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BackgroundThe incidence and mortality of lung cancer are the highest among all cancers. Patients with systemic sclerosis show a four-fold greater risk of lung cancer than the general population. However, the underlying mechanism remains poorly understood.MethodsThe expression profiles of 355 peripheral blood samples were integratedly analyzed, including 70 cases of lung cancer, 61 cases of systemic sclerosis, and 224 healthy controls. After data normalization and cleaning, differentially expressed genes (DEGs) between disease and control were obtained and deeply analyzed by bioinformatics methods. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed online by DAVID and KOBAS. The protein–protein interaction (PPI) networks were constructed from the STRING database.ResultsFrom a total of 14,191 human genes, 299 and 1644 genes were identified as DEGs in systemic sclerosis and lung cancer, respectively. Among them, 64 DEGs were overlapping, including 36 co-upregulated, 10 co-downregulated, and 18 counter-regulated DEGs. Functional and enrichment analysis showed that the two diseases had common changes in immune-related genes. The expression of innate immune response and response to virus-related genes increased significantly, while the expression of negative regulation of cell cycle-related genes decreased notably. In contrast, the expression of mitophagy regulation, chromatin binding and fatty acid metabolism-related genes showed distinct trends.ConclusionsStable differences and similarities between systemic sclerosis and lung cancer were revealed. In peripheral blood, enhanced innate immunity and weakened negative regulation of cell cycle may be the common mechanisms of the two diseases, which may be associated with the high risk of lung cancer in systemic sclerosis patients. On the other hand, the counter-regulated DEGs can be used as novelbiomarkers of pulmonary diseases. In addition, fat metabolism-related DEGs were consideredto be associated with clinical blood lipid data.

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease characterized by the production of multiple autoimmune antibodies and potentially involves any organ or tissue with a broad range of clinical manifestations. Conventional therapy still utilizes glucocorticoids and immunosuppressants. However, some patients show inadequate responses to glucocorticoids and immunosuppression, which may induce secondary immune dysfunction and severe infection as well as lead to an increased tumor risk. The lack of in vitro models has hampered progress in understanding and treating SLE. Patient-derived induced pluripotent stem cells (iPSCs) may provide a unique opportunity for modeling in vitro diseases as well as a platform for drug screening in individual patients. We isolated peripheral blood mononuclear cells from blood to explore the establishment of an in vitro model platform for SLE and directly purified CD34+ cells and seeded them for expansion. CD34+ cells were forced to express seven pluripotency factors, OCT4, SOX2, NANOG, LIN28, c-MYC, KLF4, and SV40LT, through transduction in lentiviral vectors. The morphological characteristics of induced pluripotent stem-like cells, such as prominent nucleoli and a high nucleus-to-cytoplasm ratio, were observed. The pluripotency of established SLE patient-derived iPSCs was confirmed by the expression of embryonic stem cell (ESC) markers and the ability of cells to differentiate into multiple cell lines. SLE patient-derived iPSCs exhibited human ESC properties, including morphology; growth characteristics; expression of pluripotency, genes, and surface markers; and teratoma formation. In conclusion, we generated SLE patient-derived iPSCs and validated their pluripotency. This study is a first but critical step that can provide a model platform for research aimed at understanding the SLE mechanism, which may lead to the discovery of new targets or compounds for the treatment of this disease.

Recent studies have demonstrated a central role for plasma cells in the development of autoimmune diseases, such as systemic lupus erythematosus (SLE). Currently, both the phenotypic features and functional regulation of autoreactive plasma cells during SLE pathogenesis remain largely unclear. In this study, we first found that a major subset of IL-17 receptor-expressing plasma cells potently produced anti-dsDNA IgG upon IL-17A (IL-17) stimulation in SLE patients and lupus mice. Using a humanized lupus mouse model, we showed that the transfer of Th17 cell-depleted PBMCs from lupus patients resulted in a significantly reduced plasma cell response and attenuated renal damage in recipient mice compared to the transfer of total SLE PBMCs. Moreover, long-term BrdU incorporation in lupus mice detected highly enriched long-lived BrdU(+) subsets among IL-17 receptor-expressing plasma cells. Lupus mice deficient in IL-17 or IL-17 receptor C (IL-17RC) exhibited a diminished plasma cell response and reduced autoantibody production with attenuated renal damage, while the adoptive transfer of Th17 cells triggered the plasma cell response and renal damage in IL-17-deficient lupus mice. In reconstituted chimeric mice, IL-17RC deficiency resulted in severely impaired plasma cell generation but showed no obvious effect on germinal center B cells. Further mechanistic studies revealed that IL-17 significantly promoted plasma cell survival via p38-mediated Bcl-xL transcript stabilization. Together, our findings identified a novel function of IL-17 in enhancing plasma cell survival for autoantibody production in lupus pathogenesis, which may provide new therapeutic strategies for the treatment of SLE.

Systemic lupus erythematosus (SLE), an autoimmune disease that causes multiorgan injury, has an unclear etiology and complex pathogenesis. Numerous studies have found abnormal alterations in mRNAs, proteins and/or metabolites in SLE patients. These findings have extended our understanding of the pathogenesis of SLE. Novel omics techniques, such as transcriptome, proteome and metabolome profiling, can identify and quantify large numbers of biomarkers of human diseases. However, in most cases, biological reactions are the consequences of interactions among genes, proteomes, and metabolites. Single biomolecules or signaling pathways cannot fully explain biological traits or functions. Therefore, integrative multi-omics analysis can help us systematically comprehend the intrinsic molecular mechanisms underlying biological function and pathogenesis. Integrating transcriptome, proteome, and metabolome KEGG enrichment analysis data will expand our knowledge of the pathogenesis of SLE. This review discusses the application, research progress and outlook on integrative multi-omics analysis in SLE research.

Yes‐associated protein (YAP) is a component of the canonical Hippo signaling pathway that is known to play essential roles in modulating organ size, development, and tumorigenesis. Activation or upregulation of YAP1, which contributes to cancer cell survival and chemoresistance, has been verified in different types of human cancers. However, the molecular mechanism of YAP1 upregulation in cancer is still unclear. Here we report that the E3 ubiquitin ligase STUB1 ubiquitinates and destabilizes YAP1, thereby inhibiting cancer cell survival. Low levels of STUB1 expression were correlated with increased protein levels of YAP1 in human gastric cancer cell lines and patient samples. Moreover, we revealed that STUB1 ubiquitinates YAP1 at the K280 site by K48‐linked polyubiquitination, which in turn increases YAP1 turnover and promotes cellular chemosensitivity. Overall, our study establishes YAP1 ubiquitination and degradation mediated by the E3 ligase STUB1 as an important regulatory mechanism in gastric cancer, and provides a rationale for potential therapeutic interventions.

Increased numbers of T follicular helper (Tfh) cells have been implicated in the development of autoimmune diseases including primary Sjögren’s syndrome (pSS), but how the Tfh cell response is regulated during autoimmune pathogenesis remains largely unclear. Here, we first found negative correlations between IL-10(+) regulatory B (Breg) cell numbers and Tfh cell responses and disease activity in patients with pSS and mice with experimental Sjögren’s syndrome (ESS). Moreover, we detected high expression of IL-10 receptor on Tfh cells and their precursors in both humans and mice. In culture, IL-10 suppressed human and murine Tfh cell differentiation by promoting STAT5 phosphorylation. By using an adoptive transfer approach and two-photon live imaging, we found significantly increased numbers of Tfh cells with enhanced T cell homing into B cell follicles in the draining cervical lymph nodes of RAG-2−/− mice transferred with IL-10-deficient B cells during ESS development compared with those of RAG-2−/− mice transferred with wild-type B cells. In ESS mice, CD19(+)CD1d(hi)CD5(+) Breg cells with decreased IL-10 production exhibited severely impaired suppressive effects on T cell proliferation. Consistently, CD19(+)CD24(+)CD38(hi) Breg cells from pSS patients showed significantly reduced IL-10 production with defective inhibitory function in the suppression of autologous Tfh cell expansion. Furthermore, the adoptive transfer of IL-10-producing Breg cells markedly suppressed the Tfh cell response and ameliorated ESS progression in ESS mice. Together, these findings demonstrate a critical role for IL-10-producing Breg cells in restraining the effector Tfh cell response during pSS development.

Aim The aim of this paper is to explore the expression of 6-methyladenine (6mA) DNA and to elucidate its gene regulation role in systemic lupus erythematosus (SLE). Methods Twenty SLE patients and 20 normal control healthy individuals (HCs) were included in this study. Genomic DNA was isolated from peripheral blood mononuclear cells and subsequently underwent 6mA-immunoprecipitation-sequencing (6mA-IP-Seq) after DNA quality control and 6mA precipitation. Bioinformation analysis was applied to the raw data comparing 6mA levels between SLE patients and HCs. Results We identified 5462 hypermethylation and 431 hypomethylation genes in PBMCs of individuals with SLE, which indicated that a high level of 6mA participates in the pathogenesis of SLE. Gene ontology analysis revealed that hypermethylation genes might regulate the inflammatory process, which has been well documented in the pathogenesis of SLE. Conclusion 6mA may be involved in the initial development of SLE, which may lead to its potential use as an early diagnostic marker and therapeutic target.

ObjectiveSystemic lupus erythematosus (SLE) is a complex autoimmune disease, and various immune cells are involved in the initiation, progression, and regulation of SLE. Our goal was to reveal the chromatin accessibility landscape of peripheral blood mononuclear cells (PBMCs) in SLE patients at single-cell resolution and identify the transcription factors (TFs) that may drive abnormal immune responses.MethodsThe assay for transposase accessible chromatin in single-cell sequencing (scATAC-seq) method was applied to map the landscape of active regulatory DNA in immune cells from SLE patients at single-cell resolution, followed by clustering, peak annotation and motif analysis of PBMCs in SLE.ResultsPeripheral blood mononuclear cells were robustly clustered based on their types without using antibodies. We identified twenty patterns of TF activation that drive abnormal immune responses in SLE patients. Then, we observed ten genes that were highly associated with SLE pathogenesis by altering T cell activity. Finally, we found 12 key TFs regulating the above six genes (CD83, ELF4, ITPKB, RAB27A, RUNX3, and ZMIZ1) that may be related to SLE disease pathogenesis and were significantly enriched in SLE patients (p 2). With qPCR experiments on CD83, ELF4, RUNX3, and ZMIZ1 in B cells, we observed a significant difference in the expression of genes (ELF4, RUNX3, and ZMIZ1), which were regulated by seven TFs (EWSR1-FLI1, MAF, MAFA, NFIB, NR2C2 (var. 2), TBX4, and TBX5). Meanwhile, the seven TFs showed highly accessible binding sites in SLE patients.ConclusionsThese results confirm the importance of using single-cell sequencing to uncover the real features of immune cells in SLE patients, reveal key TFs in SLE-PBMCs, and provide foundational insights relevant for epigenetic therapy.

Therapeutic proteins have exhibited promising clinical applications in the diagnosis and treatment of some diseases. Prior to the detection of analytes using enzyme-linked immunosorbent assay, biological samples of therapeutic proteins are conventionally frozen at temperatures ranging from − 20 to − 80 °C to increase the stability of analytes. However, therapeutic proteins destabilization and aggregation may occur during the frozen storage or the freeze-thawing step. In this work, an effective method was proposed to freeze-dry therapeutic protein samples to allow subsequent storage or transport of samples without freezing them. This new method was validated with quality control samples of adalimumab and etanercept, and it was also used in the bioanalysis of adalimumab and etanercept in pharmacokinetic (PK) studies. Adalimumab and etanercept were stable for 14 days at 4 °C after being prepared and stored using the new method, with detection that was accurate and repeatable. Studies of adalimumab and etanercept in animals and humans showed that the PK parameters of the analytes stored with the new method were consistent with those of analytes stored using the conventional method. This effective method will be attractive for facilitating the storage and transport of plasma samples containing therapeutic proteins.

The Janus kinases (JAKs) are intracellular tyrosine kinases involved in a broad variety of inflammatory cascades participating in the pathogenesis of systemic lupus erythematosus (SLE). Diffuse non-scarring alopecia is one of the most frequent cutaneous manifestations in SLE, resulting in devastating psychosocial consequences. Although recent studies have shown promising outcomes of the JAK inhibitors in SLE treatment, the efficacy of tofacitinib in diffuse non-scarring alopecia due to SLE has never been reported. Here we present a 29-year-old SLE patient with a 10-year history of refractory severe diffuse non-scarring alopecia who experienced dramatic hair regrowth with tofacitinib. Furthermore, we have made a systematic review regarding the potential effectiveness of tofacitinib in systemic and cutaneous lupus erythematosus. To the best of our knowledge, this is the first case study depicting an SLE patient with refractory alopecia who experienced impressive hair regrowth with the JAK1/3 inhibitor tofacitinib therapy, which contributes to expanding the field of possible uses of tofacitinib in SLE patients with difficult-to-treat cutaneous involvement, including severe alopecia.

Systemic lupus erythematosus (SLE) is a heterogeneous, autoimmune disease that can affect multiple organs and systems such as skin, joints, kidneys, hematologic system or central nervous system. Women of childbearing age are the predominate population affected by SLE. In this study, we generated an iPS cell line from a 30-year-old female who was pregnant with a gestational age of 27 weeks and diagnosed with severe preeclampsia, SLE and psoriasis. This patient-specific iPSC line will be useful to create the specific disease model of systemic lupus erythematosus to elucidate the pathological mechanisms and develop drug screening.

ObjectivePrimary Sjögren’s syndrome (pSS) is a systemic autoimmune disease, and its pathogenetic mechanism is far from being understood. In this study, we aimed to explore the cellular and molecular mechanisms that lead to pathogenesis of this disease.MethodsWe applied single-cell RNA sequencing (scRNA-seq) to 57,288 peripheral blood mononuclear cells (PBMCs) from five patients with pSS and five healthy controls. The immune cell subsets and susceptibility genes involved in the pathogenesis of pSS were analyzed. Flow cytometry was preformed to verify the result of scRNA-seq.ResultsWe identified two subpopulations significantly expand in pSS patients. The one highly expressing cytotoxicity genes is named as CD4+ CTLs cytotoxic T lymphocyte, and another highly expressing T cell receptor (TCR) variable gene is named as CD4+ TRAV13-2+ T cell. Flow cytometry results showed the percentages of CD4+ CTLs, which were profiled with CD4+ and GZMB+ staining; the total T cells of 10 patients with pSS were significantly higher than those of 10 healthy controls (P= 0.008). The expression level of IL-1β in macrophages, TCL1A in B cells, as well as interferon (IFN) response genes in most cell subsets was upregulated in the patients with pSS. Susceptibility genes including HLA-DRB5, CTLA4, and AQP3 were highly expressed in patients with pSS.ConclusionsOur data revealed disease-specific immune cell subsets and provided some potential new targets of pSS. Specific expansion of CD4+ CTLs may be involved in the pathogenesis of pSS, which might give valuable insights for therapeutic interventions of pSS.

Objectives This study aims to determine a role of interleukin‐17A (IL‐17) in salivary gland (SG) dysfunction and therapeutic effects of targeting IL‐17 in SG for treating autoimmune sialadenitis in primary Sjögren’s syndrome (pSS). Methods Salivary IL‐17 levels and IL‐17‐secreting cells in labial glands of pSS patients were examined. Kinetic changes of IL‐17‐producing cells in SG from mice with experimental Sjögren’s syndrome (ESS) were analysed. To determine a role of IL‐17 in salivary secretion, IL‐17‐deficient mice and constructed chimeric mice with IL‐17 receptor C (IL‐17RC) deficiency in non‐hematopoietic and hematopoietic cells were examined for saliva flow rates during ESS development. Both human and murine primary SG epithelial cells were treated with IL‐17 for measuring cholinergic activation‐induced calcium movement. Moreover, SG functions were assessed in ESS mice with salivary retrograde cannulation of IL‐17 neutralisation antibodies. Results Increased salivary IL‐17 levels were negatively correlated with saliva flow rates in pSS patients. Both IL‐17‐deficient mice and chimeric mice with non‐hematopoietic cell‐restricted IL‐17RC deficiency exhibited no obvious salivary reduction while chimeric mice with hematopoietic cell‐restricted IL‐17RC deficiency showed significantly decreased saliva secretion during ESS development. In SG epithelial cells, IL‐17 inhibited acetylcholine‐induced calcium movement and downregulated the expression of transient receptor potential canonical 1 via promoting Nfkbiz mRNA stabilisation. Moreover, local IL‐17 neutralisation in SG markedly attenuated hyposalivation and ameliorated tissue inflammation in ESS mice. Conclusion These findings identify a novel function of IL‐17 in driving salivary dysfunction during pSS development and may provide a new therapeutic strategy for targeting SG dysfunction in pSS patients., In this study, we found that increased salivary IL‐17 levels were negatively correlated with saliva flow rates in patients with primary Sjögren’s syndrome (pSS). We further identified a novel function of IL‐17 in driving salivary dysfunction by impairing transient receptor potential canonical 1‐mediated calcium movement during pSS pathogenesis. This pre‐clinical study demonstrated that neutralization of IL‐17 in salivary glands attenuated hyposalivation and ameliorated tissue inflammation in mice with experimental SS, suggesting a therapeutic potential of local targeting IL‐17 for treating xerostomia and autoimmune sialadenitis in pSS patients.

A detailed understanding of the gene-regulatory network in ankylosing spondylitis (AS) is vital for elucidating the mechanisms of AS pathogenesis. Assaying transposase-accessible chromatin in single cell sequencing (scATAC-seq) is a suitable method for revealing such networks. Thus, scATAC-seq was applied to define the landscape of active regulatory DNA in AS. As a result, there was a significant change in the percent of CD8+ T cells in PBMCs, and 37 differentially accessible transcription factor (TF) motifs were identified. T cells, monocytes-1 and dendritic cells were found to be crucial for the IL-17 signaling pathway and TNF signaling pathway, since they had 73 potential target genes regulated by 8 TF motifs with decreased accessibility in AS. Moreover, natural killer cells were involved in AS by increasing the accessibility to TF motifs TEAD1 and JUN to induce cytokine-cytokine receptor interactions. In addition, CD4+ T cells and CD8+ T cells may be vital for altering host immune functions through increasing the accessibility of TF motifs NR1H4 and OLIG (OLIGI and OLIG2), respectively. These results explain clear gene regulatory variation in PBMCs from AS patients, providing a foundational framework for the study of personal regulomes and delivering insights into epigenetic therapy.

Thrombotic events are the most frequent causes of death in patients with antiphospholipid syndrome (APS). Previous studies have reported infection to be the most important trigger of thrombosis in APS, with molecular mimicry considered to be a major mechanism. Although timely management of infections has been recommended in patients with high suspicion of infection, anti-infective therapy would not take effect in a short time due to the dilemma in determining the origins of infection, especially in patients undergoing immunosuppressive therapy. Here, we describe a 26-year-old patient with systemic lupus erythematosus with triple antiphospholipid antibody positivity who had a stroke involving her dorsolateral medulla, despite timely anti-infective treatment within the context of skin infection caused by Stenotrophomonas maltophilia. To the best of our knowledge, it is the first report about the association between Stenotrophomonas maltophilia infection and thrombotic complications in APS. Thus, solely focusing on anti-infective therapy by the current recommendation for the management of APS may be insufficient within the context of infection; early initiation of effective anticoagulation should also be suggested until the anti-infective therapy becomes effective, especially in patients with high-risk antiphospholipid antibody profiles, in whom the potential benefit would outweigh the risk of bleeding.

ObjectivesIn patients with systemic lupus erythematosus (SLE), immune tolerance breakdown leads to autoantibody production and immune-complex glomerulonephritis. This study aimed to identify pathogenic plasma cells (PC) in the development of lupus nephritis.MethodsPC subsets in peripheral blood and renal tissue of patients with SLE and lupus mice were examined by flow cytometry and confocal microscopy, respectively. Sorting-purified PCs from lupus mice were adoptively transferred into Rag2-deficient recipients, in which immune-complex deposition and renal pathology were investigated. In culture, PCs from lupus mice and patients with SLE were treated with a TLR4 inhibitor and examined for autoantibody secretion by enzyme-linked immunospot assay (ELISPOT). Moreover, lupus mice were treated with a TLR4 inhibitor, followed by the assessment of serum autoantibody levels and glomerulonephritis activity.ResultsThe frequencies of TLR4+CXCR4+ PCs in peripheral blood and renal tissue were found significantly increased with the potent production of anti-dsDNA IgG, which were associated with severe renal damages in patients with SLE and mice with experimental lupus. Adoptive transfer of TLR4+CXCR4+ PCs from lupus mice led to autoantibody production and glomerulonephritis development in Rag2-deficient recipients. In culture, TLR4+CXCR4+ PCs from both lupus mice and patients with SLE showed markedly reduced anti-dsDNA IgG secretion on TLR4 blockade. Moreover, in vivo treatment with TLR4 inhibitor significantly attenuated autoantibody production and renal damages in lupus mice.ConclusionsThese findings demonstrate a pathogenic role of TLR4+CXCR4+ PCs in the development of lupus nephritis and may provide new therapeutic strategies for the treatment of SLE.

Iguratimod (IGU) is a novel disease-modifying anti-rheumatic drug (DMARD) in rheumatoid arthritis (RA). Like other DMARDs, IGU exhibited significant differences in effectiveness and safety. Aim: The aim of this study was to identify genetic predictorsof efficacyand toxicity of IGU in patients with RA. Materials & methods: Seven SNPs from IGU-metabolizing genes were genotyped in 272 IGU-treated patients with RA. Results: ABCG2 rs2231142 A allele conferred a higher response to IGU, while NAT2 rs1495742 G carriersconferred a lower response to IGU. CYP2C19*2 rs4244285 A carriers had higher risk for IGU-induced toxicity compared to the GG carriers. Conclusion: Our study suggests that the polymorphisms of ABCG2 (rs2231142), NAT2 (rs1495741)and CYP2C19*2 (rs4244285) may help to predict thetherapeutic effectiveness and toxicity of IGU in patients with RA.

// Liping Ding 1 , Xiaohui Wang 2 , Xiaoping Hong 1 , Liwei Lu 2 and Dongzhou Liu 1 1 Department of Rheumatology and Immunology, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, Shenzhen, China 2 Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China Correspondence to: Dongzhou Liu, email: liu_dz2001@sina.com Liwei Lu, email: liweilu@hku.hk Keywords: interleukin-36; inflammatory disease; psoriasis; arthritis Received: September 29, 2017 Accepted: October 29, 2017 Published: December 01, 2017 ABSTRACT The inteleukin-36 (IL-36) cytokines include IL-36α, IL-36β, IL-36γ and IL-36Ra, which belong to the IL-1 family and exert pro-inflammatory effects on various target cells such as keratinocytes, synoviocytes, dendritic cells and T cells. Emerging evidence has suggested a role of IL-36 in the pathogenesis of many inflammatory diseases. Here, we provide a brief review on the activation of IL-36 family cytokines and their involvement in autoimmunity and inflammatory diseases, which will provide further insights in understanding the functions of IL-36 family cytokines in the pathophysiology of autoimmunity and inflammatory diseases.

Immunoproteasome activation in immune cells is involved in the modulation of immune responses. Increasing evidence indicates that proteasome inhibitors show beneficial effects in treating autoimmune diseases, but it remains unclear whether proteasome inhibition is an effective approach for suppressing autoimmune development in Sjogren's syndrome (SS). Our previous work has demonstrated a critical role for Th17 cells in the development of experimental SS (ESS) in mice. In this study, we detected high levels of low-molecular-weight protein 7 (LMP7), a key subunit of the immunoproteasome, in Th17 cells from ESS mice. Moreover, treatment with bortezomib (BTZ), a proteasome inhibitor, markedly suppressed Th17 differentiation in both murine and human naive T cells in culture. Furthermore, ESS mice treated with BTZ displayed significantly higher saliva flow rates and a reduction in tissue destruction in the salivary glands compared with vehicle-treated ESS mice. Notably, BTZ-treated ESS mice showed markedly decreased Th17 cells, germinal center B cells and plasma cells in the peripheral lymphoid organs. In addition, adoptively transferred wild type naive CD4+ T cells rapidly differentiated into Th17 cells and induced salivary dysfunction in IL-17-deficient mice immunized for ESS induction. However, BTZ treatment profoundly suppressed the donor T-cell-derived Th17 response and ameliorated the reduction in salivary secretion in IL-17-deficient recipient mice. Taken together, our findings demonstrate that proteasome inhibition can effectively ameliorate ESS by suppressing the Th17 response, which may contribute to the development of a novel therapeutic strategy for the treatment of SS.Cellular M doi:10.1038/cmi.2017.8.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by excessive autoantibody production and multi-organ involvement. Although the etiology of SLE still remains unclear, recent studies have characterized several pathogenic B cell subsets and regulatory B cell subsets involved in the pathogenesis of SLE. Among pathogenic B cell subsets, age-associated B cells (ABCs) are a newly identified subset of autoreactive B cells with T-bet-dependent transcriptional programs and unique functional features in SLE. Accumulation of T-bet+ CD11c+ ABCs has been observed in SLE patients and lupus mouse models. In addition, innate-like B cells with the autoreactive B cell receptor (BCR) expression and long-lived plasma cells with persistent autoantibody production contribute to the development of SLE. Moreover, several regulatory B cell subsets with immune suppressive functions have been identified, while the impaired inhibitory effects of regulatory B cells have been indicated in SLE. Thus, further elucidation on the functional features of B cell subsets will provide new insights in understanding lupus pathogenesis and lead to novel therapeutic interventions in the treatment of SLE.

Introduction Interleukin-37(IL-37), a natural inhibitor of innate immunity, has been identified to protect against various inflammatory diseases, including monosodium urate (MSU)-induced inflammation. However, the association of IL-37 with clinical indexes and pro-inflammatory mediators in gout patients remains unclear. The aim of this study was to determine IL-37 level in hyperuricemia and gout patients with or without tophus, and to investigate the correlations of IL-37 with clinical indexs such as Uric Acid (UA), CRP(C-reactive protein), Creatinine Clearance Rate (Ccr), Erythrocyte Sedimentation Rate (ESR) and so on, as well as with the pro-inflammatory mediators in serum including Interleukin-1β(IL-1β), Interleukin-6(IL-6) and Interleukin-18(IL-18) from gout patients. Methodology The serum levels of IL-37, IL-1β, IL-6 and IL-18 levels in serum of gout patients were determined by ELISA; the correlations between IL-37 and clinical values or pro-inflammatory mediators in serum of gout were analyzed by Spearman correlation test. Results The serum levels of IL-37 were higher in active gout patients than inactive gout patients and HCs, especially in active gout patients with tophus. No significant difference was observed in serum IL-37 levels between hyperuricemia and normal controls. IL-1β, IL-6 and IL-18 levels were significant elevated in gout patients with tophus than those without tophus; Serum IL-37 were positively correlated with CRP and ESR, as well as with IL-1β, IL-6 and IL-18, negatively correlated with Ccr, and not correlated with UA, creatinine (Cr) and triglyceride (TG) in gout patients. Conclusions IL-37 increased in gout patients positively associated CRP and ESR, as well as with proinflammatory mediators IL-1β, IL-6, IL-18, the presence of tophus and chronic kidney disease in gout. It may be a novel marker for predicting this pathology.

Background IL-37 has been identified as a natural inhibitor of innate immunity. Although increasing evidence shows elevated IL-37 expression in various autoimmune diseases, its correlation with clinical symptoms in gout is still unclear. Objectives This study aims to determine the correlation between the levels of IL-37 and clinical indexes in gout patients, and to examine the inhibitory effect of IL-37 on pro-inflammatory cytokine including IL-1β, IL-6 and IL-18 from peripheral blood mononuclear cells (PBMC) of gout patients in culture. Methods Levels of serum IL-37 and concentrations of IL-1β, IL-6, IL-18 in cell culture from 42 patients with gout and 40 healthy controls (HCs) were measured by enzyme-linked immunoassay (ELISA). Moreover, the relative mRNA expression of these cytokines in PBMCs was detected by real-time PCR (RT-PCR). The correlations between serum IL-37 levels and clinical values in gout patients were analysed by Spearman correlation test. Results Both protein and mRNA levels of IL-37 were higher in gout patients than healthy controls, especially in patients with tophus. Serum IL-37 levels of gout patients were positively correlated with C-reactive protein and uric acid. Furthermore, the expression of IL-1β, IL-6 and IL-18 in PBMCs from gout patients was significantly increased, which were markedly suppressed by IL-37 in culture. Conclusions Serum levels of IL-37 are closely associated with clinical symptoms in gout patients and may represent a potential biomarker for the disease activity. References [1] Richette P, Bardin T. Gout. Lancet2010;375(9711)318–28. [2] Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol2009;27(2009)621–68. [3] Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature2006;440(7081)237–41. [4] Emmerson BT. The management of gout. N Engl J Med, 1996;334(7)445–51. [5] Fiechtner JJ, Simkin PA. Urate spherulites in gouty synovia. JAMA1981;245(15)1533–6. Disclosure of Interest None declared

Background Interleukin (IL)-37 has been known to play an immunosuppressive role in various inflammatory disorders, but whether it participates in the regulation of pathogenesis of adult-onset Still’s disease (AOSD) has not been investigated. In this study, we examined serum IL-37 levels and their clinical association with AOSD, and we explored the anti-inflammatory effects of IL-37 on peripheral blood mononuclear cells (PBMCs) from patients with AOSD. Methods Blood samples were collected from 62 patients with AOSD and 50 healthy control subjects (HC). The serum IL-37 levels were determined using an enzyme-linked immunosorbent assay (ELISA). The correlations of serum IL-37 levels with disease activity, laboratory values, and inflammatory cytokines in AOSD were analyzed by Spearman’s correlation test. The correlations between serum IL-37 levels and clinical manifestations were analyzed by Mann-Whitney U test. PBMCs from ten patients with AOSD were stimulated with recombinant human IL-37 protein, and expression levels of tumor necrosis factor (TNF)-α, IL-6, IL-10, IL-1β, and IL-18 were determined by qRT-PCR and ELISA. Results A significantly higher IL-37 protein level was observed in patients with AOSD than in HC. Serum IL-37 levels correlated with systemic score, laboratory values, IL-1β, IL-18, and IL-10 in patients with AOSD. The expression levels of IL-37 were closely related to the patients with AOSD who also had fever, skin rash, lymphadenopathy, splenomegaly, myalgia, and arthralgia. Moreover, the production of proinflammatory cytokines such as IL-6, IL-1β, TNF-α, and IL-18 in PBMCs from patients with AOSD was obviously attenuated after recombinant human IL-37 stimulation. Conclusions Increased expression of IL-37 and its positive correlation with disease activity suggest its involvement in AOSD pathogenesis. More importantly, IL-37 inhibits the expression of proinflammatory cytokines in PBMCs from patients with AOSD, indicating the potential anti-inflammatory role of IL-37 in AOSD. Thus, IL-37 may be a novel disease activity biomarker and research target in AOSD. Electronic supplementary material The online version of this article (10.1186/s13075-018-1555-6) contains supplementary material, which is available to authorized users.

The objective of this study is to investigate the correlation between IL-37 level and osteoarthritis activity and to determine the anti-inflammatory effects of IL-37 in peripheral blood mononuclear cells (PBMCs) and synovial cells (SCs) from osteoarthritis (OA) patients, which including 32 patients with erosive inflammatory OA (EIOA) and 40 patients with primary generalized OA (PGOA), 40 age and sex matched healthy volunteers were recruited as healthy controls (HCs). The protein and relative mRNA levels of IL-37 were significant increased in the blood of EIOA patients compared with those of PGOA patients and HCs. Serum IL-37 levels of OA patients were positively correlated with VAS score, as well as with CRP, ESR in blood. Positive correlations were also observed among IL-37 with IL-1β, TNF-α and IL-6 in synovial cells. Furthermore, the expression of IL-1β, TNF-α and IL-6 in PBMCs and SCs from EIOA patients was suppressed by IL-37 in vitro. In conclusion, our results indicated that IL-37 increased in EIOA patients and was positively correlated with disease activity, the pro-inflammatory cytokines such as IL-1β, TNF-α and IL-6 in PBMCs and synovial cells from EIOA patients were restrained by recombinant IL-37. Thus, IL-37 may serve as a novel therapeutic target for the treatment of OA inflammation.

Notoginsenoside R7 was isolated from Panax notoginseng, a plant used commonly in traditional Chinese medicine. We investigated the anti-cancer effects of R7 in HeLa cells in vitro and in vivo, and explored the underlying mechanisms of action. R7 dose-dependently inhibited HeLa cell proliferation and induced apoptosis in vitro, In silico docking-based screening assays showed that R7 can directly bind Akt. Pretreatment with the Akt inhibitor LY294002 synergistically enhanced the R7 anti-proliferation and anti-apoptosis effects in HeLa cells, confirming that R7 acts through the PI3K/Akt pathway. Consistent with the in vitro findings, R7 exerted anti-tumor effects in a mouse xenograft model by targeting PI3K (PTEN) and Akt, activating the pro-apoptotic Bcl-2 family and, subsequently, caspase family members. R7 treatment activated PTEN and downregulated mTOR phosphorylation without affecting mTOR expression, though regulatory-associated protein of mTOR (raptor) expression declined. Our study suggests that R7 is a promising chemotherapeutic agent for the treatment of cervical cancer and other PI3K/PTEN/Akt/mTOR signaling-associated tumors.