Association between type 1 diabetes and systemic lupus erythematosus: a Mendelian randomization study.

OBJECTIVES: Observational studies have shown that there is a bidirectional relationship between type 1 diabetes (T1D) and systemic lupus erythematosus (SLE); the causality of this association remains elusive and may be affected by confusion and reverse causality. There is also a lack of large-scale randomized controlled trials to verify. Therefore, this Mendelian randomization (MR) study aimed to investigate the causal association between T1D and SLE. METHODS: We aggregated data using publicly available genome-wide association studies (GWAS), all from European populations. Select independent (R2 < 0.001) and closely related to exposure (P < 5 × 10-8) as instrumental variables (IVs). The inverse-variance weighted (IVW) method was used as the primary method. We also used MR-Egger, the weighted median method, MR-Robust, MR-Lasso, and other methods leveraged as supplements. RESULTS: T1D had a positive causal association with SLE (IVW, odds ratio [OR] = 1.358, 95% confidence interval [CI], 1.205 - 1.530; P < 0.001). The causal association was verified in an independent validation set (IVW, OR = 1.137, 95% CI, 1.033 - 1.251; P = 0.001). SLE had a positive causal association with T1D (IVW, OR = 1.108, 95% CI, 1.074 - 1.144; P < 0.001). The causal association was verified in an independent validation set (IVW, OR = 1.085, 95% CI, 1.046 - 1.127; P < 0.001). These results have also been verified by sensitivity analysis. CONCLUSION: The MR analysis results indicated a causal association between T1D and SLE. Therefore, further research is needed to clarify the potential biological mechanism between T1D and SLE. Key Points • Observational studies have shown that there is a bidirectional relationship between T1D and SLE. • We evaluated causal effects between T1D and SLE by Mendelian randomization analyses. • The MR analysis results indicated a causal association between T1D and SLE.

Risk factors of systemic lupus erythematosus: an overview of systematic reviews and Mendelian randomization studies.

BACKGROUND: The etiology of systemic lupus erythematosus is complex and incurable. A large number of systematic reviews have studied the risk factors of it. Mendelian randomization is an analytical method that uses genetic data as tool variables to evaluate the causal relationship between exposure and outcome. OBJECTIVE: To review the systematic reviews and Mendelian randomization studies that focused on the risk factors of systemic lupus erythematosus and shed light on the development of treatments for its prevention and intervention. METHODS: From inception to January 2022, we systematically searched MEDLINE (via PubMed) and Embase for related systematic reviews and Mendelian randomization studies. Extract relevant main data for studies that meet inclusion criteria. The quality of systematic reviews was assessed by using Assessment of Multiple Systematic Reviews 2 (AMSTAR-2). Finally, the risk factors are scored comprehensively according to the results' quantity, quality, and consistency. RESULTS: Our study involved 64 systematic reviews and 12 Mendelian randomization studies. The results of systematic reviews showed that diseases (endometriosis, atopic dermatitis, allergic rhinitis), lifestyle (smoking, drinking, vaccination), and gene polymorphism influenced the incidence of systemic lupus erythematosus. The results of Mendelian randomization studies identified the role of disease (periodontitis, celiac disease), trace elements (selenium, iron), cytokines (growth differentiation factor 15), and gut microbiome in the pathogenesis of systemic lupus erythematosus. CONCLUSION: We should pay attention to preventing and treating systemic lupus erythematosus in patients with endometriosis, celiac disease, and periodontitis. Take appropriate dietary supplements to increase serum iron and selenium levels to reduce the risk of systemic lupus erythematosus. There should be no excessive intervention in lifestyles such as smoking and drinking.

Jieduquyuziyin prescription enhances CD11a and CD70 DNA methylation of CD4+ T cells via miR-29b-sp1/DNMT1 pathway in MRL/lpr mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Jieduquyuziyin prescription (JP) is a traditional Chinese medicine utilized to treat systemic lupus erythematosus (SLE). Its efficacy has been confirmed through clinical trials and empirical evidence, leading to its authorized use in Chinese hospitals. The development of JP exemplifies the integration of traditional wisdom and scientific approaches, demonstrating the interdisciplinary essence of ethnopharmacology. These results emphasize the potential value of traditional medicine in addressing autoimmune disorders. AIM OF THE STUDY: This study aims to address the effect of JP in MRL/lpr mice and elucidate the pharmacological mechanism by which JP targets CD11a and CD70 DNA methylation via the miR-29b-sp1/DNMT1 pathway. MATERIALS AND METHODS: MRL/lpr mice were divided into three groups: the model group (received distilled water), the positive group (administered AAV/miR-29b-3p inhibitor), and the JP group (treated with JP decoction). C57BL/6 mice were constituted as a control group. Through ELISA assay, serum and urine samples were assessed for anti-dsDNA, TNF-α, TGF-ß, IL-2, and UP. HE and Masson staining were conducted to reveal renal pathology. Genome DNA was extracted from CD4+ T cells of mice spleens to evaluate methylation level. The methylation of CD11a, CD70, and CD40L promoter regions was analyzed by targeted bisulfate sequencing. Their expression at the mRNA and protein levels was examined using quantitative real-time PCR, western blot analysis, immunohistochemistry, and immunofluorescence staining of kidney tissues. Furthermore, the molecular mechanisms underlying the regulation of the miR-29b-sp1/DNMT1 pathway by JP were explored with Jurkat cells transfected with miR-inhibitors or miR-mimics. RESULTS: Mice treated with JP exhibited a significant decrease in anti-dsDNA, TNF-α, TGF-ß, and UP, accompanied by a significant increase in IL-2. HE staining revealed JP effectively mitigated renal inflammatory response, while Masson staining indicated a reduction in collagen fiber content. In addition, JP exhibited a significant impact on the global hypomethylation of SLE, as evidenced by the induction of high methylation levels of CD11a and CD70 promoter regions, mediated through the miR-29b-sp1/DNMT1 pathway. CONCLUSION: Our findings demonstrate JP exerts a protective effect against spontaneous SLE development, attenuates renal pathological changes, and functions as a miRNA inhibitor to enhance CD11a and CD70 DNA methylation through the modulation of the miR-29b-sp1/DNMT1 pathway.

Targets of Tripterygium glycosides in systemic lupus erythematosus treatment: A network-pharmacology study.

OBJECTIVE: We aimed to explore the underlying mechanism of Tripterygium glycosides (TGs) in treating systemic lupus erythematosus (SLE) through network-pharmacology approach. METHODS: The protein targets of TGs' three active ingredients (triptolide, tripterine, and wilforlide) and SLE were identified by database search. Then, the intersection of the two groups was studied. The drug-target network between the active ingredients of TGs and the overlapping genes was constructed, visualized, and analyzed with Cytoscape software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment were performed to analyze these genes. Finally, we validated our predictions of the potential targets through docking study. RESULTS: A total of 55 overlapping genes were discovered. Results suggested that the TGs' mechanism in SLE treatment was associated with heat shock protein family A member 5, heat shock protein family A member 8, eukaryotic translation elongation factor 1 alpha 1, and so forth with their related 4042 gene network, which regulated ribosome, spliceosome, viral carcinogenesis, Epstein-Barr virus infection signaling, and so forth. Molecular-docking analysis proved that hydrogen bonding was the main form of interaction. CONCLUSIONS: Our research provided the protein targets affected by TGs in SLE treatment. The key targets (CASP3, MAPK1, HIF1A, and so forth) involving 4042 proteins became the multitarget mechanism of TGs in SLE treatment.

Phospholipase A1 Member A Activates Fibroblast-like Synoviocytes through the Autotaxin-Lysophosphatidic Acid Receptor Axis.

Lysophosphatidylserine (lysoPS) is known to regulate immune cell functions. Phospholipase A1 member A (PLA1A) can generate this bioactive lipid through hydrolysis of sn-1 fatty acids on phosphatidylserine (PS). PLA1A has been associated with cancer metastasis, asthma, as well as acute coronary syndrome. However, the functions of PLA1A in the development of systemic autoimmune rheumatic diseases remain elusive. To investigate the possible implication of PLA1A during rheumatic diseases, we monitored PLA1A in synovial fluids from patients with rheumatoid arthritis and plasma of early-diagnosed arthritis (EA) patients and clinically stable systemic lupus erythematosus (SLE) patients. We used human primary fibroblast-like synoviocytes (FLSs) to evaluate the PLA1A-induced biological responses. Our results highlighted that the plasma concentrations of PLA1A in EA and SLE patients were elevated compared to healthy donors. High concentrations of PLA1A were also detected in synovial fluids from rheumatoid arthritis patients compared to those from osteoarthritis (OA) and gout patients. The origin of PLA1A in FLSs and the arthritic joints remained unknown, as healthy human primary FLSs does not express the PLA1A transcript. Besides, the addition of recombinant PLA1A stimulated cultured human primary FLSs to secrete IL-8. Preincubation with heparin, autotaxin (ATX) inhibitor HA130 or lysophosphatidic acid (LPA) receptor antagonist Ki16425 reduced PLA1A-induced-secretion of IL-8. Our data suggested that FLS-associated PLA1A cleaves membrane-exposed PS into lysoPS, which is subsequently converted to LPA by ATX. Since primary FLSs do not express any lysoPS receptors, the data suggested PLA1A-mediated pro-inflammatory responses through the ATX-LPA receptor signaling axis.

Genetically determined selenium concentrations and risk for autoimmune diseases.

OBJECTIVE: Observational epidemiologic studies have reported a relationship between selenium status and risk for autoimmune diseases. However, the associations are susceptible to confounding or reverse causality. Thus, the aim of this study was to investigate the potential causal associations of selenium concentrations with the risk for common autoimmune diseases using a two-sample Mendelian randomization (MR) design. METHODS: A meta-analysis of genome-wide association studies (GWASs) of selenium among 9639 individuals of European ancestry was used to identify genetic instruments. Summary statistics of systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease were obtained from publicly available GWASs, respectively. We conducted MR study using the inverse-variance weighted method, supplemented with weighted median and likelihood-based methods as sensitivity analysis. Cochran Q test and MR-Egger regression were used to detect heterogeneity and potential directional pleiotropy. MR-Pleiotropy RESidual Sum and Outlier test was used to identify outlier single-nucleotide polymorphisms. RESULTS: Genetically predicted high selenium level was associated with a decreased risk for SLE (odds ratio, 0.85; 95% confidence interval, 0.77-0.93; P = 0.001) per natural log-transformed selenium concentrations, with similar results in sensitivity analyses. No evidence of heterogeneity, pleiotropy, or outlier single-nucleotide polymorphisms were detected (all P > 0.05). However, genetically determined selenium concentrations may be not associated with risk for rheumatoid arthritis or inflammatory bowel disease in the primary analysis and subsequent sensitivity analyses. CONCLUSIONS: The present study suggested a protective role of selenium on the risk for systemic lupus erythematosus. Further studies are warranted to elucidate the underlying mechanisms.

Inositol-Requiring Enzyme 1α-Mediated Synthesis of Monounsaturated Fatty Acids as a Driver of B Cell Differentiation and Lupus-like Autoimmune Disease.

OBJECTIVE: To explore the molecular mechanisms underlying dysregulation of lipid metabolism in the pathogenesis of systemic lupus erythematosus (SLE). METHODS: B cells in peripheral blood from patients with SLE and healthy controls were stained with BODIPY dye for detection of lipids. Mice with targeted knockout of genes for B cell-specific inositol-requiring enzyme 1α (IRE-1α) and stearoyl-coenzyme A desaturase 1 (SCD-1) were used for studying the influence of the IRE-1α/SCD-1/SCD-2 pathway on B cell differentiation and autoantibody production. The preclinical efficacy of IRE-1α suppression as a treatment for lupus was tested in MRL.Faslpr mice. RESULTS: In cultures with mouse IRE-1α-null B cells, supplementation with monounsaturated fatty acids largely rescued differentiation of plasma cells from B cells, indicating that the compromised capacity of B cell differentiation in the absence of IRE-1α may be attributable to a defect in monounsaturated fatty acid synthesis. Moreover, activation with IRE-1α/X-box binding protein 1 (XBP-1) was required to facilitate B cell expression of SCD-1 and SCD-2, which are 2 critical enzymes that catalyze monounsaturated fatty acid synthesis. Mice with targeted Scd1 gene deletion displayed a phenotype that was similar to that of IRE-1α-deficient mice, with diminished B cell differentiation into plasma cells. Importantly, in B cells from patients with lupus, both IRE-1α expression and Xbp1 messenger RNA splicing were significantly increased, and this was positively correlated with the expression of both Scd1 and Scd2 as well as with the amount of B cell lipid deposition. In MRL.Faslpr mice, both genetic and pharmacologic suppression of IRE-1α protected against the pathologic development and progression of lupus-like autoimmune disease. CONCLUSION: The results of this study reveal a molecular link in the dysregulation of lipid metabolism in the pathogenesis of lupus, demonstrating that the IRE-1α/XBP-1 pathway controls plasma cell differentiation through SCD-1/SCD-2-mediated monounsaturated fatty acid synthesis. These findings provide a rationale for targeting IRE-1α and monounsaturated fatty acid synthesis in the treatment of patients with SLE.

Downregulated Serum Exosomal miR-451a Expression Correlates With Renal Damage and Its Intercellular Communication Role in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease characterized by continuous inflammation and the production of autoantibodies. Exosomes, acting as a critical tool for communication between cells, are involved in the pathogenesis of SLE, particularly in inflammation and immune imbalance. In this study, we aimed to extract and confirm the pro-inflammatory effect of serum exosomes in SLE. Then, we attempted to find differentially expressed exosomal microRNAs in the serum of healthy subjects and SLE patients via miRNA microarray analysis and validated the target exosomal microRNA, exosomal miR-451a, which expression level decreased in serum of SLE patients by RT-qPCR. Furtherly, we analyzed the correlation between exosomal miR-451a and disease activity, kidney damage and typing, and traditional medicine therapy. Finally, we investigated the intercellular communication role of exosomal miR-451a in SLE by co-culture assay in vitro. Taken together, our study demonstrated that downregulated serum exosomal miR-451a expression correlated with SLE disease activity and renal damage as well as its intercellular communication role in SLE which provided potential therapeutic strategies.

Genetically Predicted Serum Iron Status Is Associated with Altered Risk of Systemic Lupus Erythematosus among European Populations.

BACKGROUND: Observational epidemiological studies have reported an inconsistent relation between iron status and risk of systemic lupus erythematosus (SLE). Moreover, it remains uncertain whether the observed association is causal or due to confounding or reverse causality. OBJECTIVES: We aimed to investigate the association between serum iron status and risk of SLE using a 2-sample Mendelian randomization (MR) approach. METHODS: Genetic instruments for iron status including serum iron, log-transformed ferritin, transferrin saturation, and transferrin were identified from a large-scale genome-wide association study (GWAS) performed by the Genetics of Iron Status Consortium among 48,972 individuals of European ancestry (55% female). Three independent single nucleotide polymorphisms (rs1800562, rs1799945, and rs855791) concordantly related with 4 iron status biomarkers were selected as instrumental variables. Summary statistics of SLE were obtained from a publicly available GWAS of 4036 patients with SLE and 6959 controls of European descent. The MR study was conducted using the inverse-variance weighted (IVW) method, supplemented with MR-Egger regression and simple- and weighted-median methods. Leave-one-out analysis was further performed to test the robustness of our findings. ORs with 95% CIs were calculated. RESULTS: Genetically predicted iron status was associated with altered risk of SLE, with ORs of 0.79 (95% CI: 0.66, 0.94), 0.54 (95% CI: 0.34, 0.85), 0.82 (95% CI: 0.71, 0.94), and 1.36 (95% CI: 1.06, 1.76) per 1-SD increase in iron, log-transformed ferritin, transferrin saturation, and transferrin using the IVW method, respectively. MR-Egger regression did not indicate potential pleiotropic bias. Sensitivity analyses produced similar findings, suggesting the robustness of the association. CONCLUSIONS: Our study suggested that high iron status may be associated with a reduced risk of SLE among European populations. Further studies are warranted to elucidate the mechanism underlying the protective role of iron against susceptibility to SLE.

DNA methylation was involved in total glucosides of paeony regulating ERα for the treatment of female systemic lupus erythematosus mice.

Total glucosides of paeony (TGP) is a bioactive compound extracted from paeony roots and has been used in therapy for autoimmune diseases. However the molecular mechanism of TGP in the therapy of autoimmune diseases remains unclear. ERα has a pro-inflammatory role in SLE disease. In this study, we found that TGP treatment significantly decreased the expression of ERα by up-regulating ERα promoter methylation levels. Further investigation revealed that treatment with TGP increased the expression of DNMT in lupus mice. We also used DNA methyltransferase inhibitors to verify whether DNA methylation was involved in these process. HE staining results showed that TGP can reduce renal injury in SLE mice. Moreover, cytokines including IFN-γ, IL6 and IL12 expression and dsDNA levels in serum were inhibited by TGP treatment. These findings indicate that TGP inhibits autoimmunity in SLE mice possibly by downregulate ERα expression, which may in turn be due to its ability to regulate the methylation status of the ERα promoter.

Monogenic Lupus: A Developing Paradigm of Disease.

Monogenic lupus is a form of systemic lupus erythematosus (SLE) that occurs in patients with a single gene defect. This rare variant of lupus generally presents with early onset severe disease, especially affecting the kidneys and central nervous system. To date, a significant number of genes have been implicated in monogenic lupus, providing valuable insights into a very complex disease process. Throughout this review, we will summarize the genes reported to be associated with monogenic lupus or lupus-like diseases, and the pathogenic mechanisms affected by the mutations involved upon inducing autoimmunity.

Coffee consumption and the risk of rheumatoid arthritis and systemic lupus erythematosus: a Mendelian randomization study.

We aimed to analyze the causal association between coffee consumption and the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We performed a two-sample Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW), MR-Egger regression, and weighted median methods. We used publicly available summary statistics datasets of coffee consumption genome-wide association studies (GWASs) as an exposure variable and RA and SLE GWASs as outcomes. Four single-nucleotide polymorphisms (SNPs) from GWASs of coffee consumption were selected as instrumental variables (IVs) to improve inference: NCARD (rs16868941), POR (rs17685), CYP1A1 (rs2470893), and LAMB4 (rs382140). The IVW method showed a causal association between coffee consumption and RA (beta = 0.770, SE = 0.279, p = 0.006). MR-Egger regression revealed that directional pleiotropy was unlikely to be biasing the result (intercept = - 0.145, p = 0.451). While the MR-Egger analysis showed no causal association between coffee consumption and RA (beta = 2.744, SE = 1.712, p = 0.355), the weighted median approach demonstrated a causal association between coffee consumption and RA (beta = 0.751, SE = 0.348, p = 0.031). However, the associations based on the weighted median analyses after the Bonferroni correction were not significant (adjusted p values = 0.091). The IVW, MR-Egger analysis, and weighted median methods showed no causal association between coffee consumption and SLE risk (beta = 0.594, SE = 0.437, p = 0.209; beta = 3.100, SE = 3.632, p = 0.550; beta = 0.733, SE = 0.567, p = 0.196). MR analysis results do not support causal associations between coffee consumption and the development of RA and SLE.

Paeoniflorin inhibits activation of the IRAK1-NF-κB signaling pathway in peritoneal macrophages from lupus-prone MRL/lpr mice.

Systemic lupus erythematosus (SLE) is a chronic and multisystemic autoimmune disease. Interleukin-1 receptor-associated kinase 1 (IRAK1) is associated with the susceptibility of SLE in humans and paeoniflorin has recently been reported to exhibit immunosuppressive properties. The aim of this study was to determine the effect of paeoniflorin on lipopolysaccharide (LPS)-triggered macrophage activation and and its role in LPS-induced IRAK1-nuclear factor κB (NF-κB) signaling pathways. Peritoneal macrophages from lupus-prone MRL/lpr mice and ICR mice were isolated, prepared and cultured. Cells were treated with LPS alone or LPS with paeoniflorin, and macrophage proliferation was analyzed using the CCK8 assay. The expression of IRAK1 in cells was analyzed by immunofluorescence staining. The level of gene expression of IRAK1, NF-κB, tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) was measured by RT-PCR, and TNF-α, IL-6 levels in the cell supernatant were determined by ELISA. The protein expression of IRAK1 and downstream molecules tumor necrosis factor receptor-associated factor 6 (TRAF6), inhibitor of nuclear factor kappa-B kinase (IKK), NF-kappa-B inhibitor alpha (IKBα), and NF-κB was detected by Western-blot analysis. Paeoniflorin was found to decrease the phosphorylation of IRAK1 and its downstream proteins induced by LPS and inhibit the expression of TNF-α and IL-6. Taken together, the data obtained indicate that paeoniflorin inhibits LPS-induced cell activation by inhibiting the IRAK1-NF-κB pathway in MRL/lpr mouse macrophages. Therefore, paeoniflorin may be a potential therapy for SLE.

Effects of Arsenic Trioxide on INF-gamma Gene Expression in MRL/lpr Mice and Human Lupus.

Arsenic trioxide (As2O3; ATO), a traditional Chinese medicine, is used to treat patients with acute promye-locytic leukemia, while its application for treatment of systemic lupus erythematosus (SLE) is still under evaluation. The high expression of INF-gamma (INF-γ) is a primary pathogenic factor in SLE. It is found that ATO can reduce INF-γ expression levels in lupus-prone mice, whereas it is not clear whether ATO has the same effect on SLE patients. Therefore, this study was to investigate the underlying mechanism of the effects of ATO on the expression of INF-γ in splenocytes of MRL/lpr mice and PBMCs of human lupus. The mRNA and protein expression levels of INF-γ were assessed by real-time RT-PCR and ELISA, respectively. The histone acetylation status of the INF-γ promoter and the binding of RNA polymerase II (RNA Pol II) to the INF-γ promoter were detected using a chromatin immunoprecipitation (ChIP) technique. The mRNA and protein expression levels of INF-γ decreased in both splenocytes of MRL/lpr mice and PBMCs of SLE patients with ATO treatment, which were accompanied by reduced histone H4 and H3 acetylation in INF-γ promoter and decreased combination of RNA Pol II to the INF-γ promoter. Therefore, ATO may reduce the expression level of the INF-γ by altering the levels of INF-γ promoter acetylation and the combination of RNA Pol II to the INF-γ promoter in splenocytes of MRL/lpr mice and PBMCs of SLE patients.

Epigenetics of inflammatory arthritis.

PURPOSE OF REVIEW: Aberrant epigenetic changes in DNA methylation, histone marks, and noncoding RNA expression regulate the pathogenesis of many rheumatic diseases. The present article will review the recent advances in the epigenetic profile of inflammatory arthritis and discuss diagnostic biomarkers and potential therapeutic targets. RECENT FINDINGS: Methylation signatures of fibroblast-like synoviocytes not only distinguish rheumatoid arthritis (RA) and osteoarthritis (OA), but also early RA from late RA or juvenile idiopathic arthritis. Methylation patterns are also specific to individual joint locations, which might explain the distribution of joint involvement in some rheumatic diseases. Hypomethylation in systemic lupus erythematosus (SLE) T cells is, in part, because of active demethylation and 5-hydroxymethylation. The methylation status of some genes in SLE is associated with disease severity and has potential as a diagnostic marker. An integrative analysis of OA methylome, transcriptome, and proteome in chondrocytes has identified multiple-evidence genes that might be evaluated for therapeutic potential. Class-specific histone deacetylase inhibitors are being evaluated for therapy in inflammatory arthritis. SUMMARY: Disease pathogenesis is regulated by the interplay of genetics, environment, and epigenetics. Understanding how these mechanisms regulate cell function in health and disease has implications for individualized therapy.

Effect of Lang-Chuang-Ding Decoction () on DNA Methylation of CD70 Gene Promoter in Peripheral Blood Mononuclear Cells of Female Patients with Systemic Lupus Erythematosus.

OBJECTIVE: To investigate the effect of Lang-chuang-ding Decoction (, LCD) on the expression of DNA methylation of CD70 gene promoter in peripheral blood mononuclear cells (PBMCs) of females with systemic lupus erythematosus (SLE). METHODS: PBMCs isolated from female patients with SLE or healthy donors were cultured and treated with LCD medicated serum or normal serum for 24 or 48 h. The mRNA expressions of CD70 gene in PBMCs were detected by reverse transcription polymerase chain reaction (PCR); the DNA methylation of the CD70 gene promoter region was detected by methylation-specific PCR. RESULTS: After treated with medicated serum for 48 h, the mRNA expression levels of CD70 in PBMCs of SLE patients were signifificantly higher than those of healthy donors (P<0.05); the DNA methylation levels of CD70 promoter region in PBMCs of SLE patients treated with medicated serum for 48 h were signifificantly higher than those treated with fetal bovine serum (P<0.01). CONCLUSION: LCD could inhibit CD70 gene expression in PBMCs of SLE patients by promoting the DNA methylation of CD70 gene promoter.

Leptin and autoimmune disease.

Leptin is secreted from adipocytes and acts mainly on the hypothalamus causing weight loss due to suppression of appetite and increased energy expenditure. On the other hand, the leptin receptor is also expressed in hematopoietic cells and its action on the immune system has become known, and the significance of leptin in autoimmune diseases has gradually become clear. It has been shown that leptin acts as an exacerbating factor in many autoimmune diseases and it is suggested that inhibition of leptin signal may be a novel therapeutic method for autoimmune diseases. In this article, we will outline the significance of leptin in the immune system based on the current reports.

TNFAIP3 downregulation mediated by histone modification contributes to T-cell dysfunction in systemic lupus erythematosus.

Objective: TNF-α-induced protein 3 ( TNFAIP3 ) is one of the major SLE susceptibility genes involved in the regulation of inflammatory responses through modulation of the nuclear factor-κB (NF-κB) pathway. We aim to assess TNFAIP3 expression in CD4 + T cells and the molecular mechanism underlying TNFAIP3 regulation in the pathogenesis of SLE. Methods: The expression and epigenetic regulation of TNFAIP3 in CD4 + T cells from SLE patients and normal controls (NCs) were investigated by RT-quantitative PCR, western blot and chromatin immunoprecipitation. The functional effect of TNFAIP3 was further evaluated by knockdown or overproduction of TNFAIP3 in CD4 + T cells from SLE patients and NCs. Results: TNFAIP3 mRNA was significantly downregulated in the CD4 + T cells of SLE patients compared with NCs. The reduced expression of TNFAIP3 was associated with the reduction of H3K4me3 in the gene promoter region. Functional blockage of TNFAIP3 in normal CD4 + T cells using small interfering RNA increased the expression of IFN-γ and IL-17, but not IL-2, IL-4 and IL-5. Nevertheless, overexpression of TNFAIP3 in CD4 + T cells from SLE patients resulted in the suppression of IFN-γ and IL-17 production. Conclusion: The downregulation of TNFAIP3 in CD4 + T cells of SLE was potentially regulated by demethylation of histone H3K4, which led to a decreased amount of H3K4me3 in the promoter of the TNFAIP3 gene. The dysregulation of TNFAIP3 in CD4 + T cells may contribute to the pathogenesis of SLE by overproduction of inflammatory cytokine IFN-γ and IL-17. TNFAIP3 may serve as a promising target for the treatment of SLE in clinical practice.

Combined role of vitamin D status and CYP24A1 in the transition to systemic lupus erythematosus.

OBJECTIVE: We examined whether measures of vitamin D were associated with transitioning to systemic lupus erythematosus (SLE) in individuals at risk for SLE. METHODS: 436 individuals who reported having a relative with SLE but who did not have SLE themselves were evaluated at baseline and again an average of 6.3 (±3.9) years later. Fifty-six individuals transitioned to SLE (≥4 cumulative American College of Rheumatology criteria). 25-Hydroxyvitamin D (25[OH]D) levels were measured by ELISA. Six single-nucleotide polymorphisms in four vitamin D genes were genotyped. Generalised estimating equations, adjusting for correlation within families, were used to test associations between the vitamin D variables and the outcome of transitioning to SLE. RESULTS: Mean baseline 25[OH]D levels (p=0.42) and vitamin D supplementation (p=0.65) were not different between those who did and did not transition to SLE. Vitamin D deficiency (25[OH]D <20 ng/mL) was greater in those who transitioned compared with those who did not transition to SLE (46% vs 33%, p=0.05). The association between 25[OH]D and SLE was modified by CYP24A1 rs4809959, where for each additional minor allele increased 25[OH]D was associated with decreased SLE risk: zero minor alleles (adjusted OR: 1.03, CI 0.98 to 1.09), one minor allele (adjusted OR: 1.01, CI 0.97 to 1.05) and two minor alleles (adjusted OR: 0.91, CI 0.84 to 0.98). Similarly, vitamin D deficiency significantly increased the risk of transitioning to SLE in those with two minor alleles at rs4809959 (adjusted OR: 4.90, CI 1.33 to 18.04). CONCLUSIONS: Vitamin D status and CYP24A1 may have a combined role in the transition to SLE in individuals at increased genetic risk for SLE.