Search

Underexpression of p53 is considered the leading cause of the decreased miR-1246 expression in B cells of systemic lupus erythematosus (SLE) patients, yet the exact mechanism of action still remains unclear. To further explore the molecular mechanism of p53 upregulating miR-1246 expression, we targeted the methylation and acetylation of histone H3 in the miR-1246 promoter region of SLE B cells. We found that increased histone H3 trimethylation at Lys27 (H3K27me3) and decreased histone H3 acetylation at Lys9 and Lys14 (H3K9/K14ac) in the miR-1246 promoter region are essential for the low expression of miR-1246 in SLE B cells. p53 can promote miR-1246 transcription by recruiting Jumonji domain–containing protein 3 (JMJD3), E1A-binding protein p300 (EP300), and CREB-binding protein (CBP) to bind to the miR-1246 promoter, downregulating H3K27me3 and upregulating H3K9/K14ac. Furthermore, early B cell factor 1 (EBF1), CD40, CD38, and X box binding protein-1 (XBP-1) expression levels in SLE B cells transfected with p53 expression plasmid were significantly decreased, whereas autoantibody IgG production in autologous CD4+ T cells cocultured with overexpressed p53 SLE B cells was reduced. Collectively, our data suggest that the reduction of p53 decreases miR-1246 expression via upregulation of H3K27me3 and downregulation of H3K9/14ac, which in turn results in SLE B cell hyperactivity.

Background Overproduction of cAMP-responsive element modulator α (CREMα) in total T cells from patients with systemic lupus erythematosus (SLE) can inhibit IL-2 and increase IL-17A. These ultimately promote progression of SLE. This study aims to investigate the expression of CREMα in SLE CD4+ T cells and find out the mechanisms for the regulation of CREMα in SLE CD4+ T cells. Results CREMα mRNA was overexpressed in CD4+ T cells from SLE patients. The levels of histone H3 lysine 9 trimethylation (H3K9me3) and suppressor of variation 3–9 homolog 1 (SUV39H1) at the CREMα promoter of SLE CD4+ T cells were markedly decreased. Down-regulating SUV39H1 in normal CD4+ T cells elevated the levels of CREMα, IL-17A, and histone H3 lysine 4 trimethylation (H3K4me3) in the CREMα promoter region, and lowered IL-2, H3K9me3, DNA methylation, and DNA methyltransferase 3a (DNMT3a) enrichments within the CREMα promoter, while no sharp change in SET domain containing 1 (Set1) at the CREMα promoter. Up-regulating SUV39H1 in SLE CD4+ T cells had the opposite effects. The DNA methylation and DNMT3a levels were obviously reduced, and H3K4me3 enrichment was greatly increased at the CREMα promoter of CD4+ T cells from SLE patients. The Set1 binding in the CREMα promoter region upgraded significantly, and knocking down Set1 in SLE CD4+ T cells alleviated the H3K4me3 enrichment within this region, suppressed CREMα and IL-17A productions, and promoted the levels of IL-2, CREMα promoter DNA methylation, and DNMT3a. But there were no obviously alterations in H3K9me3 and SUV39H1 amounts in the region after transfection. Conclusions Decreased SUV39H1 in the CREMα promoter region of CD4+ T cells from SLE patients contributes to under-expression of H3K9me3 at this region. In the meantime, the Set1 binding at the CREMα promoter of SLE CD4+ T cells is up-regulated. As a result, DNMT3a and DNA methylation levels alleviate, and H3K4me3 binding increases. All these lead to overproduction of CREMα. Thus, the secretion of IL-2 down-regulates and the concentration of IL-17A up-regulates, ultimately promoting SLE.

Conflicting results have been reported on the association of C-reactive protein (CRP) level with adverse outcomes in patients with stable coronary artery disease (CAD). The objective of this meta-analysis was to evaluate the predictive value of baseline CRP level in stable CAD patients.Two reviewers independently searched PubMed and Embase databases from their inception to November 28, 2021 to identify studies assessing the value of baseline CRP level in predicting adverse outcomes in stable CAD patients. The endpoints of interest included cardiovascular mortality, all-cause mortality, or major adverse cardiovascular events (MACEs). The predictive value of CRP level was estimated by pooling the multivariable adjusted risk ratio with 95% confidence intervals (CI) compared the highest to the lowest CRP level.Twenty-six studies involving of 22,602 patients with stable CAD satisfied the inclusion criteria. In a comparison of the highest with the lowest CRP level, the pooled multivariable adjusted risk ratio was 1.77 (95% CI 1.60-1.96) for MACEs, 1.64 (95% CI 1.13-2.33) for cardiovascular mortality, and 1.62 (95% CI 2.62-5.12) for all-cause mortality, respectively. Subgroup analyses indicated that the values of elevated CRP level in predicting MACEs were consistently observed in each subgroup.Elevated baseline CRP level was an independent predictor of MACEs, cardiovascular mortality, and all-cause mortality in patients with stable CAD. Baseline CRP level can provide important predictive information in stable CAD patients.

This study aimed to investigate the presence of eight virulence genes (ace, asa1, esp, efaA, gelE, cylA, agg, fsr) in Enterococcus from a variety of animals and to explore the drug resistance and pathogenicity. This could provide a theoretical basis for clinical treatment of Enterococcus infections. Anal swabs from pigs, chickens, cattle, and dogs in farms and pet hospitals were collected for Enterococcus isolation and identification. Eight virulence genes were detected (PCR method), and drug resistance was assessed (drug-sensitive paper method). The strains containing different virulence genes were then divided into EV1, EV2, and EV3 groups. The LD

ObjectiveLupus erythematosus (LE) is a complicated disease with highly heterogeneous clinical manifestations. Previous studies have rarely included all subgroups of patients with lupus and have overlooked the importance of the cutaneous manifestations thereof. We aimed to compare the demographic and clinical differences among patients with different subtypes of lupus.MethodsThis is the first real-world study with a relatively large sample size that simultaneously includes patients with isolated cutaneous lupus erythematosus (iCLE) and SLE. All samples were obtained from the Lupus Erythematosus Multicenter Case–control Study in Chinese populations (LEMCSC) (registration number: ChiCTR2100048939). Comparative analyses between different LE subgroups were performed.ResultsA total of 2097 patients with lupus were included, with 1865 patients with SLE, 1648 with cutaneous lupus erythematosus (CLE), and 232 with iCLE. Among the patients with CLE, 1330 had acute cutaneous lupus erythematosus (ACLE); 160 had subacute cutaneous lupus erythematosus (SCLE); and 546 had chronic cutaneous lupus erythematosus (CCLE). The study included a relatively large number of patients with CCLE subtypes, including 311 with discoid lupus erythematosus (DLE), 262 with chilblain lupus erythematosus (CHLE) and 45 with lupus erythematosus profundus (LEP). Demographic characteristics, systemic involvement, mucocutaneous manifestations and autoantibodies were significantly different among the groups.ConclusionsCLE and iCLE are two distinct disease states, and the selection of broad or narrow CLE definitions should be emphasised in scientific reports. LE-non-specific cutaneous lesions imply more severity, while self-reported photosensitivity and LE-specific cutaneous manifestations imply milder severity. Generalised ACLE appears to be a more severe state than localised ACLE, and CHLE appears to be more severe than DLE. Anti-Sjögren’s syndrome-related antigen B (SSB) antibodies have higher specific directivity than anti-Sjögren’s syndrome-related antigen A (SSA) antibodies for SCLE lesions. Anti-double-stranded DNA antibodies have a higher co-occurrence with ACLE and a lower co-occurrence with SCLE and CCLE. Compared with DLE, CHLE has significantly higher positive rates of anti-SSA/Ro60 (71%) and anti-SSA/Ro52 (42.4%) antibodies, whereas LEP is associated with a higher positive rate of antinucleosome antibodies (31.1%).

Mastitis in dairy cows affects milk quality and thereby constrains the development of the dairy industry. A clear understanding of the pathogenesis of mastitis can help its treatment. Mastitis is caused by the invasion of pathogenic bacteria into the mammary gland through the mammary ducts. However, recent studies suggested that an endogenous entero-mammary pathway in dairy cattle might also be playing an important role in regulating mastitis. Also, probiotic intervention regulating host gut microbes has become an interesting tool to control mastitis. This review discusses the association of gastrointestinal microbes with mastitis and the mechanism of action of probiotics in dairy cows to provide new ideas for the management of mastitis in large-scale dairy farms.

The reduced expression of miR-142-3p/5p in CD4+ T cells of SLE patients caused T cell hyperactivity and B cell hyperstimulation. This study aimed to investigate the mechanisms of regulating miR-142-3p/5p expression in SLE CD4+ T cells. The BCL-6 expression was significantly increased in SLE CD4+ T cells compared with normal controls, and the BCL-6 expression was inversely correlated with miR-142-3p/5p expression. BCL-6 suppresses the expression of miR-142-3p/5p by increasing H3K27me3 level and reducing H3K9/K14ac levels in SLE CD4+ T cells. BCL-6 regulates histone modifications in miR-142 promoter by recruiting EZH2 and HDAC5. Furthermore, we observed significantly decreased CD40L, ICOS, and IL-21 expression levels in SLE CD4+ T cells with BCL-6 interference, and obviously reduced autoantibody IgG production in autologous B cells co-cultured with BCL-6 inhibited SLE CD4+ T cells. Our study found that increased BCL-6 up-regulates H3K27me3 and down-regulates H3K9/14ac at miR-142 promoter in SLE CD4+ T cells. These factors induce a declination in miR-142-3p/5p expression, consequently resulting in CD4+ T cell hyperactivity.

Systemic lupus erythematosus (SLE) is a spectrum of autoimmune disorders characterized by continuous inflammation and the production of autoantibodies. Monocytes, as precursors of dendritic cells and macrophages, are involved in the pathogenesis of SLE, particularly in the inflammatory reactions. Previous studies have proved that Pam3CSK4, as a synthetic ligand of TLR2, could stimulate monocytes to differentiated into a M2-like phenotype which presented immunosuppressive functions. However, the underlying mechanisms remain to be further studied. Here, we reported an increased expression of PPAR-γ in the CD14+ monocytes from SLE patients, particularly in the treated group of SLE patients and the group with positive anti-dsDNA antibodies. Additionally, PPAR-γ expression decreased in the SLE patients with skin lesion. Furthermore, we demonstrated that Pam3CSK4 stimulation can decrease the expression of CCR7, CD80, IL-1β, IL-6, IL-12, and NF-κB which were related to the M1-like subset of monocytes and increased the expression of ARG1 which was related to the M2-like subset through upregulated PPAR-γ expression and consequently downregulated NF-κB expression in the CD14+ monocytes in a time-dependent manner. ChIP-qPCR results further demonstrated that Pam3CSK4 pretreatment could modulate PPAR-γ expression by regulating histone modification through the inhibition of Sirt1 binding to the PPAR-γ promoter. Taken together, our study indicated a protective role of TLR2/Sirt1/PPAR-γ pathway in the pathogenesis of SLE which provided potential therapeutic strategies.

Although the original purpose of the systemic lupus erythematosus (SLE) classification criteria was to distinguish SLE from other mimic diseases, and to facilitate sample selection in scientific research, they have become widely used as diagnostic criteria in clinical situations. It is not known yet if regarding classification criteria as diagnostic criteria, what problems might be encountered? This is the first study comparing the three sets of classification criteria for SLE, the 1997 American College of Rheumatology (ACR’97), 2012 Systemic Lupus International Collaborating Clinics (SLICC’12) and 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR’19), for their ability to distinguish patients with SLE from patients with pure mucocutaneous manifestations (isolated cutaneous lupus erythematosus without internal disease, i-CLE) in the lupus disease spectrum. 1,865 patients with SLE and 232 patients with i-CLE were recruited from a multicenter study. We found that, due to low specificity, none of the three criteria are adept at distinguishing patients with SLE from patients with i-CLE. SLICC’12 performed best among the original three criteria, but if a positive ANA was removed as an entry criterion, EULAR/ACR’19 would performed better. A review of previous studies that compared the three sets of criteria was presented in this work.

The peripheral blood of systemic lupus erythematosus patients showed an increased expression of CXCR5 positive T cells. However, the molecular mechanism of the abnormal expression of CXCR5 in SLE CD4

Supplemental material, sj-pdf-1-lup-10.1177_0961203320959716 for A comparison and review of three sets of classification criteria for systemic lupus erythematosus for distinguishing systemic lupus erythematosus from pure mucocutaneous manifestations in the lupus disease spectrum by Hui Jin, Tao Huang, Ruifang Wu, Ming Zhao, Haijing Wu, Hai Long, Heng Yin, Jieyue Liao, Shuangyan Luo, Yu Liu, Qing Zhang, Peng Zhang, Yixin Tan, Shuaihantian Luo, Xin Huang, Yaxiong Deng, Wei Liao, Liu Duan, Jianbo Chen, Yin Zhou, Jinghua Yin, Hong Qiu, Jin Yuan, Zijun Wang, Mengying Li, Xiaoqi Wu, Lina Chen, Liangmin Cai, Cancan Huang, Qianwen Li, Bingsi Tang, Bihui Yu, Xin Li, Xiaofei Gao, Yixi Hu, Xiaolei Ren, Haofan Xue, Zhangming Wei, Jinwei Chen, Fen Li, Guanghui Ling, Hui Luo, Hongjun Zhao, Sen Yang, Yong Cui, Youkun Lin, Xu Yao, Lingyun Sun, Qing Guo, Hong Fang, Kang Zeng, Danqi Deng, Jianzhong Zhang, Yuzhen Li, Xiongming Pu, Xiangping Liao, Xiqiang Dang, Danlin Huang, Yumei Liang, Qing Sun, Hongju Xie, Li Zeng, Cibo Huang, Qingchun Diao, Juan Tao, Jianbin Yu, Zhenlu Li, Hanshi Xu, Hui Li, Wei Lai, Xiguang Liu, Jingjing Wu, Tienan Li, Tiechi Lei, Qiuning Sun, Yanjia Li, Guoqiang Zhang, Xin Huang and Qianjin Lu in Lupus

Supplemental material, sj-pdf-2-lup-10.1177_0961203320959716 for A comparison and review of three sets of classification criteria for systemic lupus erythematosus for distinguishing systemic lupus erythematosus from pure mucocutaneous manifestations in the lupus disease spectrum by Hui Jin, Tao Huang, Ruifang Wu, Ming Zhao, Haijing Wu, Hai Long, Heng Yin, Jieyue Liao, Shuangyan Luo, Yu Liu, Qing Zhang, Peng Zhang, Yixin Tan, Shuaihantian Luo, Xin Huang, Yaxiong Deng, Wei Liao, Liu Duan, Jianbo Chen, Yin Zhou, Jinghua Yin, Hong Qiu, Jin Yuan, Zijun Wang, Mengying Li, Xiaoqi Wu, Lina Chen, Liangmin Cai, Cancan Huang, Qianwen Li, Bingsi Tang, Bihui Yu, Xin Li, Xiaofei Gao, Yixi Hu, Xiaolei Ren, Haofan Xue, Zhangming Wei, Jinwei Chen, Fen Li, Guanghui Ling, Hui Luo, Hongjun Zhao, Sen Yang, Yong Cui, Youkun Lin, Xu Yao, Lingyun Sun, Qing Guo, Hong Fang, Kang Zeng, Danqi Deng, Jianzhong Zhang, Yuzhen Li, Xiongming Pu, Xiangping Liao, Xiqiang Dang, Danlin Huang, Yumei Liang, Qing Sun, Hongju Xie, Li Zeng, Cibo Huang, Qingchun Diao, Juan Tao, Jianbin Yu, Zhenlu Li, Hanshi Xu, Hui Li, Wei Lai, Xiguang Liu, Jingjing Wu, Tienan Li, Tiechi Lei, Qiuning Sun, Yanjia Li, Guoqiang Zhang, Xin Huang and Qianjin Lu in Lupus

In this paper, we take the new employees in the early career as the research object, and uses the "Job Demands-Resources " model to explore the impact of work demand, work resources and emotional intelligence on job burnout, as well as the regulation of work demand and emotional intelligence between work resources and job burnout. The results show that: Job demands have a significant positive correlation with job burnout, while job resources and emotional intelligence have a significant negative correlation with job burnout. Job demands have a significant positive predictive effect on job burnout, while job resources and emotional intelligence have a significant negative predictive effect on job burnout. Job demands and emotional intelligence play a significant role in regulating job resources and job burnout.

The aim of this work was to study the effect of high pressure processing (HPP) and post-HPP cold storage on the distribution of polyglutamyl and monoglutamyl folate and the absolute concentration of total folate in green beans, yardlong beans and winged beans using a validated ultra-high performance liquid chromatography-tandem mass spectrometry method. The results showed that HPP led to the deglutamylation of polyglutamyl folate to monoglutamyl folate in all of the investigated beans. The degree of deglutamylation was increased with enhancing processing pressure and extending holding time. During HPP, significant loss of total folate was observed under 600 MPa/10 min treatment. Uniquely 300 MPa/5 min and 450 MPa/5 min could significantly release more folate from yardlong beans and green beans matrix. During the following cold-storage, the deglutamylation keep progressing. For those untreated beans, no significant deglutamylation and total folate loss was observed during cold storage for yardlong beans and green beans while there is slight change for the total folate in winged beans. For those HPP treated beans, total folate loss followed the first order kinetics over the storage. The rate constant of degradation was positively proportional to the applied pressure, holding time and the proportion of monoglutamyl folate. This research provided a reference for understanding the deglutamylation of polyglutamyl folate and folate loss during HPP treatment and further shelf life.

Winged beans are an important natural source of some micronutrients. This paper presents the first complete characterization of folate derivatives including polyglutamyl 5-methyltetrahydrofolate (5-CH3-H4PteGlun), folate species and total folate accumulating in pods and immature seeds of winged beans from 9 cultivars and 7 growth stages. 5-CH3-H4PteGlun and folate species were determined with a UHPLC-MS/MS method. Accurate determination of 5-CH3-H4PteGlun and folate species was optimized and validated according to EMA guidelines including method selectivity, sensitivity, linearity, accuracy, precision, matrix effect and carry-over. The level of total folate is in the range of 73-200 μg/100 g in the pods and 33-61 μg/100 g in the immature seeds. The predominant folate species in winged beans is 5-CH3-H4PteGlu1. 5-CH3-H4PteGlu5 is the major polyglutamyl folate derivative. The level of total folate is increased about 4 fold with advancing maturity. For pods, the chain length is increased with growth which shifts from 5-CH3-H4PteGlu1 in the early stage to 5-CH3-H4PteGlu5 and 5-CH3-H4PteGlu6 in the 7th stage. Our findings demonstrate that winged beans are good source of folate. The validated UHPLC-MS/MS method allows for the determination of 5-CH3-H4PteGlun and folate species from other vegetable matrices.

ObjectiveT cell receptor (TCR) diversity determines the autoimmune responses in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) and is closely associated with autoimmune diseases prognosis and prevention. However, the characteristics of variations in TCR diversity and their clinical significance is still unknown. Large series of patients must be studied in order to elucidate the effects of these variations.MethodsPeripheral blood from 877 SLE patients, 206 RA patients and 439 healthy controls (HC) were amplified for the TCR repertoire and sequenced using a high-throughput sequencer. We have developed a statistical model to identify disease-associated TCR clones and diagnose autoimmune diseases.ResultsSignificant differences were identified in variable (V), joining (J) and V-J pairing between the SLE or RA and HC groups. These differences can be utilised to discriminate the three groups with perfect accuracy (V: area under receiver operating curve > 0.99). One hundred ninety-eight SLE-associated and 53 RA-associated TCRs were identified and used for diseases classification by cross validation with high specificity and sensitivity. Disease-associated clones showed common features and high similarity between both autoimmune diseases. SLE displayed higher TCR heterogeneity than RA with several organ specific properties. Furthermore, the association between clonal expansion and the concentration of disease-associated clones with disease severity were identified, and pathogen-related TCRs were enriched in both diseases.ConclusionsThese characteristics of the TCR repertoire, particularly the disease-associated clones, can potentially serve as biomarkers and provide novel insights for disease status and therapeutical targets in autoimmune diseases.

The reduced expression of miR-142-3p/5p in CD4

The peripheral blood of systemic lupus erythematosus patients showed an increased expression of CXCR5 positive T cells. However, the molecular mechanism of the abnormal expression of CXCR5 in SLE CD4+ T cells remains unclear. The present study demonstrated that the levels of H3K4me3 and H3K36me3 in CXCR5 promoter were significantly higher in SLE patients than those in healthy controls. Furthermore, the expression of SETD3 was upregulated in SLE CD4+ T cells as compared to the healthy controls. Excessive SETD3 increased the level of H3K4me3 and H3K36me3 and promoted the expression of CXCR5. These data strongly suggested that SETD3 plays a major role in the regulation of CXCR5 expression and the progression of SLE.

Winged beans are an important natural source of some micronutrients. This paper presents the first complete characterization of folate derivatives including polyglutamyl 5-methyltetrahydrofolate (5-CH

Age-related variations in genes and microRNAs expression and DNA methylation have been reported respectively; however, their interactions during aging are unclear. We therefore investigated alterations in the transcriptomes, miRNAomes and DNA methylomes in the same CD4+T cells from newborn (NB), middle-aged (MA) and long-lived (LL) individuals to elucidate the molecular changes and their interactions. A total 659 genes showed significantly expression changes across NB, MA and LL individuals, in which we identified four age-related co-expression modules with three hub networks of co-expressed genes and non-coding RNAs. Moreover, we identified 9835 differentially methylated regions (DMRs) including 7015 hypermethylated and 2820 hypomethylated DMRs in the NB compared with the MA, and 12,362 DMRs including 4809 hypermethylated and 7553 hypomethylated DMRs in the MA compared with the LL. The integrated analysis revealed a potential relationship between genes transcription and DNA methylation for many age- or immune-related genes, suggesting that DNA methylation-dependent transcription regulation is involved in development and functions of T cells during aging. Our results reveals age-related transcription and methylation changes and their interactions in human T cells from the cradle to the grave. Longitudinal work is required to establish the relationship between identified age-associated genes/DNA methylation and T cells aging phenotypes.

Henoch-Schönlein purpura (HSP), the most common type of leukocytoclastic vasculitis, is caused by T cell-mediated autoimmune reactions. In this study, we analyze histone modification patterns in peripheral blood mononuclear cells (PBMCs) of HSP patients, and investigate the expression levels of inflammatory cytokines (IFN-γ, IL-2, IL-4, IL-6 and IL-13), transcription factors (T-bet, GATA-3 and TIM-1) and chemokines (CXCL4 and CXCL10) in HSP patients. Our results show that histone H3 acetylation and methylation are significantly enhanced in PBMCs from HSP patients. We also demonstrate specifically that marked increases in histone H3 acetylation and H3 lysine 4 trimethylation occur at the IL-4 loci in these patients. In addition, the expression levels of IL-4, IL-6, IL-13, GATA-3, TIM-1 and CXCL4 are also increased. These findings suggest that abnormal histone modifications are present in the PBMCs of patients with HSP, possibly contributing to the activation of pathological immune responses associated with HSP.

Age-related variations in genes and microRNAs expression and DNA methylation have been reported respectively; however, their interactions during aging are unclear. We therefore investigated alterations in the transcriptomes, miRNAomes and DNA methylomes in the same CD4+T cells from newborn (NB), middle-aged (MA) and long-lived (LL) individuals to elucidate the molecular changes and their interactions. A total 659 genes showed significantly expression changes across NB, MA and LL individuals, in which we identified four age-related co-expression modules with three hub networks of co-expressed genes and non-coding RNAs. Moreover, we identified 9835 differentially methylated regions (DMRs) including 7015 hypermethylated and 2820 hypomethylated DMRs in the NB compared with the MA, and 12,362 DMRs including 4809 hypermethylated and 7553 hypomethylated DMRs in the MA compared with the LL. The integrated analysis revealed a potential relationship between genes transcription and DNA methylation for many age- or immune-related genes, suggesting that DNA methylation-dependent transcription regulation is involved in development and functions of T cells during aging. Our results reveals age-related transcription and methylation changes and their interactions in human T cells from the cradle to the grave. Longitudinal work is required to establish the relationship between identified age-associated genes/DNA methylation and T cells aging phenotypes.

Total glucosides of paeony (TGP), an active compound extracted from Paeony root, has been used in therapy for autoimmune diseases. However the molecular mechanism of TGP in the prevention of autoimmune response remains unclear. In this study, we found that TGP treatment significantly increased the percentage and number of Treg cells in lupus CD4(+) T cells. Further investigation revealed that treatment with TGP increased the expression of Foxp3 in lupus CD4(+) T cells by down-regulating Foxp3 promoter methylation levels. However, we couldn't observe similar results in healthy control CD4(+) T cells treated by TGP. Moreover, our results also showed that IFN-γ and IL-2 expression was enhanced in TGP-treated lupus CD4(+) T cells. These findings indicate that TGP inhibits autoimmunity in SLE patients possibly by inducing Treg cell differentiation, which may in turn be due to its ability to regulate the methylation status of the Foxp3 promoter and activate IFN-γ and IL-2 signaling.

Background The pathogenesis of systemic lupus erythematosus (SLE) has not yet been completely elucidated. One of the hallmarks of SLE is the production of autoantibodies by uncontrolled over-activated B cells. Early B cell factor 1 (EBF1) contributes to the development, activation, and proliferation of B cells through activation of the AKT signaling pathway. Accumulating evidence has demonstrated that several microRNAs (miRNAs) contribute to the pathogenesis of autoimmune diseases through the regulation of B cells in SLE. We aim to investigate the expression patterns of miR-1246 in B cells and its contribution to pathogenesis of SLE. Results Our results showed that the expression of miR-1246 was significantly decreased in B cells from SLE patients. We verified that miR-1246 specifically targeted the EBF1 messenger RNA (mRNA) by interacting with its 3′-untranslated region (3′-UTR) and regulated the expression of EBF1. Transfection of miR-1246 inhibitors into healthy B cells upregulated the expression of EBF1, enhanced B cell function, and increased the production of B cell surface co-stimulatory molecules CD40, CD80, and CD86. We also observed that abnormal activation of the AKT signaling pathway was associated with decreased P53 expression, leading to the downregulation of the miR-1246 expression; and upregulation of the miR-1246 expression reversed the responsiveness of B cells by inhibiting EBF1 expression. Conclusions Activated B cells in lupus could decrease the expression of miR-1246 through the AKT-P53 signaling pathway, which in turn enhances the expression of EBF1, thereby promoting further activation of B cells. Conversely, upregulation of miR-1246 could interrupt this amplification pathway. Our findings thus provide a theoretical framework towards the research of novel biological targets in SLE treatment. Electronic supplementary material The online version of this article (doi:10.1186/s13148-015-0063-7) contains supplementary material, which is available to authorized users.

Systemic lupus erythematosus (SLE) is an autoimmune disease well known for its clinical heterogeneity, and its etiology secondary to a cross-talk involving genetic predisposition and environmental stimuli. Although genome-wide analysis has contributed greatly to our understanding of the genetic basis of SLE, there is increasing evidence for a role of epigenetics. Indeed, recent data have demonstrated that in patients with SLE, there are striking alterations of DNA methylation, histone modifications, and deregulated microRNA expression, the sum of which contribute to over-expression of select autoimmune-related genes and loss of tolerance. To address this issue at the level of clinical phenotype, we performed DNA methylation, mRNA and microRNA expression screening using high-throughput sequencing of purified CD4+ T cells from patients with SLE, compared to age and sex matched controls. In particular, we studied 42 patients with SLE and divided this group into three clinical phenotypes: a) the presence of skin lesions without signs of systemic pathology; b) skin lesions but also chronic renal pathology; and c) skin lesions, chronic renal pathology and polyarticular disease. Interestingly, and as expected, sequencing data revealed changes in DNA methylation in SLE compared to controls. However, and more importantly, although there were common methylation changes found in all groups of SLE compared to controls, there was specific DNA methylation changes that correlated with clinical phenotype. These included changes in the novel key target genes NLRP2, CD300LB and S1PR3, as well as changes in the critical pathways, including the adherens junction and leukocyte transendothelial migration. We also noted that a significant proportion of genes undergoing DNA methylation changes were inversely correlated with gene expression and that miRNA screening revealed the existence of subsets with changes in expression. Integrated analysis of this data highlights specific sets of miRNAs controlled by DNA methylation, and genes that are altered by methylation and targeted by miRNAs. In conclusion, our findings suggest select epigenetic mechanisms that contribute to clinical phenotypes and further shed light on a new venue for basic SLE research.

To investigate the effect of total glucosides of peony (TGP) on expression and DNA methylation status of ITGAL gene (CD11a) in CD4(+) T cells from patients with systemic lupus erythematosus (SLE).CD4(+) T cells were isolated by positive selection using CD4 beads. CD4(+) T cells were treated by TGP at 0, 62.5, 312.5 and 1562.5 mg/L for 48 h. The MTT method was used to assess cell viability; mRNA expression level was measured by realtime-PCR; protein level of CD11a was measured by flow cytometric analysis; DNA methylation status was assayed by bisulfite sequencing.No significant change in cell viability was found in CD4(+) T cells among the different concentration groups (P0.05). Compared with control, the mRNA and protein levels of ITGAL were down-regulated significantly in SLE CD4(+) T cells treated with TGP (1562.5 mg/L) (P0.01). Furthermore, the extent of DNA methylation of ITGAL promoter was increased in TGP (1562.5 mg/L) treated CD4(+) T cells compared with control group (P0.01).TGP can repress CD11a gene expression through enhancing DNA methylation of ITGAL promoter in CD4(+) T cells from patients with SLE. This observation represents a preliminary step in understanding the mechanism of TGP in SLE therapy.

Data outsourcing is an emerging paradigm that allows users and companies to give their (potentially sensitive) data to external data storage provider that then become responsible for their storage, management, and dissemination. Although data outsourcing provides many benefits, it introduces new privacy and security concerns. How to protect the outsourcing data privacy when the access control policies are changed dynamically is an important problem. Existing solutions to the problem adopt over-encryption to protect data privacy, it is low efficiency, because every time the users request data from the data storage provider, the data storage provider must encrypt the data with a new key and the users decrypt the data twice. In this paper we present a novel solution to this issue, which based on proxy re-encryption. In the proposed solution, when the users request data from the DSP, the DSP send the cipher text to the users directly without encrypting the data with another second-level key, and the users decrypt the cipher text to get the data with only a new key. Therefore, high efficiency is achieved. We analyze the performance and security of our approach.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by T cell overactivation and B cell hyper-stimulation. Hematopoietic progenitor kinase 1 (HPK1, also called MAP4K1) negatively regulates T cell-mediated immune responses. However, the role of HPK1 and the mechanisms that regulate HPK1 expression in SLE remain poorly understood. Using chromatin immunoprecipitation (ChIP) microarray data, we identified markedly increased histone H3 lysine 27 trimethylation (H3K27me3) enrichment at the HPK1 promoter of SLE CD4+ T cells relative to controls, and confirmed this observation using ChIP and real-time PCR experiments. We further found that HPK1 mRNA and protein levels were significantly decreased in CD4+ T cells of patients with SLE, and that this decrease was not caused by exposure to standard SLE medications. Down-regulating HPK1 in healthy CD4+ T cells significantly accelerated T cell proliferation and production of IFNγ and IgG. Consistent with these findings, overexpressing HPK1 in SLE CD4+ T cells caused a significant decrease in T cell reactivity. In addition, we observed a striking decrease in jumonji domain containing 3 (JMJD3) binding, but no marked change in enhancer of zeste homolog 2 (EZH2) binding, at the HPK1 promoter region in SLE CD4+ T cells compared to healthy controls. SiRNA knock down of JMJD3 in healthy CD4+ T cells led to decreased JMJD3 binding and increased H3K27me3 enrichment at the HPK1 promoter region, thus inhibiting the expression of HPK1. Concordantly, plasmid-induced overexpression of JMJD3 in SLE CD4+ T cells led to increased JMJD3 binding, decreased H3K27me3 enrichment, and up-regulated HPK1 expression. Our results show for the first time that inhibited HPK1 expression in SLE CD4+ T cells is associated with loss of JMJD3 binding and increased H3K27me3 enrichment at the HPK1 promoter, contributing to T cell overactivation and B cell overstimulation in SLE. These findings suggest that HPK1 may serve as a novel target for effective SLE therapy.

Introduction Regulatory factor X-box 1 (RFX1) can interact with DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1), and RFX1 down-regulation contributes to DNA hypomethylation and histone H3 hyperacetylation at the cluster of differentiation (CD) 11a and CD70 promoters in CD4+ T cells of patients with systemic lupus erythematosus (SLE). This leads to CD11a and CD70 overexpression, thereby triggering autoimmune responses. In order to provide more insight into the epigenetic mechanisms leading to the deregulation of autoimmune-related genes in SLE, we asked whether RFX1 is involved in regulating histone 3 lysine 9 (H3K9) tri-methylation at the CD11a and CD70 promoters in SLE CD4+ T cells. Methods CD4+ T cell samples were isolated from 15 SLE patients and 15 healthy controls. H3K9 tri-methylation levels were measured by chromatin immunoprecipitation (ChIP) and real-time quantitative PCR. CD4+ T cells were transfected with plasmids using the Human T cell Nucleofector Kit. RFX1 and histone methyltransferase suppressor of variegation 3-9 (Drosophila) homolog 1 (SUV39H1) interaction was determined by co-immunoprecipation (co-IP) and Western blot and immunofluorescence staining. CD11a and CD70 mRNA levels were measured by real-time RT-PCR. Results H3K9 tri-methylation levels were significantly reduced within the CD11a and CD70 promoter regions in SLE CD4+ T cells. RFX1 co-immunoprecipitated with SUV39H1 at the CD11a and CD70 promoters in healthy control CD4+ T cells. Overexpressing or knocking-down RFX1 revealed that RFX1 expression correlated with H3K9 tri-methylation levels, as well as CD11a and CD70 expression levels in CD4+ T cells. Conclusions RFX1 recruits SUV39H1 to the promoter regions of the CD11a and CD70 genes in CD4+ T cells, thereby regulating local H3K9 tri-methylation levels. These findings shed further light on the central role of RFX1 down-regulation in the epigenetic de-repression of auto-immune genes in SLE.