both mMer expression on CD14+ monocytes/macrophages and sMer levels in plasma significantly increased in SLE patients compared to healthy subjects. The frequency of anti-inflammatory MerTK expressing CD14+CD16+ monocytes decreased in SLE. mMer expression was positively correlated with CD163 expression on CD14+ cells. Both the mMer expression on CD14+ monocytes/macrophages and sMer levels in plasma were positively correlated with SLEDAI. Furthermore, more elevated mMer and sMer levels were found in patients with higher SLEDAI, presence of anti-SSA, anti-Sm autoantibodies, and lupus nephritis. Conclusion. Both mMer and sMer levels significantly increased in SLE and positively correlated with disease activity and severity. The upregulation of MerTK expression may serve as a biomarker of the disease activity and severity of SLE. [ABSTRACT FROM AUTHOR]

It is well known that B-1 B cells are the main cell type that is responsible for the production of natural immunoglobulin M (IgM) and can respond to infection by increasing IgM secretion. However, we unexpectedly found that some epithelial cells also can express rearranged IgM transcript that has natural IgM characteristics, such as germline-encoded and restricted rearrangement patterns. Here we studied IgM expression in human non-B cells and found that IgM was frequently expressed by many human epithelial cancer cells as well as non-cancer epithelial cells. Moreover, CD79A and CD79B, two molecules that are physically linked to membranous IgM on the surface of B cells to form the B cell antigen receptor complex, were also expressed on the cell surface of epithelial cancer cells and co-located with IgM. Like the natural IgM, the epithelial cancer cell-derived IgM recognized a series of microbial antigens, such as single-stranded DNA, double-stranded DNA, lipopolysaccharide, and the HEp-2 cell antigen. More important, stimulation of the toll-like receptor 9 (TLR9), which mimics bacterial infection, substantially increased the secretion of IgM in human epithelial cancer cells. These findings indicate that human epithelial cancer cells as well as non-cancer epithelial cells can spontaneously produce IgM with natural antibody activity. [ABSTRACT FROM AUTHOR]