msc治疗SLE相关并发精神障碍

Background Anti-inflammatory polarized macrophages are reported to alleviate systemic lupus erythematosus (SLE). Our previous studies have demonstrated that exosomes from adipose-derived stem cells promote the anti-inflammatory polarization of macrophages. However, the possible therapeutic effect of exosomes from stem cells on SLE remains unexplored. Methods Exosomes were isolated from the conditioned medium of bone marrow-derived mesenchymal stem cells using ultrafiltration and size-exclusion chromatography and were identified by nanoparticle tracking analysis and immunoblotting of exosomal-specific markers. Macrophages were collected from the MRL/lpr mouse kidney. The phenotype of macrophages was identified by immunoblotting for intracellular markers-inducible nitric oxide synthase (iNOS) and arginase-1 (Arg-1), and flow cytometry for macrophage markers F4/80, CD86, CD206, B7H4, and CD138. Pristane-induced murine lupus nephritis models were employed for in vivo study. Results When macrophages from the kidney of the MRL/ lpr mice were treated with exosomes from bone marrow-derived mesenchymal stem cells (BM-MSCs), the upregulation of CD206, B7H4, CD138, Arg-1, CCL20, and anti-inflammatory cytokines was observed, which suggested that the macrophages were polarized to a specific anti-inflammatory phenotype. These anti-inflammatory macrophages produced low levels of reactive oxygen species (ROS) but had a high efferocytosis activity and promoted regulatory T (T reg ) cell recruitment. Moreover, exosome injection stimulated the anti-inflammatory polarization of macrophages and increased the production of IL-17 + T reg cells in a pristane-induced murine lupus nephritis model. We observed that exosomes from BMMSCs depleted of microRNA-16 (miR-16) and microRNA-21 (miR-21) failed to downregulate PDCD4 and PTEN in macrophages, respectively, and attenuated exosome-induced anti-inflammatory polarization. Conclusion Our findings provide evidence that exosomes from BMMSCs promote the anti-inflammatory polarization of macrophages. These macrophages alleviate SLE nephritis in lupus mice by consuming apoptotic debris and inducing the recruitment of T reg cells. We identify that exosomal delivery of miR-16 and miR-21 is a significant contributor to the polarization of macrophages. Graphical abstract

The autoimmune diseases are associated with the host immune system, chronic inflammation, and immune reaction against self-antigens, which leads to the injury and failure of several tissues. The onset of autoimmune diseases is related to unbalanced immune homeostasis. Mesenchymal stem cells (MSCs) are multipotent cells which have capability to self-renew and differentiate into various cell types that exert a critical role in immunomodulation and regenerative therapy. Under the certain condition in vitro, MSCs are able to differentiate into multiple lineage such as osteoblasts, adipocytes, and neuron-like cells. Consequently, MSCs have a valuable application in cell treatment. Accordingly, in this review we present the last observations of researches on different MSCs and their efficiency and feasibility in the clinical treatment of several autoimmune disorders including rheumatoid arthritis, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, autoimmune liver disease, and Sjogren’s syndrome.

Mesenchymal stem cell therapy (MSCT) for immune and inflammatory diseases continues to be popular based on progressive accumulation of preclinical mechanistic evidence. This has led to further expansion in clinical indications from graft rejection, autoimmune diseases, and osteoarthritis, to inflammatory liver and pulmonary diseases including COVID‐19. A clear trend is the shift from using autologous to allogeneic MSCs, which can be immediately available as off‐the‐shelf products. In addition, new products such as cell‐free exosomes and human pluripotent stem cell (hPSC)‐derived MSCs are exciting developments to further prevalent use. Increasing numbers of trials have now published results in which safety of MSCT has been largely demonstrated. While reports of therapeutic endpoints are still emerging, efficacy can be seen for specific indications—including graft‐vs‐host‐disease, strongly Th17‐mediated autoimmune diseases, and osteoarthritis—which are more robustly supported by mechanistic preclinical evidence. In this review, we update and discuss outcomes in current MSCT clinical trials for immune and inflammatory disease, as well as new innovation and emerging trends in the field.

Stem cell therapy is being intensely investigated within the last years. Expectations are high regarding mesenchymal stem cell (MSC) treatment in translational medicine. However, many aspects concerning MSC therapy should be profoundly defined. Due to a variety of approaches that are investigated, potential effects of stem cell therapy are not transparent. On the other hand, most results of MSC administration in vivo have confirmed their safety and showed promising beneficial outcomes. However, the therapeutic effects of MSC-based treatment are still not spectacular and there is a potential risk related to MSC applications into specific cell niche that should be considered in long-term observations and follow-up outcomes. In this review, we intend to address some problems and critically discuss the complex nature of MSCs in the context of their effective and safe applications in regenerative medicine in different diseases including graft versus host disease (GvHD) and cardiac, neurological, and orthopedic disorders.

Systemic lupus erythematosus (SLE), an autoimmune disease, can cause psychiatric disorders, particularly depression, via immune activation. Human umbilical cord mesenchymal stromal cell (hUCMSC) transplantation (MSCT) has been shown to ameliorate immune dysfunction in SLE by inducing immune tolerance. However, whether MSCT can relieve the depressive symptoms in SLE remains incompletely understood. Here, we demonstrate that MSCT relieved early-onset depression-like behavior in both genetically lupus-prone (MRL/lpr) and pristane-induced lupus mice by rescuing impaired hippocampal synaptic connectivity. Transplanted hUCMSCs targeted Th1 cell–derived IFN-γ to inhibit neuronal JAK/STAT1 signaling and downstream CCL8 expression, reducing phagocytic microglia apposition to alleviate synaptic engulfment and neurological dysfunction in young (8-week-old) lupus mice. Systemic delivery of exogenous IFN-γ blunted MSCT-mediated alleviation of synaptic loss and depressive behavior in lupus mice, suggesting that the IFN-γ/CCL8 axis may be an effective therapeutic target and that MSCT is a potential therapy for lupus-related depression. In summary, transplanted hUCMSCs can target systemic immunity to ameliorate psychiatric disorders by rescuing synaptic loss, highlighting the active role of neurons as intermediaries between systemic immunity and microglia in this process.

BACKGROUND Not all neuropsychiatric (NP) manifestations in patients with systemic lupus erythematosus (SLE) are secondary to lupus. The clarification of the cause of NP symptoms influences therapeutic strategies for SLE. AIM To understand the attribution of psychiatric manifestations in a cohort of Chinese patients with SLE. METHODS This retrospective single-center study analyzed 160 inpatient medical records. Clinical diagnosis, which is considered the gold standard, was used to divide the subjects into a psychiatric SLE (PSLE) group (G1) and a secondary psychiatric symptoms group (G2). Clinical features were compared between these two groups. The sensitivity and specificity of the Italian attribution model were explored. RESULTS A total of 171 psychiatric syndromes were recorded in 138 patients, including 87 cases of acute confusional state, 40 cases of cognitive dysfunction, 18 cases of psychosis, and 13 cases each of depressive disorder and mania or hypomania. A total of 141 (82.5%) syndromes were attributed to SLE. In contrast to G2 patients, G1 patients had higher SLE Disease Activity Index-2000 scores (21 vs 12, P = 0.001), a lower prevalence of anti-beta-2-glycoprotein 1 antibodies (8.6% vs 25.9%, P = 0.036), and a higher prevalence of anti-ribosomal ribonucleoprotein particle (rRNP) antibodies (39.0% vs 22.2%, P = 0.045). The Italian attribution model exhibited a sensitivity of 95.0% and a specificity of 70.0% when the threshold value was set at 7. CONCLUSION Patients with PSLE exhibited increased disease activity. There is a correlation between PSLE and anti-rRNP antibodies. The Italian model effectively assesses multiple psychiatric manifestations in Chinese SLE patients who present with NP symptoms.

Aim and background: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with diverse neuropsychiatric manifestations which are classified and diagnosed under ACR 1999 guidelines and contribute significantly to overall disease morbidity and mortality. Data are scarce regarding neuropsychiatric manifestations of SLE in Eastern India as well as the utility of psychiatric rating scales for classifying, assessing disease severity, and prognostication. This study focuses on deriving the prevalence of psychiatric manifestations among SLE patients and their correlation with disease severity using several psychiatric rating scales and markers of disease severity. Methods: This is a single center-based cross-sectional study involving 50 consented adult SLE patients fulfilling Systemic Lupus Erythematosus International Collaboration Committee (SLICC) criteria at NRS Medical College & Hospital over 18 months using a pretested questionnaire that includes psychiatric rating scales as well as disease severity assessment tools. Patients with drug abuse, pre-existing psychiatric disorders, dyselectrolytemia, and ongoing infection were excluded from the study. Results: All the participants had anxiety disorder (100%) followed by depression (80%), psychosis (58%), mood disorders (54%), and cognitive dysfunction (8%). Systemic lupus activity measure, revised (SLAM-R) score had a positive correlation with General Health Questionnaire (GHQ) ( r = 0.518, p < 0.05) and brief psychiatric rating scale (BPRS) ( r = 0.589, p < 0.05). Brief psychiatric rating scale and GHQ had a positive correlation between them ( r = 0.774, p < 0.05). Conclusion: Psychiatric manifestations of SLE are quite prevalent in the study niche and their clinical severity is comparable to that estimated using screening questionnaires and disease severity tools used in this study. Clinical significance: This study showed positive implications of implementing psychiatric rating scales as a screening tool in SLE patients for early diagnosis of psychiatric manifestations and use as corroborative

Introduction Early detection of neuropsychiatric systemic lupus erythematosus (NPSLE) remains a challenge in clinical settings. Previous studies have found different autoantibodies as markers for NPSLE. This study aimed to describe the distribution of psychiatric syndromes in a group of patients with systemic lupus erythematosus (SLE) and to investigate the association between psychiatric syndromes and specific autoantibodies. Methods This retrospective study was conducted at a single medical center in China. We reviewed medical records of hospitalized patients with SLE who were consulted by psychiatrists due to potential mental disorders. Results of serum autoantibodies and general laboratory tests were collected. The correlation between clinical variables was examined. Binary logistic regression analyses were used to determine factors related to NPSLE and different psychiatric diagnoses. Results Among the 171 psychiatric manifestations in 160 patients, 141 (82.4%) were attributed to SLE. Acute confusional state (ACS) had the highest prevalence (57.4%). Anti-cardiolipin (ACL) antibody (X2 = 142.261, p < 0.001) and anti-β2 glycoprotein I (-β2GP1) antibody (X2 = 139.818, p < 0.001) varied significantly between groups, with the highest positive rate found in patients with mood disorders (27.3% and 18.2%). SLE disease activity index – 2000 (SLEDAI-2K) score excluding item ACS and item psychosis was a predictor of NPSLE (OR 1.172 [95% CI 1.105 - 1.243]). Conclusions Disease activity reflected by SLEDAI-2K score is a predictor for NPSLE. Antiphospholipid antibodies are associated with mood disorders in SLE. Further separate investigation of neuropsychiatric disorders is needed in order to better comprehend NPSLE’s pathological mechanism.

Systemic lupus erythematosus (SLE) is an autoimmune condition whereby autoantibodies target systemic tissues, causing manifestations of inflammation and tissue damage. Neurologic inflammation in SLE can cause an array of neuropsychiatric (NP) symptoms, including headaches, depression, seizures, demyelinating conditions, mania, and psychosis. Patients treated for SLE are often on anti-inflammatory regimens, including high-dose steroids, which can independently precipitate psychosis. Steroid-induced psychosis (SIP) and lupus cerebritis (LC) are two distinct conditions that patients with SLE may have but often have overlapping presentations, which present a challenge for clinicians. Accurately differentiating between SIP and LC in an emergency setting is crucial for directing appropriate management and preventing potential complications. A clear timeline of the history of symptoms can help narrow down the cause. Diagnostic tools, mainly MRI patterns, can further clarify and indicate the presence of LC. We present a case of a 19-year-old African American female with a history of one steroid-induced psychotic episode five months prior in the setting of SLE who developed subsequent psychosis while on a steroid taper. MRI imaging elucidated a diagnosis of LC rather than a second SIP episode. There are few, if any, case reports that describe a patient with past SIP with a subsequent flare of cerebritis with psychotic symptoms. Strategic approaches to differentiating SIP from LC in the setting of SLE can lead to improved patient outcomes, follow-up care, and an overall understanding of the neuropsychiatric complexities of SLE.

Neuropsychiatric systemic lupus erythematosus is a severe neurological and psychiatric manifestation following systemic lupus erythematosus. Neuropsychiatric systemic lupus erythematosus is a global concern with limited data on its impact on quality of life in Africa. Furthermore, there is a lack of published research on neuropsychiatric systemic lupus erythematosus in Ethiopia. In this article, we present two case reports of Ethiopian patients with systemic lupus erythematosus and neuropsychiatric systemic lupus erythematosus, highlighting the challenges of diagnosing neuropsychiatric systemic lupus erythematosus worldwide. Although the patients were treated with alternative pharmacological agents based on available medications, interdisciplinary collaboration between psychologists, psychiatrists, neurologists, and internists is necessary to decrease the burden of systemic lupus erythematosus patients with neuropsychiatric manifestations. Overall, symptomatic therapy for neuropsychiatric systemic lupus erythematosus in developing countries is a good approach until future evidence-based pharmacotherapy is developed.

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Background Systemic Lupus Erythematosus (SLE) is an autoimmune disease with multiorgan involvement presenting with a myriad of symptoms, including neuropsychiatric symptoms. Although many studies have evaluated screening questionnaires based psychiatric morbidity, very few studies have used contemporary diagnostic criteria. Objective This study aimed to evaluate the prevalence of psychiatric disorders in patients with SLE admitted to a tertiary care hospital. Methods A total of 79 patients diagnosed with SLE for at least for 1 year, who were not in delirium were assessed by a qualified psychiatrist for psychiatric morbidity as per the International Classification of Diseases, 10th Revision (ICD-10) criteria. Additionally, these patients were assessed on Patient Health Questionnaire-9 (PHQ-9) item version, Patient Health Questionnaire-15 (PHQ-15) item version, Generalized Anxiety Disorder-7 item scale and Montreal Cognitive Assessment (MoCA). Results 51% (n = 40) of the participants were diagnosed with a psychiatric diagnosis, with depressive disorders being the most common, seen in 36.7% (n = 29) of the participants. Additionally, 10% (n = 8) participants were diagnosed with adjustment disorder and 2.5% (n = 2) were diagnosed with anxiety (not otherwise specified). Only one patient was diagnosed with organic psychosis. On PHQ-9, 39.8% (n = 33) were diagnosed with depression. 44.3% (n = 35) expressed death wishes and/or suicidal ideations. On PHQ-15, 17.7% (n = 14) of the participants scored for severe somatic distress (score >15). On GAD-7, 55.7% (n = 44) screened positive for anxiety symptoms, but only 7.6% (n = ) had a score of 15 or more to indicate severe anxiety. Nearly half (n = 43; 52%) of the participants also had cognitive impairment as assessed on MoCA, with 13.3% (n = 11) of the participants having scores indicating severe dementia. Conclusions Patients with SLE have a high prevalence of psychiatric comorbidities and should be routinely screened for psychiatric morbidity. They should be appropriately treated, to improve the overall treatment outcomes.

BACKGROUND This study aims to investigate the association between systemic lupus erythematosus (SLE) and the risk of seven psychiatric disorders through the application of Mendelian randomization (MR) analysis due to previous observational studies that have suggested a potential link between SLE and psychiatric disorders. METHODS We collected genetic instruments for SLE from a genome-wide association study (GWAS) involving 23,210 individuals. Seven psychiatric traits were enrolled from the recent largest GWAS, including major depression disorder (MDD), generalized anxiety disorder (GAD), schizophrenia (SCZ), bipolar disorder (BID), autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), and insomnia. Summary statistics for psychiatric disorders were obtained from different GWAS meta-analysis studies. The inverse variance weighted (IVW) method was used as the main MR analysis. RESULTS The IVW method indicated that SLE is associated with a higher risk of GAD (OR = 1.072, 95 % CI [1.017-1.129], P = 0.008) and SCZ (OR = 3.242, 95 % CI [1.578-6.660], P = 0.007). However, no evidence was found for the causal associations between SLE and other psychiatric disorders. Further analyses found no evidence of pleiotropy and heterogeneity. CONCLUSIONS This two-sample MR analysis provides evidence that genetically predicted SLE may increase the risk of GAD and SCZ in a European population. Future studies are needed to elucidate and investigate the mechanisms underlying these causal relationships. Considering the existence of racial genomic heterogeneity, our findings must be viewed with caution.

Objective This study aimed to identify the presence of psychiatric comorbidities as well as investigate the relationship between psychiatric interventions for mental symptoms and mortality in patients with systemic lupus erythematosus (SLE). Method We retrospectively evaluated the records of 160 inpatients with SLE who required psychiatric consultation for further therapeutic intervention from 2013 to 2020 in a tertiary general hospital. We collected clinical data, including diagnoses, medications, and mortality rate. We compared clinical characteristics among the diagnosis groups and correlations between variables. Results A total of 138 (86.3%) patients met the diagnostic criteria for at least one mental disorder, with the most common being delirium (54.4%). The average Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score significantly differed among the diagnosis groups (p = 0.003). The mortality rate among patients with delirium was significantly higher than that in the other patient groups (x2 = 12.967, p = 0.024). SLEDAI-2K score was not significantly correlated with mortality (r = 0.123, p = 0.087). Antipsychotics use was associated with mortality (odds ratio 0.053, p = 0.021). Conclusion Antipsychotic use may decrease death risk for patients with NPSLE. Early psychiatric consultation is necessary for patients with SLE who have developed or have suspected psychiatric symptoms in order to establish a comprehensive intervention plan.

Background In systemic lupus erythematosus (SLE), fatigue is the most common and aggravating symptom which has been reported to be influenced by several factors, such as disease activity, psychosocial stressors, and psychiatric disorders. Therefore, this study aims to determine the association between disease activity, psychosocial stressors, and psychiatric disorders with fatigue in SLE patients. Method In this cross-sectional study, 73 female SLE patients were accepted to participate by filling out the informed consent. Besides, disease activity was divided into Lupus Low Disease Activity State (LLDAS) and non-LLDAS. The Holmes-Rahe Stress Scale and Fatigue Severity Scale (FSS) were employed to assess psychosocial stress and fatigue severity. The Mini-International Neuropsychiatric Interview (MINI) ICD-10 was used to examine psychiatric disorders. The Chi-square test was conducted to determine the association between dependent variables (fatigue) and independent variables (psychosocial stress, psychosocial stress severity, and psychiatric disorders). Result Out of the participants, 49 (67.1%) suffered from fatigue, and the LLDAS group contained fewer individuals than non-LLDAS, 46.6% versus 53.4%. The majority (86.3%) also experienced psychosocial stress, ranging from mild to severe, and 56 (76.7%) patients had psychiatric disorders. No significant association was discovered between SLE disease activity and fatigue. However, fatigue had significant associations with psychiatric disorders in both LLDAS (p = 0.02) and non-LLDAS groups (p = 0.04), as well as with psychosocial stress severity (p = 0.02). Histories of major personal illness (p = 0.01) and changes in eating habits (p = 0.02) were associated with fatigue among the LLDAS participants. Conclusion Psychosocial stressors and psychiatric disorders were significantly associated with fatigue in SLE. Histories of major personal disease and changes in eating habits were also significantly associated with fatigue in the LLDAS participants. Therefore, early recognition of these factors is necessary to manage and prevent fatigue in SLE patients.

Objectives Systemic lupus erythematosus (SLE) is a systemic autoimmune disease associated with neuro-psychiatric (NP) manifestations. Frequency and patterns of neuro-psychiatric systemic lupus erythematosus (NPSLE) vary substantially between patients. We conducted a systematic review (SR) of the literature and examined prevalence and characteristics of NPSLE in the Swiss SLE cohort study (SSCS). Methods The SR search was performed between January 1999 and January 2020. We included prospective/cross-sectional studies focusing on NPSLE. We secured study characteristics, cohort compositions and frequencies of NP manifestations, assessed heterogeneity across reports and investigated sources of variation using meta-regression models. Regarding the SSCS, we reviewed all patients included and classified NP manifestations. Results The SR searches identified 530 studies. We included 22 studies in our meta-analysis, the mean frequency of NPSLE ranged from 10.6% to 96.4%. The frequency of NPSLE in the SSCS was 28.1%. Severe events including cerebrovascular insults, seizures and psychosis appeared in 7.1%, 5.3% and 6.5% respectively. There was a linear relationship between duration of SLE and cumulative incidence of NPSLE. Conclusions The spectrum of NPSLE is very broad. The diagnostic work-up and rates of reported manifestations varied substantially across studies. We call for concerted efforts and consensus regarding definitions of NPSLE that will facilitate accurate diagnosis and attribution to SLE, particularly with a view to timely intervention and patient outcomes.

Objective To examine the effect of psychiatric diagnoses on healthcare use in youth with systemic lupus erythematosus (SLE) during their first year of SLE care. Methods We conducted a retrospective cohort study using claims from 2000 to 2013 from Clinformatics Data Mart (OptumInsight). Youth aged 10 years to 24 years with an incident diagnosis of SLE (≥ 3 International Classification of Diseases, 9th revision, codes for SLE 710.0, > 30 days apart) were categorized as having: (1) a preceding psychiatric diagnosis in the year before SLE diagnosis, (2) an incident psychiatric diagnosis in the year after SLE diagnosis, or (3) no psychiatric diagnosis. We compared ambulatory, emergency, and inpatient visits in the year after SLE diagnosis, stratified by nonpsychiatric and psychiatric visits. We examined the effect of childhood-onset vs adult-onset SLE by testing for an interaction between age and psychiatric exposure on outcome. Results We identified 650 youth with an incident diagnosis of SLE, of which 122 (19%) had a preceding psychiatric diagnosis and 105 (16%) had an incident psychiatric diagnosis. Compared with those without a psychiatric diagnosis, youth with SLE and a preceding or incident psychiatric diagnosis had more healthcare use across both ambulatory and emergency settings for both nonpsychiatric and psychiatric-related care. These associations were minimally affected by age at time of SLE diagnosis. Conclusion Psychiatric comorbidity is common among youth with newly diagnosed SLE and is associated with greater healthcare use. Interventions to address preceding and incident psychiatric comorbidity may decrease healthcare burden for youth with SLE.

Background The Kynurenine Pathway (KP) of tryptophan degradation and glutamate toxicity is implicated in several neurological disorders, including depression. The therapeutic potential of mesenchymal stromal cells (MSC), owing to their well documented phagocytosis-driven mechanism of immunomodulation and neuroprotection, has been tested in many neurological disorders. However, their potential to influence KP and the glutamatergic system has not yet been investigated. Hence, this study sought to investigate the effect of HUCPVC, a rich and potent source of MSC, on Lipopolysaccharide (LPS)-activated KP metabolites, KP enzymes, and key components of glutamate neurotransmission. Methods The immunomodulatory effect of peripherally administered HUCPVC on the expression profile of kynurenine pathway metabolites and enzymes was assessed in the plasma and brain of mice treated with LPS using LCMS and QPCR. An assessment of the glutamatergic system, including selected receptors, transporters and related proteins was also conducted by QPCR, immunohistochemistry and Western blot. Results HUCPVC were found to modulate LPS-induced activation of KP enzymes and metabolites in the brain associated with neurotoxicity. Moreover, the reduced expression of the glutamatergic components due to LPS was also found to be significantly improved by HUCPVC. Conclusions The immunomodulatory properties of HUCPVC appear to confer neuroprotection, at least in part, through their ability to modulate the KP in the brain. This KP modulation enhances neuroprotective regulators and downregulates neurotoxic consequences, including glutamate neurotoxicity, which is associated with neuroinflammation and depressive behavior.

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Background Reports of clinical improvement following mesenchymal stromal cell (MSC) infusions in refractory lupus patients at a single centre in China led us to perform an explorative phase I trial of umbilical cord derived MSCs in patients refractory to 6 months of immunosuppressive therapy. Methods Six women with a SLEDAI >6, having failed standard of care therapy, received one intravenous infusion of 1×106 MSCs/kg of body weight. They maintained their current immunosuppressives, but their physician was allowed to adjust corticosteroids initially for symptom management. The clinical endpoint was an SRI of 4 with no new British Isles Lupus Activity Guide (BILAG) As and no increase in Physician Global Assessment score of >0.3 with tapering of prednisone to 10 mg or less by 20 weeks. Results Of six patients, five (83.3%; 95% CI 35.9% to 99.6%) achieved the clinical endpoint of an SRI of 4. Adverse events were minimal. Mechanistic studies revealed significant reductions in CD27IgD double negative B cells, switched memory B cells and activated naïve B cells, with increased transitional B cells in the five patients who met the endpoint. There was a trend towards decreased autoantibody levels in specific patients. Two patients had increases in their Helios+Treg cells, but no other significant T cell changes were noted. GARP-TGFβ complexes were significantly increased following the MSC infusions. The B cell changes and the GARP-TGFβ increases significantly correlated with changes in SLEDAI scores. Conclusion This phase 1 trial suggests that umbilical cord (UC) MSC infusions are very safe and may have efficacy in lupus. The B cell and GARP-TGFβ changes provide novel insight into mechanisms by which MSCs may impact disease. Trial registration number NCT03171194.

Abstract Mesenchymal stem cells (MSCs) are identified as a promising tool for the treatment of autoimmune diseases, and several microRNAs (miRNAs) are shown to exhibit vital roles in immune diseases. However, their function and mechanism in systemic lupus erythematosus (SLE) is still unclear. The qRT-PCR analysis was employed to investigate level of miR-153-3p. Subsequently, western blot and luciferase reporter assays were carried out to determine miR-153-3p targets. Cell proliferation and migration were determined using EdU proliferation assays and transwell migration assays. Apoptosis levels were evaluated by annexin V staining and flow cytometry. We used human umbilical cord-derived mesenchymal stem cells (UC-MSCs) transplantation to treat MRL/lpr mice. It was observed that miR-153-3p was upregulated in patients with SLE, and was closely related to SLE disease activity. Overexpression of miR-153-3p decreased UC-MSCs proliferation and migration, and weakened UC-MSCs-mediated decrease of follicular T helper (Tfh) cells and increase of regulatory T (Treg) cells through repressing PELI1 in vitro. We also found that PELI1 overexpression abolished the function of miR-153-3p on UC-MSCs. Furthermore, miR-153-3p overexpression weakened the therapeutic effect of UC-MSCs in MRL/lpr mice in vivo. Taken together, all data suggested that miR-153-3p is a mediator of SLE UC-MSCs regulation and may function as a new therapeutic target for the treatment of lupus.

Objectives The present study aimed to explore the effect of umbilical cord mesenchymal stem cells (UC-MSCs) on the modulation of T lymphocytes from system lupus erythematosus (SLE) patients and the possible mechanism. Methods A total of 24 hospitalized SLE patients and 28 healthy individuals were enrolled. T lymphocytes were sorted using Miltenyi magnetic beads. After the addition of recombinant human interleukin (IL)-2 and CD3CD28 T-cell activator, cells were loaded onto six-well plates pre-inoculated or not with UC-MSCs for 1 week of culture. The supernatants were collected for testing inflammatory factors by enzyme-linked immunosorbent assay. Meanwhile, T lymphocytes were collected to assess the expression levels of genes, proteins in relation to SLE and miR-181a by polymerase chain reaction and Western blot. Results Compared with T lymphocytes cultured alone, interferon-γ, IL-4, IL-6 and IL-10 levels were significantly decreased in T lymphocytes from SLE patients co-cultured with UC-MSCs. In addition, the gene and protein expression levels of TNF alpha, osteopontin and nuclear factor-kappa B in T lymphocytes were significantly decreased, while miR-181a expression was markedly elevated (p < 0.05 or 0.008). Conclusion UC-MSCs have showed certain immunomodulatory and inhibitory effects in vitro on T lymphocytes from SLE patients, which could potentially be a beneficial treatment of the disease. UC-MSCs may up-regulate miR-181a and down-regulate inflammation-related gene expression.

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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-Faslpr (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.

IntroductionIn our present single-center pilot study, umbilical cord (UC)–derived mesenchymal stem cells (MSCs) had a good safety profile and therapeutic effect in severe and refractory systemic lupus erythematosus (SLE). The present multicenter clinical trial was undertaken to assess the safety and efficacy of allogeneic UC MSC transplantation (MSCT) in patients with active and refractory SLE.MethodsForty patients with active SLE were recruited from four clinical centers in China. Allogeneic UC MSCs were infused intravenously on days 0 and 7. The primary endpoints were safety profiles. The secondary endpoints included major clinical response (MCR), partial clinical response (PCR) and relapse. Clinical indices, including Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, British Isles Lupus Assessment Group (BILAG) score and renal functional indices, were also taken into account.ResultsThe overall survival rate was 92.5% (37 of 40 patients). UC-MSCT was well tolerated, and no transplantation-related adverse events were observed. Thirteen and eleven patients achieved MCR (13 of 40, 32.5%) and PCR (11 of 40, 27.5%), respectively, during 12 months of follow up. Three and four patients experienced disease relapse at 9 months (12.5%) and 12 months (16.7%) of follow-up, respectively, after a prior clinical response. SLEDAI scores significantly decreased at 3, 6, 9 and 12 months follow-up. Total BILAG scores markedly decreased at 3 months and continued to decrease at subsequent follow-up visits. BILAG scores for renal, hematopoietic and cutaneous systems significantly improved. Among those patients with lupus nephritis, 24-hour proteinuria declined after transplantation, with statistically differences at 9 and 12 months. Serum creatinine and urea nitrogen decreased to the lowest level at 6 months, but these values slightly increased at 9 and 12 months in seven relapse cases. In addition, serum levels of albumin and complement 3 increased after MSCT, peaked at 6 months and then slightly declined by the 9- and 12-month follow-up examinations. Serum antinuclear antibody and anti-double-stranded DNA antibody decreased after MSCT, with statistically significant differences at 3-month follow-up examinations.ConclusionUC-MSCT results in satisfactory clinical response in SLE patients. However, in our present study, several patients experienced disease relapse after 6 months, indicating the necessity to repeat MSCT after 6 months.Trial registryClinicalTrials.gov identifier: NCT01741857. Registered 26 September 2012.

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.

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Systemic lupus erythematosus (SLE) was an autoimmune disease leading to high morbidity and mortality without effective and low-side effect conventional drugs. Our previous clinical studies demonstrated umbilical cord derived mesenchymal stromal cells (MSCs) were a safe and effective treatment, but its therapeutic mechanism is still unclear. In this study, we first observed clinical used MSCs exhibited higher CCL2 expression than primary and aged MSCs, and abnormal bone marrow derived MSC (BM-MSC) from SLE patients performed decreased CCL2 expression compared to healthy control. Then, we constructed CCL2-deficient MSCs, and found the immunosuppressive activity of CCL2-deficient MSCs was impaired in the peripheral blood mononuclear cell (PBMC) inhibitory assay in vitro. CCL2-deficient MSCs also failed to relieve SLE in MRL/lpr and pristine-induced mice. To further explore the role of CCL2 in MSC therapy, we performed transcriptomic profiling of CCL2-deficient MSCs and MSCs, and identified the differential expressed genes were related to chemotaxis, including monocyte chemotaxis. Subsequently, we found that MSCs restored the imbalance in M1/M2 macrophage polarization via CCL2 in vitro. These findings provided valuable insight for investigating the therapeutic mechanism of MSC on SLE.

Inflammation instigated by interleukin (IL)‐17‐producing cells is central to the development and pathogenesis of several human autoimmune diseases and animal models of autoimmunity. The expansion of IL‐17‐producing cells from healthy donors is reportedly promoted by mesenchymal stem cells derived from fetal bone marrow. In the present study, human umbilical cord‐derived mesenchymal stem cells (hUC‐MSCs) were examined for their effects on lymphocytes from healthy donors and from patients with systemic lupus erythematosus (SLE). Significantly higher levels of IL‐17 were produced when CD4+ T cells from healthy donors were co‐cultured with hUC‐MSCs than those that were cultured alone. Blocking experiments identified that this effect might be mediated partially through prostaglandin E2 (PGE2) and IL‐1β, without IL‐23 involvement. We then co‐cultured hUC‐MSCs with human CD4+ T cells from systemic lupus erythematosus patients. Ex‐vivo inductions of IL‐17 by hUC‐MSCs in stimulated lymphocytes were significantly higher in SLE patients than in healthy donors. This effect was not observed for IL‐23. Taken together, our results represent that hUC‐MSCs can promote the IL‐17 production from CD4+ T cells in both healthy donor and SLE patients. PGE2 and IL‐1β might also be partially involved in the promotive effect of hUC‐MSCs.

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Introduction The area postrema, located on the floor of the fourth ventricle, regulates vomiting, fluid balance, osmoregulation, and immunomodulation. First documented in 1896, it has been a subject of scientific interest ever since. Area postrema syndrome (APS) is characterised by intractable nausea, vomiting, or hiccups, typically associated with neuromyelitis optica spectrum disorder (NMOSD). This paper presents a case of APS related with autoimmunity due to systemic lupus erythematosus (SLE) and not related to NMOSD. Additionally, a comprehensive review of the literature is conducted. Case report A 27-year-old Colombian female with a five-year history of systemic lupus erythematosus (SLE) presented with vomiting, epigastric pain, dysphagia, and seizures. Initial tests suggested acute pancreatitis and a lupus flare, but imaging of the gastrointestinal tract showed no abnormalities. Brain MRI revealed a lesion in the area postrema, indicating area postrema syndrome (APS). Treatment with hydrocortisone and later high-dose methylprednisolone and cyclophosphamide led to improvement. Negative anti-aquaporin 4 antibodies ruled out neuromyelitis optica spectrum disorder (NMOSD), leading to a probable diagnosis of APS associated with SLE. Conclusion Given the patient's negative AQP4-IgG results, clinical profile, and medical history, we propose APS associated with SLE, marking the first reported case in Latin America.

Systemic lupus erythematosus (SLE) treatment requires balancing rapid autoimmunity control with long-term organ repair. Mesenchymal stromal cells (MSCs) and multi-target pharmacotherapy represent fundamentally different therapeutic strategies. MSCs exert context-dependent immunomodulation, whereas the latter relies on broad immunosuppression. This contrast makes direct comparison essential to guide therapy decisions. Here, we conducted a head-to-head evaluation of these two strategies in a lupus murine model. Lupus mice received either umbilical cord-derived MSCs or TMP (tacrolimus, mycophenolate mofetil and prednisone) over an 8-week period. Both treatments significantly alleviated core lupus symptoms, including enlarged spleen/lymph nodes and excessive antibody production. However, MSCs showed greater efficacy in suppressing pathogenic autoantibodies, repairing podocyte damage, and increasing protective regulatory T cells in the kidney and peripheral tissues. TMP more effectively reduced peripheral circulating immune cells. These findings highlight the complementary therapeutic profiles of MSCs and multi-target pharmacotherapy in SLE, providing a critical rationale for personalized treatment stratification.

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Considerable experimental and clinical evidences have proved that human umbilical cord mesenchymal stem cells (UC-MSCs) transplantation was powerful in systemic lupus erythematosus (SLE) treatment. MSCs could upregulate regulatory B cells (Bregs) in the mice model of the other immune disease. However, the regulation of MSCs on Bregs in SLE environment remains unclear. To assess the abilities of UC-MSCs to treat SLE, MSCs were transferred intravenously to 17- to 18-week-old MRL/lpr mice. Four weeks later, mice were sacrificed. Survival rates, anti-dsDNA antibodies and renal histology were evaluated. CD4+ T helper (Th) cell subgroups and interleukin (IL)-10+ Bregs (B10) in the spleen were quantitated by flow cytometry. The changes of transforming growth factor (TGF)-β1, IL-6 and indoleamine 2,3-dioxyenase (IDO) mRNAs expressed by MSCs after co-cultured with B cells were detected using real-time polymerase chain reaction (RT-PCR). MSCs were infected by lentivirus carrying TGF-β1 shRNAs, then MSCs with low expression of TGF-β1 were conducted for co-culture in vitro and transplantation experiments in vivo. UC-MSCs transplantation could efficiently downregulate 24 h proteinuria and anti-dsDNA antibodies, correct Treg/Th17/Th1 imbalances and increase the frequency of B10 cells. The expression of TGF-β1 in MSCs was significantly increased after co-culture with B cells. Downregulation of TGF-β1 in MSCs could significantly attenuate the upregulation of B10 by MSCs in vitro and in vivo. Downregulation of TGF-β1 also compromised the immunomodulation effects of MSCs on Th17 and Treg cells and the therapeutic effects of MSC transplantation. UC-MSCs could protect against SLE in mice and upregulate IL-10+ Bregs via TGF-β1.

Objectives To quantify signal abnormalities in the hippocampus (Hsig) of patients with systemic lupus erythematosus (SLE) and to determine if Hsig predict hippocampal atrophy (HA) in SLE. Methods We included all SLE patients and healthy age- and sex-matched individuals with two magnetic resonance imaging (MRI) scans performed with a minimum of 1 year interval. All individuals underwent a standardized neuropsychological evaluation. Individual results were converted into standard scores and compared to normative data. SLE patients were additionally assessed for disease activity (SLE Disease Activity Index (SLEDAI)), damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI)), and the presence of antiphospholipid antibodies. MRI was performed on an Elscint 2 T scanner and T1 inversion recovery and T2 coronal images were used for analysis. Volumetric (HV) and signal quantification (Hsig) were determined by standardized protocols. Results We included 54 SLE patients (48 women; mean age 32.2 ± 10.56 years). Hsig were found at study entry in 15 (45.5%) patients. Hsig in the body and tail of non-atrophic hippocampi correlated with progression of volume loss during the follow-up period ( r = 0.8, p < 0.001). The presence of Hsig in the head of atrophic hippocampi correlated with progression of HA ( r = 0.73, p = 0.005) during the same period. No correlation of Hsig and disease activity or prednisone dose was observed. Conclusion HA is frequently observed in SLE patients and volume loss is progressive in a subgroup of patients. The evaluation of Hsig is an easy tool to determine patients that may have progressive hippocampal volume loss and should be followed more closely with MRI and cognitive evaluation.