Kuan Lai

Systemic lupus erythematosus (SLE) is a chronic, heterogeneous autoimmune disease influenced by various genetic and environmental factors, and recent advances have established type I interferons (IFN‐I) as pivotal drivers. This study comprehensively characterises IFN‐I risk gene signatures in SLE. The IFN‐I–related genes were obtained from GSE185047, and then Mendelian randomisation analysis using data from the FinnGen cohort (705 SLE cases, 385 509 controls) was utilised as a discovery set to identify IFN‐I related risk genes. Single‐cell RNA sequencing (scRNA‐seq) and external cohorts were used to validate the four key signatures. Univariate and multivariate linear regression models assessed associations between gene expression and clinical parameters. DNA methylation analysis further evaluated epigenetic dysregulation in SLE immune subsets. Thirty‐eight IFN‐I‐related genes were identified, and Mendelian randomisation analysis revealed robust causal associations between four genes ( HERC5 , IFIT3 , IFI44L and IFI6 ) and SLE risk, with no heterogeneity or pleiotropy. ScRNA‐seq demonstrated significant upregulation of these gene signatures in SLE PBMCs and monocytes (except IFIT3 in monocytes), along with altered immune cell proportions—specifically, increased monocytes and decreased T cells. External validation confirmed elevated expression of all four genes in SLE, with high diagnostic accuracy. Clinically, increased expression of these genes correlated with SLEDAI, reduced lymphocyte counts and lower complement C4 levels. Furthermore, DNA hypomethylation of IFI44L was observed across multiple SLE immune subsets, indicating epigenetic dysregulation. This study establishes HERC5 , IFIT3 , IFI44L and IFI6 as causal IFN‐I risk genes in SLE and identifies IFI44L hypomethylation as a key epigenetic driver of IFN‐I pathway activation. These findings offer new insights into SLE pathogenesis and highlight potential diagnostic biomarkers and therapeutic targets.

Objectives: This retrospective study aims to characterise the epidemiological features of systemic lupus erythematosus (SLE) concomitant with chronic spontaneous urticaria (CSU), examines the correlation between CSU occurrence and lupus disease activity, and identifies comorbidity patterns and risk factors associated with SLE-CSU. Methods: A total of 40 SLE patients with concomitant CSU and 160 age-matched and sex-matched SLE controls without CSU were included. The Mann-Whitney U-test was used to assess disease activity at SLE onset in both groups. A Wilcoxon signed-rank test was conducted to compare the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores before and after CSU onset in patients with SLE. χ ² tests were applied to evaluate differences in SLE activity grading, clinical manifestations, laboratory findings and treatments between patients with SLE with and without CSU. In addition, univariate and multivariate logistic regression analyses were performed to identify risk factors for CSU development in patients with SLE. Results: Wilcoxon signed-rank tests revealed that in the SLE-CSU group, the occurrence of CSU did not result in an increase of SLEDAI scores. Univariate analysis revealed significant differences between the SLE-CSU and SLE-only groups in the presence of cylindruria, elevated IgM, IgA, IgG, serositis, mucosal ulcers and anti-Pm-Scl antibodies (p<0.05). Multivariate logistic regression analysis identified cylindruria (OR: 6.152, CI 2.352 to 16.093, p＜0.001), elevated IgA (OR: 7.598, CI 1.194 to 48.368, p=0.032), elevated IgG (OR: 3.252, CI 1.331 to 7.946, p=0.010) and mucosal ulcers (OR: 3.838, CI 1.166 to 12.637, p=0.027) as independent risk factors for CSU occurrence in patients with SLE. Conclusion: The presence of CSU in patients with SLE does not necessarily indicate increased lupus activity. Rather, cylindruria, mucosal ulcers and elevated IgA and IgG levels were identified as independent risk factors for CSU in patients with SLE.

Background: Systemic lupus erythematosus is a common autoimmune disease. Studies have suggested that defective stem cells could be involved in the pathogenesis of systemic lupus erythematosus, which leads to changes in the function of immune cells. By observing the cell morphology, autophagy, and senescence of bone marrow mesenchymal stem cells (BMSCs) from lupus mice and normal controls, this study investigated the role of IL-6 in autophagy and senescence of BMSCs and explored relevant mechanisms. Method: Female MRL/lpr and C57 mice with similar weights and sizes at 20–22 weeks old were selected. BMSCs were isolated using the whole bone marrow adherent method. Quantitative real-time polymerase chain reaction, β-galactosidase staining, western blotting, and ELISA were used to detect autophagy and senescence. Result: Compared with BMSCs from normal mice, BMSCs from lupus mice exhibited low autophagy and premature senescence with a senescence-associated secretory phenotype. The addition of exogenous IL-6 increased the protein levels of p-STAT3 and Bcl-2, and in the IL-6-treated group, the premature senescence of cells increased and autophagy decreased. Conclusion: The biological functions of BMSCs from MRL/lpr lupus mice were impaired. IL-6 prevents autophagy and subsequently promotes the senescence of BMSCs by activating the IL-6/STAT3 pathway.

Introduction Systemic lupus erythematosus (SLE) is a heterogeneous and chronic autoimmune disease. Aberrant DNA methylation occurs during various processes of SLE development regulating the mRNA expression of interrelated genes. This study aims to screen potential DNA methylation markers for SLE. Methods Gene expression and methylation datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between SLE patients and healthy controls were screened using the limma R package, and differentially methylated positions (DMPs) and regions (DMRs) were identified using dmpfinder and bumphunter (minfi). Additionally, the DNA methylation markers to distinguish SLE patients from healthy controls were explored through receiver operating characteristic (ROC) curves and logistic regression analyses. Finally, we validated the results of the bioinformatic analysis by pyrosequencing. Results In total, 91 DEGs, 90,092 DMPs, 15 DMRs, and 13 DMR-associated genes were identified. Through the integrative analysis of DEG- and DMR-associated genes, we identified five type I interferon (IFN)-related genes as key epigenetic-driven genes in SLE. GO enrichment analysis showed that the five SLE-associated epigenetic-driven genes were mainly enriched in the type I IFN signaling pathway involved in immune response and defense response to virus. Moreover, we identified two SLE-specific DNA methylation markers, three SLE without lupus nephritis (SLE-LN⁻)-specific DNA methylation markers, and two SLE with lupus nephritis (SLE-LN⁺)-specific DNA methylation markers by stepwise logistic regression. Conclusions Overall, our study demonstrates potential DNA methylation markers of SLE, SLE-LN⁻, and SLE-LN⁺, which may help the diagnosis, boost the development of new epigenetic therapy, and contribute to individualized treatment. Key Points • This study identified five type I IFN-related genes as key epigenetic-driven genes in SLE, which support the importance of the type I IFN pathway in the pathogenesis of SLE • We identified novel DNA methylation biomarkers in SLE, SLE-LN−, and SLE-LN+ by a comprehensive analysis of bioinformatics methods and executed experimental validation, and binary logistic regression analysis showed that they have excellent potential • These results may provide new insights into the biological mechanisms of SLE, and identify reliable biomarkers for SLE, SLE-LN−, and SLE-LN+, which may contribute to diagnosis and individualized treatment

Objective. Lupus nephritis is the most common and severe complication of systemic lupus erythematosus. The aim of our study was to investigate the efficacy of miR-20a overexpressing adipose-derived stem cell (ADSC) transplantation in murine lupus nephritis (LN) and explore potential molecular mechanisms. Methods. Mouse ADSCs were transfected with a miR-20a lentiviral vector to obtain miR-20a overexpression ADSCs (miR-20a-ADSCs). We first observed the influence of miR-20a on ADSC viability and apoptosis in vitro. B6.MRL/lpr mice were administered ADSC/miR-20a-ADSC intravenously every week from age 30 to 33 weeks, and the lupus and normal control groups received PBS on the same schedule. Results. miR-20a expression increased in miR-20a-ADSC-derived exosomes, and miR-20a overexpression promoted ADSC proliferation and inhibited apoptosis. Compared with ADSCs, miR-20a-ADSC treatment significantly improved serologic and histologic abnormalities, as evidenced by reduced serum creatinine, anti-dsDNA antibody, 24h urine protein levels, nephritis scores, and C3/IgG deposits. Furthermore, miR-20a-ADSC treatment resulted in downregulated Akt, mTOR, and p62 expression and upregulated miR-20a, Beclin 1, and LC3 II/I expression compared with ADSC treatment. After treatment with miR-20a-ADSC, a significant increase in the number of autophagosomes within podocytes was observed, along with upregulated expression of podocin and nephrin, compared with the ADSC group. Conclusions. miR-20a-ADSC transplantation prevents the development of lupus nephritis and significantly ameliorates already-established disease, and its mechanism is related to autophagy by targeting the miR-20a-regulated mTOR pathway.

Background: Pemphigus is an autoimmune disease of the skin and mucous membranes. Glucocorticoids have been the most effective drug for the treatment of pemphigus; however, some patients are insensitive to glucocorticoid therapy. Cyclophosphamide has been extensively used in the treatment of pemphigus. Objectives: To observe and evaluate the efficacy and safety of high-dose glucocorticoid with weekly intravenous cyclophosphamide in the treatment of refractory pemphigus vulgaris insensitive to glucocorticoids. Methods: Clinical data of 19 patients with refractory pemphigus vulgaris (insensitive to glucocorticoid) who were treated with high-dose glucocorticoids(1.5 mg/kg/day prednisone) and weekly intravenous infusion of cyclophosphamide, and 24 patients who were sensitive to glucocorticoid therapy received a medium dose of glucocorticoid alone (1 mg/kg/day prednisone) were retrospectively analyzed. Results: By the time the disease was brought under control, the average total dose of cyclophosphamide was 2.02 g. Comparison between the glucocorticoid-insensitive and glucocorticoid-sensitive groups showed that the average time to disease control was 2.68 vs. 2 weeks, and the average daily dosage of steroid was 1.33 ± 0.53 vs. 0.90 ± 0.28 mg/kg. At the 12- and 18-month follow-ups, the recurrence rate of the glucocorticoid-insensitive group was significantly lower than that of the sensitive group (5.3 vs. 37.5%, 15.8 vs. 45.8%). No serious adverse reactions were observed. Conclusion: High-dose glucocorticoid plus weekly intravenous infusion of cyclophosphamide safely, effectively, and rapidly controlled the conditions of the patients with refractory pemphigus who were insensitive to glucocorticoids, shortened the duration of hospitalization, avoided the risk of complications that could be caused by further increasing the dose of glucocorticoids (>1.5 mg/kg/day), and lowered the recurrence rate within 18 months.

(2019). Proliferative Sweet syndrome associated with pregnancy and low-molecular-weight heparin sodium. Scandinavian Journal of Rheumatology. Ahead of Print.

Objective: The aim of our study was to investigate the efficacy of adipose-derived stem cells (ADSC) transplantation in systemic lupus erythematosus (SLE) and to determine the mechanism of ADSC transplantation. Methods: B6.MRL/lpr mice were administered ADSC intravenously every week from age 28 to 31 weeks, while the lupus control group and the normal control received phosphate buffered solution (PBS) on the same schedule. Results: Compared with the lupus control group, the ADSC treatment group had a significant improvement of histologic abnormalities, serologic abnormalities, and immunologic function. Anti-double-stranded DNA antibodies, spleen/weight ratio, deposits of C3/IgG in the kidney, and serum creatinine and blood urea nitrogen levels were significantly decreased with the transplantation of ADSC. A significant decrease of the Th17/CD4⁺ T cell ratio in the spleen, the serum IL-17 concentration, as well as renal IL-17 expression was observed in the ADSC treatment group. Western blot results also showed that ADSC treatment had a lower expression of protein kinase B (Akt), p-Akt, mTOR, p-mTOR, p70S6K, p-p70S6K, and HIF-1α. Conclusion: ADSC treatment can prevent the development of lupus nephritis and significantly ameliorate already-established disease. ADSC treatment reduced Akt, mTOR, p70S6K, HIF-1α, and that this inhibition can avert IL-17-induced inflammation, suggesting that ADSC may be a promising treatment for SLE.