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Abstract Vitamin D deficiency is increasingly common in systemic lupus erythematosus (SLE) patients and is associated with the disease activity and proteinuria. Recently, alterations in metabolism have been recognized as key regulators of SLE pathogenesis. Our objective was to identify differential metabolites in the serum metabolome of SLE with vitamin D deficiency. In this study, serum samples from 31 SLE patients were collected. Levels of 25(OH)D3 were assayed by ELISA. Patients were divided into two groups according to their vitamin D level (20 ng/ml). Untargeted metabolomics were used to study the metabolite profiles in serum by high-performance liquid chromatography-tandem mass spectrometry. Subsequently, we performed metabolomics profiling analysis to identify 52 significantly altered metabolites in vitamin D deficient SLE patients. The area under the curve (AUC) from ROC analyses was calculated to assess the diagnostic potential of each candidate metabolite biomarker. Lipids accounted for 66.67% of the differential metabolites in the serum, highlighted the disruption of lipid metabolism. The 52 differential metabolites were mapped to 27 metabolic pathways, with fat digestion and absorption, as well as lipid metabolism, emerging as the most significant pathways. The AUC of (S)-Oleuropeic acid and 2-Hydroxylinolenic acid during ROC analysis were 0.867 and 0.833, respectively, indicating their promising diagnostic potential. In conclusion, our results revealed vitamin D deficiency alters SLE metabolome, impacting lipid metabolism, and thrown insights into the pathogenesis and diagnosis of SLE.

Abstract Background Apoptotic cell‐conditioned mesenchymal stem cells (AC‐MSCs) exhibit stronger T cell suppressive ability via cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2); however, whether AC‐MSCs exhibit enhanced therapeutic effects on systemic lupus erythematosus (SLE) remains unknown. Methods Splenocytes from MRL/MPJ‐Faslpr (MRL/lpr) mice were cocultured with AC‐MSCs, and the proportion of plasma cells was determined by flow cytometry. MSCs, AC‐MSCs, COX2 knockdown MSCs, and COX2 knockdown AC‐MSCs were infused into MRL/lpr mice (n = 10/group). Survival rates and lupus symptoms, including proteinuria, kidney injury, renal immune complex deposition, and autoantibody production, were assessed. Additionally, the number of plasma cells and serum levels of inflammatory cytokines were measured. Results The AC‐MSCs significantly inhibited plasma cells via PGE2 after 24 h coculture in vitro, whereas MSCs did not. In the MRL/lpr mice, AC‐MSC treatment led to a significantly higher survival rate than phosphate‐buffered saline (PBS) treatment (90% vs. 50%, p

Abstract Introduction This study aimed to analyze the risk factors associated with isoniazid-resistant and rifampicin-susceptible tuberculosis (Hr-TB) in adults. Method The clinical data of 1,844 adult inpatients diagnosed with culture-positive pulmonary tuberculosis (PTB) in Nanjing Second Hospital from January 2019 and December 2021 were collected. All culture positive strain from the patient specimens underwent drug susceptibility testing (DST). Among them, 166 patients with Hr-TB were categorized as the Hr-TB group, while the remaining 1,678 patients were classified as having drug-susceptible tuberculosis (DS-TB). Hierarchical logistic regression was employed for multivariate analysis to identify variables associated with Hr-TB. Results: Multivariate logistic regression analysis revealed that individuals with diabetes mellitus (DM) (OR 1.472, 95% CI 1.037–2.088, p = 0.030) and a history of previous tuberculosis treatment (OR 2.913, 95% CI 1.971–4.306, p = 0.000) were at higher risk of developing adult Hr-TB, with this risk being more pronounced in male patients. Within the cohort, 1,640 patients were newly treated, and among them, DM (OR 1.662, 95% CI 1.123–2.461, p = 0.011) was identified as risk factors for Hr-TB. Conclusions: Diabetes mellitus is a risk factor for Hr-TB in adults, and the contribution of diabetes as a risk factor was more pronounced in the newly treatment or male subgroup. And previous TB treatment history is also a risk factor for Hr-TB in adults.

Abstract Lupus nephritis (LN) occurs in 50% of cases of systemic lupus erythematosus (SLE) and is one of the most serious complications that can occur during lupus progression. Mesangial cells (MCs) are intrinsic cells in the kidney that can regulate capillary blood flow, phagocytose apoptotic cells, and secrete vasoactive substances and growth factors. Previous studies have shown that various types of inflammatory cells can activate MCs for hyperproliferation, leading to disruption of the filtration barrier and impairment of renal function in LN. Here, we characterized the heterogeneity of kidney cells of LN mice by single-nucleus RNA sequencing (snRNA-seq) and revealed the interaction between macrophages and MCs through the CXC motif chemokine ligand 12 (CXCL12)/dipeptidyl peptidase 4 (DPP4) axis. In culture, macrophages modulated the proliferation and migration of MCs through this ligand–receptor interaction. In LN mice, treatment with linagliptin, a DPP4 inhibitor, effectively inhibited MC proliferation and reduced urinary protein levels. Together, our findings indicated that targeting the CXCL12/DPP4 axis with linagliptin treatment may serve as a novel strategy for the treatment of LN via the CXCL12/DPP4 axis.

Abstract Introduction The association between mycophenolate mofetil (MMF) and infection in patients with systemic lupus erythematosus (SLE) has not been clarified. This study evaluated the degree and factors in effect of MMF use on infection in patients with SLE. Methods A hospitalized-based observational study was conducted to collect medical records on patients with SLE during 2010–2021. A nested case–control study was performed among 3339 patients with SLE, including 1577 cases and 1762 controls by whether they developed any type of infection. The exposure of MMF use was determined within 1 year before diagnosed infection or the end of follow-up. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for association between MMF and subsequent infection. Results MMF was significantly associated with the risk of overall infection (adjusted OR 1.90, 95% CI 1.48–2.44) and different types of infections, including bacterial infection (adjusted OR 2.07, 95% CI 1.55–2.75), viral infection (adjusted OR 1.92, 95% CI 1.23–3.01), and opportunistic infection (adjusted OR 2.13, 95% CI 1.31–3.46). The top three risks of specific types of infections were bacteremia/septicemia, urinary tract infection/pyelonephritis, and herpes zoster. Stratification analysis showed risk of overall infection increased especially in MMF users with age over 55 years, diabetes, central nervous system involvement, and thrombocytopenia. Moreover, the risk of infection increased with increasing dosage and duration of MMF use. Additionally, the combination of MMF with CYC and other immunosuppressants significantly increases the risk of infections compared to using a single one. Conclusions MMF use is associated with various type of infections in patients with SLE, particularly in those with longer use, older age, complications with comorbidities, and concomitant use of CYC or other immunosuppressants.

Abstract Background Pulmonary arterial hypertension (PAH) associated with connective tissue diseases (CTD) (CTD‐PAH) remains a difficult challenge in clinical practice. We aimed to evaluate the effects of targeted vasodilators in patients with severe CTD‐PAH. Methods The data of 53 patients with severe CTD‐PAH hospitalized at the Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital of Nanjing University Medical School, were retrospectively reviewed. Patients were followed up for an average of 2 years to track their outcomes. The efficacy of treatment and the survival rate of patients with severe CTD‐PAH were determined. Results Among the causes of severe CTD‐PAH, systemic lupus erythematosus (SLE) was the most common (39.6%), and the age at onset in patients with SLE‐PAH was younger than that of patients with other CTD. Bosentan was more effective than sildenafil in reducing pulmonary artery pressure, improving cardiac function, and increasing survival time. Combination therapy with targeted vasodilators significantly improved the prognosis of patients with severe CTD‐PAH compared with monotherapy. Conclusions Patients with severe CTD‐PAH should be treated early with targeted vasodilators. In this study, bosentan was superior to sildenafil. Combined treatment might be an option for severe CTD‐PAH.

Objective Patients with systemic lupus erythematosus (SLE) have an increased risk of venous thromboembolism (VTE). We conducted this study to develop a risk score algorithm for VTE in patients with SLE that provides individualised risk estimates.Methods We developed a clinical prediction model of VTE in 4502 patients with SLE based on the Chinese SLE Treatment and Research group cohort (CSTAR) from January 2009 to January 2020 and externally validated in 3780 patients with SLE in CSTAR from January 2020 to January 2022. Baseline data were obtained and VTE events were recorded during the follow-up. The prediction model was developed to predict VTE risk within 6 months in patients with SLE, using multivariate logistic regression and least absolute shrinkage and selection operator. SLE-VTE score and nomogram were established according to the model.Results A total of 4502 patients included in the development cohort, 135 had VTE events. The final prediction model (SLE-VTE score) included 11 variables: gender, age, body mass index, hyperlipidaemia, hypoalbuminaemia, C reactive protein, anti-β2GPI antibodies, lupus anticoagulant, renal involvement, nervous system involvement and hydroxychloroquine, with area under the curve of 0.947 and 0.808 in the development (n=4502) and external validation cohort (n=3780), respectively. According to the net benefit and predicted probability thresholds, we recommend annual screening of VTE in high risk (≥1.03%) patients with SLE.Conclusion Various factors are related to the occurrence of VTE in patients with SLE. The proposed SLE-VTE risk score can accurately predict the risk of VTE and help identify patients with SLE with a high risk of VTE who may benefit from thromboprophylaxis.

Introduction Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a variable clinical course, ranging from mild to severe forms. It mainly occurs in women, especially those of fertile age. The aim of the study was to systematically analyze the associations of perinatal disease activity with adverse outcomes of Chinese patients with SLE and their off-spring. Material and methods Data of prenatal SLE patients and healthy pregnant woman admitted to our hospital during the period October 2001 to January 2018 were retrospectively collected, and the status of offspring of SLE patients was followed up in March 2020. Disease activity was evaluated by SLE disease activity index 2000 (SLEDAI-2k), and those with scores > 6 were defined as having active disease. Results In total, 198 deliveries of 194 SLE patients and 199 deliveries of healthy women were documented. Maternal and fetal adverse outcomes occurred in 74 (37.4%) and 90 (45.5%) deliveries of SLE patients, respectively, which were significantly higher than those of healthy subjects. Among SLE patients, the active group had higher rates of gestational hypertension (p < 0.001), reeclampsia/eclampsia (p < 0.001), low birth weight (p < 0.001), premature birth (p < 0.001) and fetal growth restriction (FGR) (p < 0.01) than the inactive group. Multivariate logistic analysis revealed that perinatal renal activity was associated with gestational hypertension (OR 4.43, p < 0.001), preeclampsia/ eclampsia (OR 9.14, p < 0.001), low birth weight (OR 2.24, p < 0.05) and premature birth (OR 4.20, p < 0.001). Compared with the general population, offspring of SLE patients had relatively high rates of eczema (50/142, 35.2%) and congenital heart disease (6/142, 4.2%), which were irrelevant to perinatal disease activity, but related to specific antibodies. Conclusions For perinatal women with SLE, renal activity is associated with a variety of adverse pregnancy outcomes. However, maternal perinatal dis�ease activity does not seem to affect the growth of their offspring

Abstract Studies on clinical features of systemic lupus erythematosus among different age-onset patients are lacking in China. This multicentre study aimed to systemically compare clinical manifestations, comorbidities, organ involvement, and laboratory findings among 797 Chinese juvenile-onset, adult-onset, and late-onset SLE (JSLE, ASLE, and LSLE) patients. They were classified into JSLE, ASLE, and LSLE groups if first diagnosed at < 18, 18–50, and > 50 years old, respectively. Chi-square test and analysis of variance were employed for categorical and continuous variables respectively. In younger-onset patients, the SLE Disease Activity Index 2000 score was significantly higher (JSLE vs. ASLE vs. LSLE = 17.43 ± 9.139 vs. 16.34 ± 8.163 vs. 14.08 ± 6.474, p = 0.031). Mucocutaneous symptoms (79.5% vs. 73.4% vs. 62.0%, p = 0.042), especially malar rash (76.1% vs. 66.1% vs. 53.5%, p = 0.011) occurred more frequently, and proteinuria rate was higher (54.5% vs. 56.3% vs. 36.6%, p = 0.007). In later-onset patients, cardiopulmonary involvement increased (11.4% vs. 24.3% vs. 29.6%, p = 0.012). In ASLE, hypoalbuminemia rate elevated (46.6% vs. 59.9% vs. 47.9%, p = 0.015). Our study demonstrated in a Chinese population that JSLE may be more active and suffer mucocutaneous disorders, while LSLE tended to suffer cardiopulmonary involvement at-onset. These findings may help identify treatment priorities when facing different age-onset SLE patients.

Abstract Environmental exposures interact with genetic factors has been thought to influence susceptibility of systemic lupus erythematosus (SLE) development. To evaluate the effects of environmental exposures on SLE, we conducted a population-based cohort study across Jiangsu Province, China, to examine the associations between the living environment including air and water pollution, population density, economic income level, etc. and the prevalence and mortality of hospitalized SLE (h-SLE) patients. A total of 2231 h-SLE patients were retrieved from a longitudinal SLE database collected by the Jiangsu Lupus Collaborative Group from 1999 to 2009. The results showed that: It existed regional differences on the prevalence of h-SLE patients in 96 administrative districts; The distribution of NO2 air concentration monitored by atmospheric remote sensors showed that three of the ultra-high-prevalence districts were located in the concentrated chemical industry emission area; h-SLE patient prevalence was positively correlated with the excessive levels of nitrogen in drinking water; The positive ratio of pericarditis and proteinuria was positively correlated with the prevalence of h-SLE patients and pollution not only induced a high h-SLE patient prevalence but also a higher mortality rate, which might be attributed to NOx pollution in the air and drinking water. In summary, our data suggested that NOx in air and drinking water may be one of the important predispositions of SLE, especially for patients with renal involvement.

Abstract Objective To explore the modulation of mesenchymal stem cells (MSCs) on T helper 17 (Th17) cells in systemic lupus erythematosus (SLE) and underlying mechanism. Methods The concentration of matrix metalloproteinases (MMPs), CC chemokine ligand‐2 (CCL2), and interleukin‐17 (IL‐17) in the serum of SLE patients and mice were detected by enzyme‐linked immunosorbent assay. The expression of CCR2 and IL‐17 of T lymphocytes were determined by flow cytometry. The effects of MSCs on Th17 cells were analyzed in lupus mice and coculture system in vitro. Results The levels of MMPs, CCL2, IL‐17, CCR2, and percentages of Th17 cells were significantly increased in SLE patients. These molecules and numbers of Th17 cells were downregulated by umbilical cord‐derived MSCs (UC‐MSCs) which relieve SLE disease. CCL2 neutralizing antibody blocked the effects of MSCs on Th17 cells. MMPs reversed the function of CCL2. Conclusion The beneficial effects of MSCs on SLE patients rely on secreting MMPs, which reverse the activity of CCL2 to inhibit Th17 cells, suggesting the crucial MSCs–MMP–CCL2–CCR2–Th17–IL‐17 pathway in SLE.

BackgroundThe aim of this study is to develop survival analysis models of hospitalized systemic lupus erythematosus (h-SLE) patients in Jiangsu province using data mining techniques to predict patient survival outcomes and survival status.MethodsIn this study, based on 1999–2009 survival data of 2453 hospitalized SLE (h-SLE) patients in Jiangsu Province, we not only used the Cox proportional hazards model to analyze patients’ survival factors, but also used neural network models to predict survival outcomes. We used semi-supervised learning to label the censored data and introduced cost-sensitivity to achieve data augmentation, addressing category imbalance and pseudo label credibility. In addition, the risk score model was developed by logistic regression.ResultsThe overall accuracy of the survival outcome prediction model exceeded 0.7, and the sensitivity was close to 0.8, and through the comparative analysis of multiple indicators, our model outperformed traditional classifiers. The developed survival risk assessment model based on logistic regression found that there was a clear threshold, i.e., a survival threshold indicating the survival risk of patients, and cardiopulmonary and neuropsychiatric involvement, abnormal blood urea nitrogen levels and alanine aminotransferase level had the greatest impact on patient survival time. In addition, the study developed a graphical user interface (GUI) integrating survival analysis models to assist physicians in diagnosis and treatment.ConclusionsThe proposed survival analysis scheme identifies disease-related pathogenic and prognosis factors, and has the potential to improve the effectiveness of clinical interventions.

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies. Ribonuclease A family member 2 (RNase2) is known to have antiviral activity and immunomodulatory function. Although RNASE2 level has been reported to be elevated in SLE patients based on mRNA microarray detection, its pathologic mechanism remains unclear. Here, we confirmed that RNASE2 was highly expressed in PBMCs from SLE patients and associated with the proportion of CD11c+T-bet+ B cells, a class of autoreactive B cells also known as age-associated B cells (ABCs). We showed that reduction of RNASE2 expression by small interfering RNA led to the decrease of ABCs in vitro, accompanied by total IgG and IL-10 reduction. In addition, we demonstrated that both RNASE2 and IL-10 in peripheral blood of lupus patients were mainly derived from monocytes. RNASE2 silencing in monocytes down-regulated IL-10 production and consequently reduced ABCs numbers in monocyte-B cell co-cultures, which could be restored by the addition of recombinant IL-10. Based on above findings, we concluded that RNASE2 might induce the production of ABCs via IL-10 secreted from monocytes, thus contributing to the pathogenesis of SLE.

Systemic lupus erythematosus (SLE) patients exist an imbalance between regulatory T (Treg) and T helper 17 cells (Th17), which might be contributed by defective immune regulation of bone marrow derived mesenchymal stem cells (BM-MSCs) from SLE patients. Our microRNA array analysis showed markedly down-regulated expression levels of microRNA let-7f in BM-MSCs from SLE patients compared to those from normal controls (NOR). To explore the role of let-7f in the disease pathogenesis, we showed that expression levels of let-7f in SLE BM-MSCs were negatively associated with SLE disease activity, and the predicted let-7 family targeted gene expression of interlukin-6 (IL-6) was significantly higher in BM-MSCs from SLE patients compared to normal controls (NOR). Transient transfection of BM-MSCs with let-7f mimics or inhibitors showed reduced levels of let-7f impaired the proliferation rate of BM-MSCs, BM-MSC-mediated downregulation of Th17 cells and upregulation of Treg cells, increased the apoptosis rate of BM-MSCs through targeting IL-6 and activating signal transducers and activators of transcription-3 (STAT3) pathway, but had no significant effect on the differentiation of Th1 and Th2. Our findings showed a key role of let-7f in the imbalance of Treg/Th17 mediated by SLE BM-MSCs, suggesting the potential of manipulating let-7f expression in BM-MSCs for treating SLE patients.

Abstract Objective The aim of this study was to evaluate the safety of mesenchymal stem cell infusion in patients with autoimmune diseases. Methods A total of 404 patients with autoimmune diseases who received mesenchymal stem cell infusion between 2007 and 2016 were included in this study. Adverse events in these patients were collected, mainly including infections and malignancies. Sources of information included hospitalization records and data from outpatient visits and each follow-up. Results The mean follow-up period of all patients was 43.4 ± 25.9 months (range 1–109). Majority of stem cells were from the umbilical cord. The most common indications for mesenchymal stem cell infusion were systemic lupus erythematosus, Sjögren’s syndrome, and systemic sclerosis. The median age at infusion was 38.7 ± 15.7 years. The 5-year and 8-year survival rates were 90.4% and 88.9%, respectively. Median follow-up of survivors was 45.1 ± 25.7 months. The incidence rate of infections was 29.5% (119/404), and that of serious infections was 12.9% (52/404). Five patients (1.2%) experienced malignancies. Deaths occurred in 45 patients, and transplantation-related mortality was 0.2%. The most common causes of deaths in our study were disease relapse and complications associated with the underlying disease. Conclusion Autoimmune disease is an emerging indication for mesenchymal stem cell infusion. Our data shows that mesenchymal stem cell infusion is a safe therapy for patients with autoimmune diseases. The incidences of adverse events, whether infections or malignancies, are acceptable in these patients. Trial registration ClinaicalTrials.gov, NCT00698191. Registered 17 June 2008—Retrospectively registered

Abstract Allogeneic mesenchymal stem cell (MSC) transplantation has recently become a promising therapy for patients with systemic lupus erythematosus (SLE). MSCs are a kind of multipotent stem cell than can efficiently modulate both innate and adaptive immune responses, yet those from SLE patients themselves fail to maintain the balance of immune cells, which is partly due to the abnormal genetic background. Clarifying genetic factors associated with MSC dysfunction may be helpful to delineate SLE pathogenesis and provide new therapeutic targets. In this review, the scientific evidence on the genetic contribution to MSC dysfunction in SLE is summarized.

Summary: Allogeneic mesenchymal stem/stromal cells (MSCs) have been widely studied as an alternative cell source for regenerative medicine. Here, we report a long-term follow-up study of allogeneic bone marrow and/or umbilical cord MSC transplantation (MSCT) in severe and drug-refractory systemic lupus erythematosus (SLE) patients. Eighty-one patients were enrolled, and the 5-year overall survival rate was 84% (68/81) after MSCT. At 5-year follow-up, 27% of patients (22/81) were in complete clinical remission and another 7% (6/81) were in partial clinical remission, with a 5-year disease remission rate of 34% (28/81). In total, 37 patients had achieved clinical remission and then 9 patients subsequently relapsed, with 5-year overall rate of relapse of 24% (9/37). SLE Disease Activity Index scores, serum albumin, complement C3, peripheral white blood cell, and platelet numbers, as well as proteinuria levels, continued to improve during the follow-up. Our results demonstrated that allogeneic MSCT is safe and resulted in long-term clinical remission in SLE patients. : In this article, Sun and colleagues show that allogeneic bone marrow and/or umbilical cord-derived mesenchymal stem/stromal cell transplantation both result in good clinical safety and effect in treating drug-refractory systemic lupus erythematosus patients, by introducing a 5- to 8-year follow-up study for all the 81 enrolled patients. Keywords: bone marrow, mesenchymal stem cells, systemic lupus erythematosus, safety, umbilical cord

Objective(s): This study aims to investigate the pathogenicity and possible mechanisms of S100A9 function in mice models of scleroderma. Materials and Methods: The content of S100A9 in the skin tissues of mice with scleroderma was determined. Different concentrations of bleomycin (BLM) and S100A9 were subcutaneously injected into the backs of mice simultaneously, and then pathological changes in the skin of these mice were monitored. Specifically, the levels of inflammatory cytokines and alpha smooth muscle actin (α-SMA), the activation of extracellular regulated kinase 1/2 (ERK1/2), mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways, and the expression of the receptor for advanced glycation end-product (RAGE) in the skin were determined. Results: The content of S100A9 in the skin tissues of mice with scleroderma was determined. Different concentrations of BLM and S100A9 were subcutaneously injected into the backs of mice simultaneously, and then pathological changes in the skin of these mice were monitored. Specifically, the levels of inflammatory cytokines and alpha smooth muscle actin (α-SMA), the activation of extracellular regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways, and the expression of the receptor for advanced glycation end-product (RAGE) in the skin were determined. Conclusion: S100A9 aggravates dermal fibrosis in BLM-induced scleroderma (BIS ) mice, and its mechanisms might be mediated by RAGE, ERK1/2, and NF-κB pathway.

Abstract Background Systemic sclerosis (SSc) is an autoimmune disease involving the skin and several internal organs. Most therapies available for this disease are symptomatic. Given the difficulty in treating SSc, we conducted this study to investigate the effect of combined plasmapheresis (PE) and allogeneic mesenchymal stem cells transplantation (MSCT) therapy on SSc. Methods Fourteen patients underwent three repeated PE treatments with subsequent pulse cyclophosphamide on days 1, 3 and 5. Patients received a single MSCT (1 × 106 cells/kg of body weight) on day 8. During follow up, evaluations performed included complete physical examination, serologic testing, and organ function. Results The mean modified Rodnan skin score (MRSS) improved from 20.1 ± 3.1 to 13.8 ± 10.2 (P

Objective. To investigate the effects of umbilical cord mesenchymal stem cell (UC-MSC) transplantation on joint damage and osteoporosis in collagen-induced arthritis (CIA) mice and to explore the mechanisms by which UC-MSCs modulate the osteogenic differentiation. Methods. CIA mice were divided into the following treated groups: UC-MSC transplantation group, antitumor necrosis factor- (TNF-) α group, and zoledronic acid (ZA) group. Microcomputed tomography (micro-CT) was used to analyze the bone morphology parameters. Osteogenic differentiation of treated CIA mice was determined. Bone marrow mesenchymal stem cells (BM-MSCs) from CIA mice were treated with TNF-α in vitro to explore their effects on osteogenesis. Results. The arthritis score was significantly reduced in the UC-MSC transplantation and anti-TNF-α-treated CIA groups, compared with control mice (P

The aberrant generation or activation of T follicular helper (Tfh) cells contributes to the pathogenesis of systemic lupus erythematosus (SLE), yet little is known about how these cells are regulated. In this study, we demonstrated that the frequency of Tfh cells was increased in lupus-prone B6.MRL- Fas lpr (B6. lpr ) mice and positively correlated to plasma cell proportions and serum total IgG as well as anti-dsDNA antibody levels. Transplantation of mesenchymal stem cells derived from Wharton's jelly of human umbilical cords (hUC-MSCs) ameliorated lupus symptoms in B6. lpr mice, along with decreased percentages of Tfh cells. In vitro studies showed that the differentiation and proliferation of Tfh cells were markedly suppressed by hUC-MSCs. The production of inducible nitric oxide synthase (iNOS) was dramatically upregulated in hUC-MSCs when cocultured with CD4 + T cells directly, while adding the specific inhibitor of iNOS into the coculture system significantly reversed the inhibitory effect of hUC-MSCs on Tfh cell generation. Interestingly, the efficacy of hUC-MSCs in inhibiting Tfh cells was impaired in the Transwell system, with the reduction of iNOS in both mRNA and protein levels. Taken together, our findings suggest that hUC-MSCs could effectively inhibit Tfh cell expansion through the activation of iNOS in lupus-prone B6. lpr mice, which is highly dependent on cell-to-cell contacts.

Aberrant autophagy played an important role in the pathogenesis of autoimmune diseases, especially in systemic lupus erythematosus (SLE). In this study, we showed that T cells from SLE patients had higher autophagic activity than that from healthy controls. A correlation between autophagic activity and apoptotic rate was observed in activated T cells. Moreover, activation of autophagy with rapamycin increased T cell apoptosis, whereas inhibition of autophagy with 3-MA decreased T cell apoptosis. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) could inhibit respiratory mitochondrial biogenesis in activated T cells to downregulate autophagy and consequently decrease T cell apoptosis through mitochondrial transfer and thus may play an important role in SLE treatment.

To identify early signs associated with poor prognosis in Chinese patients with systemic lupus erythematosus (SLE) through a large population-based follow-up study.Medical records of > 2,500 SLE patients that first hospitalized between 1999-2009 were collected from 26 centers across Jiangsu province, China, and entered into a database. These patients were followed-up for 5 to 15 years, and those remained contact and had known survival status in 2015 were assessed for the association of factors presented at the initial hospitalization with mortality at two time points (≤1year and > 1year). The independency of mortality factors was evaluated using multivariate Cox regression analysis.Among 1,372 patients we assessed, 92.3% were women and 17.2% were deceased in 2015. The main causes of death were infection (30.1%), neuropsychiatric impairment (14.8%), renal failure (14.4%) and cardiopulmonary involvement (8.5%). Hazard ratios (HR) of independent predictors for mortality (≤1year and > 1year, respectively) included hospital presentation of neuropsychiatric involvement (2.03 and 1.91), cardiopulmonary involvement (1.94 and 1.61) and increased serum creatinine (2.52 and 2.58). Patients older than 45 years and with disease durations more than 2 years at admission had unfavorable short-term outcome (HR 1.76 and 1.79), while the presence of anti-dsDNA and anti-Sm antibodies indicated diverse prognosis after 1 year (HR 1.60 and 0.45). Treatment with cyclophosphamide was beneficial for patient's first-year outcome (HR 0.50), and anti-malarial drugs significantly reduced the risk of mortality over different time points (HR 0.48 and 0.54). SLEDAI score, proteinuria or hypocomplementemia was not independently associated with the outcome in this cohort.SLE patients presented with vital organ damages rather than active disease at initial hospitalization are likely to have a poor outcome, especially for those with neuropsychiatric, cardiopulmonary involvements and renal insufficiency. Early and effective intervention with the use of anti-malarial drugs may decrease mortality.

To establish a mouse model of accelerated atherosclerosis in lupus, we generated apolipoprotein E-deficient (apoE−/−) and Faslpr/lpr (Fas−/−) C57BL/6 mice. On a normal chow diet, 5 month old apoE−/−Fas−/− mice had enlarged glomerular tuft areas, severe proteinuria, increased circulating autoantibody levels, and increased apoptotic cells in renal and vascular lesions compared with either single knockout mice. Also, double knockout mice developed increased atherosclerotic lesions but decreased serum levels of total and non-HDL cholesterol compared with apoE−/−Fas+/+ littermates. Moreover, female apoE−/−Fas−/− mice had lower vertebral bone mineral density (BMD) and bone volume density (BV/TV) than age-matched female apoE−/−Fas+/+ mice. Compared with apoE−/−Fas+/+ and apoE+/+Fas−/− mice, apoE−/−Fas−/− mice had decreased circulating oxidized phospholipid (OxPL) content on apoB-100 containing lipoprotein particles and increased serum IgG antibodies to OxPL, which were significantly correlated with aortic lesion areas (r = 0.58), glomerular tuft areas (r = 0.87), BMD (r = −0.57), and BV/TV (r = −0.72). These results suggest that the apoE−/−Fas−/− mouse model might be used to study atherosclerosis and osteopenia in lupus. Correlations of IgG anti-OxPL with lupus-like disease, atherosclerosis, and bone loss suggested a shared pathway of these disease processes.

Mesenchymal stem cells (MSCs) possess multipotent and immunomodulatory properties and are suggested to be involved in the pathogenesis of immune-related diseases. This study explored the function of bone marrow MSCs from rheumatoid arthritis (RA) patients, focusing on immunomodulatory effects. RA MSCs showed decreased proliferative activity and aberrant migration capacity. No significant differences were observed in cytokine profiles between RA and control MSCs. The effects of RA MSCs on proliferation of peripheral blood mononuclear cells (PBMCs) and distribution of specific CD4+ T cell subtypes (Th17, Treg, and Tfh cells) were investigated. RA MSCs appeared to be indistinguishable from controls in suppressing PBMC proliferation, decreasing the proportion of Tfh cells, and inducing the polarization of Treg cells. However, the capacity to inhibit Th17 cell polarization was impaired in RA MSCs, which was related to the low expression of CCL2 in RA MSCs after coculture with CD4+ T cells. These findings indicated that RA MSCs display defects in several important biological activities, especially the capacity to inhibit Th17 cell polarization. These functionally impaired MSCs may contribute to the development of RA disease.

This study aimed to determine whether umbilical cord-derived mesenchymal stem cells (UCMSC) regulate Cadherin-11 (CDH11) expression by fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA). FLS were isolated from the synovium of RA and osteoarthritis (OA) patients. FLS from RA patients were cocultured with UCMSC in a transwell system. CDH11 mRNA levels in FLS were tested, and levels of soluble factors expressed by UCMSC, such as indoleamine 2,3-dioxygenase (IDO), hepatocyte growth factor (HGF), and interleukin- (IL-) 10, were determined. IDO, HGF, and IL-10 were upregulated in cocultures, so that appropriate inhibitors were added before determination of CDH11 expression. The effects of UCMSC on arthritis were investigated in the collagen-induced arthritis (CIA) model in Wistar rats. FLS from RA patients expressed higher CDH11 levels than those from OA patients, and this effect was suppressed by UCMSC. The inhibitory effect of UCMSC on CDH11 expression by FLS was abolished by suppression of IL-10 activity. CDH11 expression in synovial tissues was higher in the context of CIA than under basal conditions, and this effect was prevented by UCMSC administration. IL-10 mediates the inhibitory effect of UCMSC on CDH11 expression by FLS, and this mechanism might be targeted to ameliorate arthritis.

Previous studies indicated that bone marrow mesenchymal stem cells (BMSCs) from patients with systemic lupus erythematosus (SLE) exhibited impaired capacities of proliferation, differentiation, and immune modulation. Considering that migration capacity is important for the exertion of BMSCs functions, the defects in migration might contribute to BMSCs dysfunction in SLE patients. In this study, we showed that the migration capacity of SLE BMSCs was remarkably impaired in comparison with those of healthy controls. Increased tumor necrosis factor α (TNF-α) in SLE serum significantly inhibited the migration capacity and in vivo homing capacity of SLE BMSCs via a specific TNF receptor I (TNFRI) manner, in which decreased HGF mRNA production caused by the activation of I kappa B kinase beta (IKK-β) pathway is partially involved. To our knowledge, this is the first report to discuss the possible mechanisms for impaired migration of BMSCs in SLE patients. Our results suggest that inhibition of TNF-α pathway might be helpful for accelerating BMSCs migration to the inflammatory microenvironment in SLE patients, thereby having a potential role in SLE treatment.

Mesenchymal stem cells (MSCs) are multipotential nonhematopoietic progenitors and are capable of differentiating into several tissues of mesenchymal origin. We have shown that bone marrow-derived MSCs from both SLE patients and lupus-prone MRL/lpr mice are defective structurally and functionally. Here we observe the long-term safety and efficacy of allogeneic MSC transplantation (MSCT) in treatment-resistant SLE patients. Eighty-seven patients with persistently active SLE who were refractory to standard treatment or had life-threatening visceral involvement were enrolled. Allogeneic bone marrow or umbilical cord-derived MSCs were harvested and infused intravenously (1 × 10 6 cells/kg of body weight). Primary outcomes were rates of survival, disease remission and relapse, as well as transplantation-related adverse events. Secondary outcomes included SLE disease activity index (SLEDAI) and serologic features. During the 4-year follow-up and with a mean follow-up period of 27 months, the overall rate of survival was 94% (82/87). Complete clinical remission rate was 28% at 1 year (23/83), 31% at 2 years (12/39), 42% at 3 years (5/12), and 50% at 4 years (3/6). Rates of relapse were 12% (10/83) at 1 year, 18% (7/39) at 2 years, 17% (2/12) at 3 years, and 17% (1/6) at 4 years. The overall rate of relapse was 23% (20/87). Disease activity declined as revealed by significant changes in the SLEDAI score, levels of serum autoantibodies, albumin, and complements. A total of five patients (6%) died after MSCT from non-treatment-related events in the 4-year follow-up, and no transplantation-related adverse event was observed. Allogeneic MSCT resulted in the induction of clinical remission and improvement in organ dysfunction in drug-resistant SLE patients.

Objective. To investigate the frequency of peripheral γδ T cells in patients with systemic lupus erythematosus (SLE) and its correlation with disease activity and to analyze the apoptotic status, proliferation ability, and intracellular cytokine profile of these cells. Methods. Flow cytometry was performed to detect the percentage and intracellular cytokine expression of peripheral γδ T cells from SLE patients. Annexin-V/PI double staining was applied to determine the proportion of apoptotic γδ and CD3+ T cells. γδ T cell proliferation was analyzed by CFSE labeling technique. Results. The percentage and absolute number of γδ T cells were remarkably decreased in active SLE patients compared to those in inactive patients and healthy controls, with γδ T cell count negatively correlated with disease activity. Compared with healthy controls, peripheral γδ T cells from active SLE patients exhibited higher apoptotic rate and lower proliferation ability, as well as elevated expression of intracellular IFN-γ, IL-4, IL-10, and TGF-β, but not IL-17 or Foxp3. Conclusion. Decreased γδ T cells in the peripheral blood of SLE patients might be caused by upregulated apoptosis and downregulated cell proliferation. These γδ T cells may secret both pro- and anti-inflammatory cytokines to perform their functions in SLE.

The clinical trial of allogenic mesenchymal stem cells (MSCs) transplantation for refractory SLE patients has shown significant safety and efficacy profiles. However, the optimum frequency of the MSCs transplantation (MSCT) is unknown. This study was undertaken to observe whether double transplantations of MSCs is superior to single transplantation. Fifty-eight refractory SLE patients were enrolled in this study, in which 30 were randomly given single MSCT, and the other 28 were given double MSCT. Patients were followed up for rates of survival, disease remission, and relapse, as well as transplantation-related adverse events. SLE disease activity index (SLEDAI) and serologic features were evaluated. Our results showed that no remarkable differences between single and double allogenic MSCT were found in terms of disease remission and relapse, amelioration of disease activity, and serum indexes in an SLE clinical trial with more than one year followup. This study demonstrated that single MSCs transplantation at the dose of one million MSCs per kilogram of body weight was sufficient to induce disease remission for refractory SLE patients.

To observe the proportion of peripheral T follicular helper (Tfh) cells in patients with systemic lupus erythematosus (SLE) and to assess the role of steroids on Tfh cells from SLE patients.Peripheral blood mononuclear cells (PBMCs) from 42 SLE patients and 22 matched healthy subjects were collected to assess proportions of circulating CXCR5(+)PD1(+)/CD4(+) T cells (Tfh), CD4(+)CCR6(+) T cells (Th17-like) and CD19(+)CD138(+) plasma cells by flow cytometry. 8 of the patients had their blood redrawn within one week after receiving methylprednisolone pulse treatment. Disease activity was evaluated by SLE disease activity index. To test the effect of IL-21 and corticosteroids on Tfh cells in vitro, PBMCs harvested from another 15 SLE patients were cultured with medium, IL-21, or IL-21+ dexamethasone for 24 hours and 72 hours. PBMCs from an independent 23 SLE patients were cultured with different concentrations of dexamethasone for 24 hours.Compared to normal controls, percentages of circulating Tfh cells, but not Th17 cells, were elevated in SLE patients and correlated with disease activity. Proportions of Tfh cells in SLE patients were positively correlated with those of plasma cells and serum levels of antinuclear antibodies. After methylprednisolone pulse treatment, both percentages and absolute numbers of circulating Tfh cells were significantly decreased. In vitro cultures showed an increase of Tfh cell proportion after IL-21 stimulation that was totally abolished by the addition of dexamethasone. Both 0.5 and 1 µM dexamethasone decreased Tfh cells dose dependently (overall p = 0.013).We demonstrated that elevated circulating Tfh cell proportions in SLE patients correlated with their disease activities, and circulating levels of plasma cells and ANA. Corticosteroids treatment down-regulated aberrant circulating Tfh cell proportions both in vivo and in vitro, making Tfh cells a new treatment target for SLE patients.

Introduction: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disorder with a variable clinical course, ranging from mild to severe forms. It mainly occurs in women, especially those of fertile age. The aim of the study was to systematically analyze the associations of perinatal disease activity with adverse outcomes of Chinese patients with SLE and their offspring. Material and methods: Data of prenatal SLE patients and healthy pregnant woman admitted to our hospital during the period October 2001 to January 2018 were retrospectively collected, and the status of offspring of SLE patients was followed up in March 2020. Disease activity was evaluated by SLE disease activity index 2000 (SLEDAI-2k), and those with scores > 6 were defined as having active disease. Results: In total, 198 deliveries of 194 SLE patients and 199 deliveries of healthy women were documented. Maternal and fetal adverse outcomes occurred in 74 (37.4%) and 90 (45.5%) deliveries of SLE patients, respectively, which were significantly higher than those of healthy subjects. Among SLE patients, the active group had higher rates of gestational hypertension (p < 0.001), preeclampsia/eclampsia (p < 0.001), low birth weight (p < 0.001), premature birth (p < 0.001) and fetal growth restriction (FGR) (p < 0.01) than the inactive group. Multivariate logistic analysis revealed that perinatal renal activity was associated with gestational hypertension (OR = 4.43, p < 0.001), preeclampsia/eclampsia (OR = 9.14, p < 0.001), low birth weight (OR = 2.24, p < 0.05) and premature birth (OR = 4.20, p < 0.001). Compared with the general population, offspring of SLE patients had relatively high rates of eczema (50/142, 35.2%) and congenital heart disease (6/142, 4.2%), which were irrelevant to perinatal disease activity, but related to specific antibodies. Conclusions: For perinatal women with SLE, renal activity is associated with a variety of adverse pregnancy outcomes. However, maternal perinatal disease activity does not seem to affect the growth of their offspring. [ABSTRACT FROM AUTHOR]

Background Glibenclamide has garnered attention due to its multifaceted neuroprotective effects in cases of acute central nervous system injury. We initiated a trial to explore the effectiveness and safety of a high dose of glibenclamide in the management of cerebral oedema following aneurysmal subarachnoid haemorrhage (aSAH).Methods This trial constituted a single-centre, randomised clinical study. Half of the 56 patients assigned to the glibenclamide group received 15 mg of glibenclamide tablets daily for 10 days (5 mg, three times/day). The primary outcome was the proportion of patients achieving the subarachnoid haemorrhage early brain oedema score dichotomy (defined as Subarachnoid Haemorrhage Early Brain Oedema Score 0–2) at the 10-day postmedication. The secondary outcome of cerebral oedema was the concentration of sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) in the plasma and cerebrospinal fluid.Results We enrolled 56 patients diagnosed with aSAH, who were admitted to the neurosurgery intensive care unit between 22 August 2021 and 25 April 2023. The primary outcome revealed that the glibenclamide group exhibited a notably higher proportion of mild cerebral oedema in comparison to the placebo group (60.7% vs 42.9%, adjusted OR: 4.66, 95% CI 1.14 to 19.10, p=0.032). Furthermore, the concentration of SUR1-TRPM4 in the cerebrospinal fluid of the glibenclamide group was significantly higher than the placebo group (p=0.0002; p=0.026), while the plasma TRPM4 concentration in the glibenclamide group was significantly lower than the placebo group (p=0.001).Conclusion Oral administration of high-dose glibenclamide notably reduced radiological assessment of cerebral oedema after 10 days of medication. Significant alterations were also observed in the concentration of SUR1-TRPM4 in plasma and cerebrospinal fluid. However, it is worth noting that glibenclamide was associated with a higher incidence of hypoglycaemia. Larger trials are warranted to evaluate the potential benefits of glibenclamide in mitigating swelling and then improving neurological function.Trial registration number ChiCTR2100049908.

Objectives: This study evaluated the characteristics of serosal involvement in adult-onset Still’s disease (AOSD). Methods: Patients meeting the Yamaguchi classification criteria were classified into AOSD with and without serosal involvement according to their manifestations and sonography/radiography. Clinical data was retrospectively reviewed from 102 patients with AOSD in two centres. Results: Forty-two patients (41.2%) had serosal involvement. The frequencies of pulmonary infiltrate and impaired liver function were significantly higher in patients with serosal involvement (푝 = .002 and 푝 = .007, respectively), who also had a higher modified systemic score (푝 = .009). In addition, the percentages of CD3+ T cells (푝 < .001) and, especially, the CD8+ T cells (푝 = .004) were significantly increased in the peripheral blood of AOSD patients with serosal involvement. Notably, patients with serosal involvement were more likely to develop macrophage activation syndrome (푝 = .047) and a chronic pattern (푝 = .016) during the follow-up. Conclusions: Patients with serosal involvement demonstrated the more severe disease activity and different immune phenotypes; these patients were more likely to develop macrophage activation syndrome, and they may require more aggressive treatment at an early time to control their systemic inflammation. [ABSTRACT FROM AUTHOR]