Systemic Lupus Erythematosus Individuals Research Articles

IRF5 Variants Are Risk Factors for Systemic Lupus Erythematosus in Two Mexican Populations.

Interferon regulatory factor 5 ( IRF5 ) is one of the pivotal genes implicated in systemic lupus erythematosus (SLE) among diverse ethnic groups, including Europeans, Asians, Hispanics, and Africans. Notably, its significance appears particularly pronounced among Hispanic populations. Previous studies have identified several single-nucleotide variants within IRF5 , such as rs2004640G/T, rs2070197T/C, and rs10954213G/A, as associated with susceptibility to SLE among patients from Mexico City. However, the population of Yucatan, located in the Southeast of Mexico and characterized by a greater Amerindian genetic component, remains largely unexplored in this regard. Our study aimed to replicate the observed association between IRF5 variants and susceptibility to SLE among patients from Central Mexico and Yucatan. Furthermore, we investigated the impact of IRF5 rs59110799G/T, a variant that has not been previously studied in SLE individuals. Our study included 204 SLE patients and 160 controls from Central Mexico, as well as 184 SLE patients and 184 controls from Yucatan. All participants were females 18 years and older. We employed a TaqMan assay to detect the presence of the following single-nucleotide variants: rs2004640G/T, rs2070197T/C, rs10954213G/A, and rs59110799G/T. Furthermore, we utilized 2 distinct web tools and databases to predict the potential functional implications of IRF5 variants. In SLE patients from Central Mexico, several IRF5 alleles showed significant associations with the disease following adjustment by the Bonferroni test: the rs2070197C allele (odds ratio [OR], 2.08), the rs10954213A allele (OR, 1.59), and the rs59110799G allele (OR, 1.71). Conversely, among patients from Yucatan, the following alleles showed associations: rs2004640T (OR, 1.51), rs2070197C (OR, 1.62), rs10954213A (OR, 1.67), and rs59110799G (OR, 1.44). Our findings highlight genetic variations between Mexican populations and emphasize the role of IRF5 as a risk factor in SLE patients from both Central Mexico and Yucatan.

Imbalance of Th17 cells, Treg cells and associated cytokines in patients with systemic lupus erythematosus: a meta-analysis.

This article aims to investigate the changes of T helper 17 (Th17) cells, regulatory T (Treg) cells and their associated cytokines in patients with systemic lupus erythematosus (SLE). Multiple databases were investigated to identify articles that explored Th17 cells, Treg cells and relevant cytokines in SLE patients. A random effects model was used for calculating pooled standardized mean differences. Stata version 15.0 was utilized to conduct the meta-analysis. The levels of Th17 cells, IL-17, IL-6, IL-21 and IL-10 were higher in SLE patients than in healthy controls (HCs), but the TGF-β levels were lower. The percentage of Treg cells was lower than HCs in SLE individuals older than 33. Among studies that had 93% or lower females, the percentage of Th17 cells was greater in patients than in HCs. However, the percentage of Treg cells was lower when the proportion of females was less than 90%. Patients with lupus nephritis or active SLE had an increased proportion of Th17 cells and a decreased proportion of Treg cells. The increased level of Th17 cells and related cytokines could be the main reason for the elevated Th17/Treg ratio in SLE. The percentages of Th17 and Treg cells were associated with gender, age, disease activity and kidney function. Furthermore, the reduced proportions of Treg cells may primarily result in a rise in the Th17/Treg ratio in older or active SLE patients. https://www.crd.york.ac.uk/prospero, identifier CRD42023454937.

Single-cell RNA sequencing of peripheral blood mononuclear cells from pregnant women with Systemic lupus erythematosus

Systemic lupus erythematosus (SLE), an autoimmune condition, presents pregnancy-related risks, impacting maternal and fetal health. The immune cell composition and gene expression profiles in pregnant SLE patients, as well as the molecular mechanisms of active SLE patients during pregnancy, remain unclear. In our study, we enrolled 12 patients: three active SLE individuals (SLE-AT group, SLEDAI > 12, non-pregnant women), three inactive SLE individuals (SLE-NP group, SLEDAI ranging 0 to 6, non-pregnant women), three pregnant women with active SLE (SLE-C group, SLEDAI > 12), and three pregnant women with inactive SLE (SLE-NC group, SLEDAI range 0 to 6 score). Transcriptome analysis of peripheral blood mononuclear cells (PBMCs) was conducted using the 10x Genomics technique. We observed upregulation of genes like CCDC15 and TRBV4-2 in T cells and CMPK2, IFIT1, and OAS2 in monocytes in the SLE-C group. Notably, gene sets related to Cell Cycle and IFN Response showed significant differences between the SLE-C and SLE-NC groups in naïve CD8 T cells. Our comparison of immune cell type ratios and transcriptional patterns between active and inactive SLE during pregnancy sheds light on the single-cell level changes in SLE status during pregnancy, offering insights for future SLE prediction and treatment strategies.

Notch1 hyperactivity drives ubiquitination of NOX2 and dysfunction of CD8+ regulatory T cells in patients with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) display heightened immune activation and elevated IgG autoantibody levels, indicating compromised regulatory T cell (Tregs) function. Our recent findings pinpoint CD8+ Tregs as crucial regulators within secondary lymphoid organs, operating in a NOX2-dependent mechanism. However, the specific involvement of CD8+ Tregs in SLE pathogenesis and the mechanisms underlying their role remain uncertain. SLE and healthy individuals were enlisted to assess the quantity and efficacy of Tregs. CD8+CD45RA+CCR7+ Tregs were generated ex vivo, and their suppressive capability was gauged by measuring pZAP70 levels in targeted T cells. Notch1 activity was evaluated by examining activated Notch1 and HES1, with manipulation of Notch1 accomplished with Notch inhibitor DAPT, Notch1 shRNA, and Notch1-ICD. To create humanized SLE chimeras, immune-deficient NSG mice were engrafted with PBMCs from SLE patients. We observed a reduced frequency and impaired functionality of CD8+ Tregs in SLE patients. There was a downregulation of NOX2 in CD8+ Tregs from SLE patients, leading to a dysfunction. Mechanistically, the reduction of NOX2 in SLE CD8+ Tregs occurred at a post-translational level rather than at the transcriptional level. SLE CD8+ Tregs exhibited heightened Notch1 activity, resulting in increased expression of STUB1, an E3 ubiquitin ligase that binds to NOX2 and facilitates its ubiquitination. Consequently, restoring NOX2 levels and inhibiting Notch1 activity could alleviate the severity of the disease in humanized SLE chimeras. Notch1 is the cell-intrinsic mechanism underlying NOX2 deficiency and CD8+ Treg dysfunction, serving as a therapeutic target for clinical management of SLE.

Accumulation of Microvascular Target Organ Damage in Systemic Lupus Erythematosus Patients Is Associated with Increased Cardiovascular Risk.

Background: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease associated with increased cardiovascular (CV) burden. Besides increased arterial stiffness and subclinical atherosclerosis, microvascular dysfunction is considered an important component in the pathophysiology of CV disease. However, there is a lack of data regarding the effect of multiple target organ damage (TOD) on CV health. Objectives: This study aimed to evaluate (i) the presence of microvascular changes in SLE in various vascular beds, (ii) the possible associations between the accumulation of microvascular TOD and CV risk and (iii) whether Galectin-3 represents a predictor of combined microvascular TOD. Methods: Participants underwent (i) evaluation of skin microvascular perfusion (laser speckle contrast analysis), (ii) fundoscopy (non-mydriatic fundus camera), (iii) indirect assessment of myocardial perfusion (subendocardial viability ratio) and (iv) determination of urine albumin-to-creatinine ratio (UACR). CV risk was calculated using the QResearch Risk Estimator version 3 (QRISK3). Serum Galectin-3 levels were determined. Results: Forty-seven SLE patients and fifty controls were studied. SLE patients demonstrated impaired skin microvascular reactivity (160.2 ± 41.0 vs. 203.6 ± 40.1%), retinal arteriolar narrowing (88.1 ± 11.1 vs. 94.6 ± 13.5 μm) and higher UACR levels compared to controls. Furthermore, SLE individuals had significantly higher Galectin-3 levels [21.5(6.1) vs. 6.6(6.6) ng/dL], QRISK3 scores [7.0(8.6) vs. 1.3(3.6)%] and a greater chance for microvascular dysfunction. In the SLE group, patients with multiple TOD exhibited higher QRISK3. In the multivariate analysis, the accumulation of TOD correlated with disease activity and Galectin-3 (p < 0.05). Conclusions: Our study showed for the first time that SLE patients exhibit a greater number of cases of TOD. The accumulation of TOD was associated with increased CV risk. Clinicians dealing with SLE should be aware and seek microvascular alterations.

Comparison of late-onset and non-late-onset systemic lupus erythematosus individuals in a real-world electronic health record cohort.

Objective: Late-onset systemic lupus erythematosus (LO-SLE) is defined as SLE diagnosed at age 50 years or later. Current studies on LO-SLE are small and have conflicting results.Methods: Using a large, electronic health record (EHR)-based cohort of SLE individuals, we compared demographics, disease characteristics, SLE-specific antibodies, and medication prescribing practices in LO (n = 123) vs. NLO-SLE (n = 402) individuals.Results: The median age (interquartile range) at SLE diagnosis was 60 (56-67) years for LO-SLE and 28 (20-38) years for NLO-SLE. Both groups were predominantly female (85% vs. 91%, p = 0.10). LO-SLE individuals were more likely to be White than NLO-SLE individuals (74% vs. 60%, p = 0.005) and less likely to have positive dsDNA (39% vs. 58%, p = 0.001) and RNP (17% vs. 32%, p = 0.02) with no differences in Smith, SSA, and SSB. Autoantibody positivity declined with increasing age at SLE diagnosis. LO-SLE individuals were less likely to develop SLE nephritis (9% vs. 29%, p < 0.001) and less likely to be prescribed multiple classes of SLE medications including antimalarials (90% vs. 95%, p = 0.04), azathioprine (17% vs. 31%, p = 0.002), mycophenolate mofetil (12% vs. 38%, p < 0.001), and belimumab (2% vs. 8%, p = 0.02).Conclusion: LO-SLE individuals may be less likely to fit an expected course for SLE with less frequent positive autoantibodies at diagnosis and lower rates of nephritis, even after adjusting for race. Understanding how age impacts SLE disease presentation could help reduce diagnostic delays in SLE.

Qualitative Proteome-wide Lysine Crotonylation Profiling Reveals Protein Modification Alteration in the Leukocyte Extravasation Pathway in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a severe systemic autoimmune disease with multiple manifestations. Lysine crotonylation (Kcr) is a newly discovered posttranslational modification epigenetic pattern that may affect gene expression and is linked to diseases causally. We collected blood samples from 11 SLE individuals and 36 healthy subjects. Then, we used highly sensitive liquid chromatography-mass spectrometry technology to carry out proteomics and quantitative crotonylome analysis of SLE peripheral blood mononuclear cells in this investigation, which indicated the unique etiology of SLE. Finally, we verified the expression of critical protein in the leukocyte extravasation pathway by online database analysis and Western blot. There were 618 differentially expressed proteins (DEPs), and 612 crotonylated lysine sites for 272 differentially modified proteins (DMPs) found. These DEPs and DMPs are primarily enriched in the leukocyte extravasation signaling pathway, such as MMP8, MMP9, and ITGAM. This is the first study of crotonylated modification proteomics in SLE. The leukocyte extravasation signaling pathway had a considerable concentration of DEPs and DMPs, indicating that this pathway may be involved in the pathogenic development of SLE.

Exploring the role of LIAS-related cuproptosis in systemic lupus erythematosus.

Cuproptosis is a novel mode of cell death, which is strongly related to energy metabolism in mitochondria and regulated by protein lipoylation. Currently, the molecular mechanisms of cuproptosis-related genes (CRGs) involved in systemic lupus erythematosus (SLE) largely remained unclear, our study is aimed to explore the mechanisms of cuproptosis and CRGs involved in SLE. Bulk RNA-seq datasets were collected to display the expressions of CRGs in peripheral blood mononuclear cells (PBMCs) of SLE and healthy individuals, and then ROC analysis was used to establish the diagnostic models of CRGs. Next, the immune infiltration analyses were applied to reveal the difference of immune cells infiltration in LIAS-low and LIAS-high group. Additionally, WGCNA analysis was performed to find the gene modules significantly correlated with the LIAS expression level. We also performed the functional enrichment analyses for LIAS-related gene modules to determine the potential pathways involved in the development of SLE. Finally, scRNA-seq dataset was used to cluster immune cell subsets, reveal the activated pathways, and study cell-cell interactions in LIAS-low and LIAS-high cells. We found CDKN2A was significantly increased and LIAS was significantly decreased in SLE patients compared with healthy individuals. The AUC score showed that LIAS had a great diagnostic value than other CRGs. Additionally, the results of immune infiltration analyses showed that immune cells proportion were diverse in LIAS-low and LIAS-high samples. The gene sets related to LIAS expression level were involved in dephosphorylation of JAK1 by SHP1, phosphorylation of STAT2, cytokine signaling in immune system, expression of interferon-alpha and beta, inhibition of JAK kinase activity by SOCS1/3, and so on. Finally, the results of cell-cell communication showed that CCL- (CCL5 + CCR1) and ANNEXIN- (ANXA1 + FPR1) might play an essential role in the communication network between LIAS-low and LIAS-high cells. Above findings inferred that LIAS-mediated cuproptosis might involve in a comprehensive cellular and molecular mechanism to cause the occurrence and development of SLE.

Phenotype Risk Score but Not Genetic Risk Score Aids in Identifying Individuals With Systemic Lupus Erythematosus in the Electronic Health Record.

Systemic lupus erythematosus (SLE) poses diagnostic challenges. We undertook this study to evaluate the utility of a phenotype risk score (PheRS) and a genetic risk score (GRS) to identify SLE individuals in a real-world setting. Using a de-identified electronic health record (EHR) database with an associated DNA biobank, we identified 789 SLE cases and 2,261 controls with available MEGAEX genotyping. A PheRS for SLE was developed using billing codes that captured American College of Rheumatology SLE criteria. We developed a GRS with 58 SLE risk single-nucleotide polymorphisms (SNPs). SLE cases had a significantly higher PheRS (mean ± SD 7.7 ± 8.0 versus 0.8 ± 2.0 in controls; P < 0.001) and GRS (mean ± SD 12.2 ± 2.3 versus 11.0 ± 2.0 in controls; P < 0.001). Black individuals with SLE had a higher PheRS compared to White individuals (mean ± SD 10.0 ± 10.1 versus 7.1 ± 7.2, respectively; P = 0.002) but a lower GRS (mean ± SD 9.0 ± 1.4 versus 12.3 ± 1.7, respectively; P < 0.001). Models predicting SLE that used only the PheRS had an area under the curve (AUC) of 0.87. Adding the GRS to the PheRS resulted in a minimal difference with an AUC of 0.89. On chart review, controls with the highest PheRS and GRS had undiagnosed SLE. We developed a SLE PheRS to identify established and undiagnosed SLE individuals. A SLE GRS using known risk SNPs did not add value beyond the PheRS and was of limited utility in Black individuals with SLE. More work is needed to understand the genetic risks of SLE in diverse populations.

Agomir miRNA-150-5p alleviates pristane-induced lupus by suppressing myeloid dendritic cells activation and inflammation via TREM-1 axis.

Triggering receptors expressed on myeloid cells-1 (TREM-1) has been shown to participate in inflammatory autoimmune diseases. Nevertheless, the detailed underlying mechanisms and therapeutic benefits by targeting TREM-1 remain elusive, especially in myeloid dendritic cells (mDCs) and systemic lupus erythematosus (SLE). Disorders of epigenetic processes including non-coding RNAs give rise to SLE, resulting in complicated syndromes. Here, we aim to address this issue and explore the miRNA to inhibit the activation of mDCs and alleviate the progress of SLE by targeting TREM-1 signal axis. Bioinformatics methods were used to analyze the differentially expressed genes (DEGs) between patients with SLE and healthy individuals by four mRNA microarray datasets from Gene Expression Omnibus (GEO). Then we identified the expression of TREM-1 and its soluble form (sTREM-1) in clinical samples by ELISA, quantitative real-time PCR and Western blot. Phenotypic and functional changes of mDCs elicited by TREM-1 agonist were determined. Three databases of miRNAs target prediction and a dual-luciferase reporter assay were used to screen and verify miRNAs that can directly inhibit TREM-1 expression in vitro. Moreover, pristane-induced lupus mice were injected with miR-150-5p agomir to evaluate the effects of miR-150-5p on mDCs in lymphatic organs and disease activity in vivo. We screened TREM-1 as one of the hub genes closely correlated with the progression of SLE and identified sTREM-1 in serum as a valuable diagnostic biomarker for SLE. Moreover, activation of TREM-1 by its agonist promoted activation and chemotaxis of mDCs and increased the production of inflammatory cytokines and chemokines, showing higher expression of IL-6, TNF-α, and MCP-1. We showed that lupus mice displayed a unique miRNA signature in spleen, among which miR-150 was the most significantly expressed miRNA that targeting TREM-1 compared with wild type group. Transfection of miRNA-150-5p mimics directly suppressed the expression of TREM-1 by binding to its 3' UTR. Our in vivo experiments first indicated that administration of miR-150-5p agomir effectively ameliorated lupus symptoms. Intriguingly, miR-150 inhibited the over activation of mDCs through TREM-1 signal pathway in lymphatic organs and renal tissues. TREM-1 represents a potentially novel therapeutic target and we identify miR-150-5p as one of the mechanisms to alleviate lupus disease, which is attributable for inhibiting mDCs activation through TREM-1 signaling pathway.

Predictors of a weak antibody response to COVID-19 mRNA vaccine in systemic lupus erythematosus.

To characterize the antibody response to COVID-19 mRNA vaccination in patients with Systemic Lupus Erythematosus (SLE) and identify predictors of poor response. SLE patients who are followed at the Beth Israel Deaconess Medical Center Lupus Cohort (BID-LC) were enrolled. SARS-CoV-2 IgG Spike antibody was measured in patients who received two doses of either the BNT162b2 (Pfizer-BioNTech) or the mRNA-1273 (Moderna) COVID-19 vaccine (n = 62). We defined non-responders as patients with an IgG Spike antibody titer less than two-fold (< 2) the index value of the test and responders as patients with antibody levels greater or equal to two-fold (≥ 2). A web-based survey was used to collect information regarding immunosuppressive medication use and SLE flares after vaccination. In our cohort of lupus patients, 76% were vaccine responders. The use of two or more immunosuppressive drugs was associated with being a non-responder (Odds Ratio 5.26; 95% CI 1.23-22.34, p = 0.02). Both Belimumab use and higher Prednisone dose were associated with vaccine non-response (p = 0.04 and p = 0.04). The non-responder group had higher mean levels of serum IL-18 than the responder group (p = 0.04) as well as lower C3 levels (p = 0.01). Lupus flares and breakthrough infections were uncommon post-vaccination. Immunosuppressive medications have a negative impact on vaccine humoral response in SLE individuals. We observed a trend towards vaccine no-response in BNT162b2 recipients and a relationship between IL-18 and impaired antibody response that merits further investigation.

Fungal gut microbiota dysbiosis in systemic lupus erythematosus.

Despite recent developments in our comprehension of how the gut microbiota and systemic lupus erythematosus (SLE) are related. The mycobiome: which is a small but crucial part of the gut microbiota and is involved in hosts' homeostasis and physiological processes, remained unexplored in SLE. We profiled the gut fungal mycobiota based on internal transcribed spacer region 1 (ITS1) sequencing for the gut microbial DNA from the SLE individuals with lupus nephritis (LN) (n = 23), SLE without LN (n = 26) and healthy controls (n = 14) enrolled in Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School. The ITS sequencing generated a total of 4.63 million valid tags which were stratified into 4,488 operational taxonomic units (OTUs) and identified about 13 phyla and 262 genera. Patients with SLE were characterized with unique fungal flora feature. The fungal microbiomes of the three groups displayed distinct beta diversity from each other. Compared with HC group, the abundance of fungal dysbiosis was reflected in a higher ratio of opportunistic fungi in SLE or LN group, as well as the loss of Rhizopus and Malassezia. The main principal components of the flora between the SLE and LN group were generally consistent. The relative abundance of Vanrija in the fecal fungal community was higher in LN group, while the relative abundance of Fusarium was higher in SLE group. Moreover, our data revealed superior diagnostic accuracy for SLE with the fungal species (e.g. Candida, Meyerozyma). Correlations between gut fungi and clinical parameters were identified by Spearman's correlation analysis. Interestingly, Aspergillus in SLE patients was positively correlated with ACR, 24 h proteinuria, proteinuria, anti-dsDNA, ANA, and SLEDAI, while Rhizopus was negatively correlated with lymphocytes and Hb. Finally, we successfully cultured the fungi and identified it as Candida glabrata by microscopic observation and mass spectrometry. We first explored the highly significant gut fungal dysbiosis and ecology in patients with SLE, and demonstrated the applicability of fungal species as SLE diagnostic tools, signifying that the gut fungal mycobiome-host interplay can potentially contribute in disease pathogenesis.

Deficient leptin receptor signaling in T cells of human SLE.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease mainly mediated by IgG autoantibody. While follicular helper T (Tfh) cells are crucial for supporting IgG autoantibody generation in human SLE, underlying mechanisms for Tfh cell mal-differentiation remain unclear. In total, 129 SLE patients and 37 healthy donors were recruited for this study. Circulating leptin was determined by ELISA from patients with SLE and healthy individuals. CD4 T cells isolated from SLE patients and healthy donors were activated with anti-CD3/CD28 beads under cytokine-unbiased conditions in the presence or absence of recombinant leptin protein, followed by detection for Tfh cell differentiation by quantifying intracellular transcription factor Bcl-6 and cytokine IL-21. AMPK activation was assessed by analyzing phosphor-AMPK using phosflow cytometry and immunoblots. Leptin receptor expression was determined using flow cytometry and its overexpression was achieved by transfection with an expression vector. Humanized SLE chimeras were induced by injecting patients' immune cells into immune-deficient NSG mice and used for translational studies. Circulating leptin was elevated in patients with SLE, inversely associated with disease activity. In healthy individuals, leptin efficiently inhibited Tfh cell differentiation through inducing AMPK activation. Meanwhile, leptin receptor deficiency was a feature of CD4 T cells in SLE patients, impairing the inhibitory effect of leptin on the differentiation of Tfh cells. As a result, we observed the coexistence of high circulating leptin and increased Tfh cell frequencies in SLE patients. Accordingly, overexpression of leptin receptor in SLE CD4 T cells abrogated Tfh cell mal-differentiation and IgG anti-dsDNA generation in humanized lupus chimeras. Leptin receptor deficiency blocks the inhibitory effect of leptin on SLE Tfh cell differentiation, serving as a promising therapeutic target for lupus management.

MiRNA-binding site polymorphismin IL-15RA gene in rheumatoid arthritis and systemic lupus erythematosus: correlation with disease risk and clinical characteristics.

MiRSNPs may interfere with mRNA stability through effects on microRNAs (miRNAs)-mRNA interactions via direct changes in miRNA binding site or effect on the secondary structure of this region and changes in accessibility of this region to miRNAs. Studies have confirmed that an elevated level of interleukin-15 receptor alpha (IL-15RA) has an important role in the pathogenesis of systemic lupus erythematosus(SLE) andrheumatoid arthritis(RA). In the present study, for the first time, we aimed to evaluate the possible correlation between a miRSNP, rs2296135, in IL-15RA gene with the risk of SLE and RA. In this case-control study, 100 SLE patients, 100 RA patients, and 110 healthy participants were enrolled to assess rs2296135 genotypes with real-time PCR high-resolution melting method. According to our findings, AA genotype and A allele of rs2296135 were considerably associated with enhanced risk of RA (for AA genotype, OR = 2.29; 95% CI [1.06-5.02]; for A allele, OR = 1.65; 95% CI [1.10-2.48]). However, this common variant was not significantly correlated with SLE risk in population under study. Stratification analysis in the RA group verified that patients with the A allele had considerably higher serum concentrations of C-reactive protein (CRP) (P < 0.001). In SLE subjects, the frequency of arthritis (P: 0.021) and renal involvement (P: 0.025) in patients with A allele was significantly higher than in other SLE individuals. The current study proposes a substantial association between rs2296135 polymorphism in IL-15RA gene with augmented risk of RA and some clinical characteristics in RA and SLE patients.

The Behaviour of Serum Survivin in Patients With Lupus Nephritis.

Background:Systemic lupus erythematosus (SLE) is a chronic, multi phenotypic, autoimmune inflammatory disease and renal involvement significantly worsens its prognosis. Apoptosis dysregulation plays a key pathogenic role. Survivin, a protein from the apoptosis inhibitors family, has been considered a promising strategy in cancer therapy and evaluated as one of the regulatory pathways in the scenario of immune-mediated disorders.Objective:This study aims to explore survivin behaviour in SLE patients with lupus nephritis (LN), assessing its potential as a therapeutic and prognostic biomarker.Methods:297 SLE patients were classified based on the American College of Rheumatology (ACR) 1997 criteria, from 2000 to 2015. In a cross-sectional study, the serum level of survivin was measured by an ELISA test and compared between 200 SLE individuals and healthy controls. In a longitudinal cohort, 97 patients with active LN had the concentration of survinin measured, before and after treatment with cyclophosphamide pulse therapy.Results:The serum concentration of survivin was significantly lower in the SLE group than in healthy controls, regardless of concomitant NL or disease activity. The longitudinal evaluation revealed a significant reduction in survivin serum level after treatment. However, survivin rates were not able to discriminate groups that achieved remission from those that maintained nephritis activity.Conclusion:Our study suggests that survivin levels in SLE patients are lower than in the general population. Even so, its use as a biomarker in SLE seems limited, not reflecting disease activity or response to LN treatment, as in other contexts.

First exposure to rituximab is associated to high rate of anti-drug antibodies in systemic lupus erythematosus but not in ANCA-associated vasculitis

BackgroundAnti-drug antibodies (ADAs) can impact on the efficacy and safety of biologicals, today used to treat several chronic inflammatory conditions. Specific patient groups may be more prone to develop ADAs. Rituximab is routinely used for ANCA-associated vasculitis (AAV) and as off-label therapy for systemic lupus erythematosus (SLE), but data on occurrence and predisposing factors to ADAs in these diseases is limited.ObjectivesTo elucidate the rate of occurrence, and risk factors for ADAs against rituximab in SLE and AAV.MethodsADAs were detected using a bridging electrochemiluminescent (ECL) immunoassay in sera from rituximab-naïve (AAV; n = 41 and SLE; n = 62) and rituximab-treated (AAV; n = 22 and SLE; n = 66) patients. Clinical data was retrieved from medical records. Disease activity was estimated by the SLE Disease Activity Index-2000 (SLEDAI-2 K) and the Birmingham Vasculitis Activity Score (BVAS).ResultsAfter first rituximab cycle, no AAV patients were ADA-positive compared to 37.8% of the SLE patients. Samples were obtained at a median (IQR) time of 5.5 (3.7–7.0) months (AAV), and 6.0 (5.0–7.0) months (SLE). ADA-positive SLE individuals were younger (34.0 (25.9–40.8) vs 44.3 (32.7–56.3) years, p = 0.002) and with more active disease (SLEDAI-2 K 14.0 (10.0–18.5) vs. 8.0 (6.0–14), p = 0.0017) and shorter disease duration (4.14 (1.18–10.08) vs 9.19 (5.71–16.93), p = 0.0097) compared to ADA-negative SLE. ADAs primarily occurred in nephritis patients, were associated with anti-dsDNA positivity but were not influenced by concomitant use of corticosteroids, cyclophosphamide or previous treatments.Despite overall reduction of SLEDAI-2 K (12.0 (7.0–16) to 4.0 (2.0–6.7), p < 0.0001), ADA-positive individuals still had higher SLEDAI-2 K (6.0 (4.0–9.0) vs 4.0 (2.0–6.0), p = 0.004) and their B cell count at 6 months follow-up was higher (CD19 + % 4.0 (0.5–10.0) vs 0.5 (0.4–1.0), p = 0.002). At retreatment, two ADA-positive SLE patients developed serum sickness (16.7%), and three had infusion reactions (25%) in contrast with one (5.2%) serum sickness in the ADA-negative group.ConclusionsIn contrast to AAV, ADAs were highly prevalent among rituximab-treated SLE patients already after the first course of treatment and were found to effect on both clinical and immunological responses. The high frequency in SLE may warrant implementations of ADA screening before retreatment and survey of immediate and late-onset infusion reactions.

Patrolling human SLE haematopoietic progenitors demonstrate enhanced extramedullary colonisation; implications for peripheral tissue injury

Systemic lupus erythematosus (SLE) is an autoimmune disease where bone-marrow-derived haematopoietic cells have a key role in its pathogenesis with accumulating evidence suggesting an aberrant function of haematopoietic stem/progenitor cells (HSPCs). We examined whether patrolling HSPCs differ from bone-marrow HSPCs both in SLE and healthy individuals, and how they participate in peripheral tissue injury. By employing next-generation RNA sequencing, the transcriptomes of CD34+ HSPCs deriving from the bone marrow and those patrolling the bloodstream of both healthy and individuals with SLE were compared. Patrolling SLE and Healthy human HSPC kinetics were examined through their inoculation into humanised mice. Patrolling and bone-marrow HSPCs have distinct molecular signatures, while patrolling SLE HSPCs showed an enhanced extramedullary gene expression profile. Non-mobilised, SLE-derived circulating HSPCs demonstrated altered homing capacities. Xenotransplantation of circulating HSPCs in humanised mice showed that human peripheral blood HSPCs possess the ability for extramedullary organ colonisation to the kidneys. Circulating and bone marrow-derived HSPCs are distinct in steady and diseased states. Patrolling SLE CD34+ HSPCs are able to home at extramedullary sites such as the spleen and kidneys, potentially participating in peripheral tissue injury.

Genetic Polymorphisms in Genes Involved in the Type I Interferon System (IFIH1/MDA-5, TNFAIP3/A20, and STAT4): Association with SLE Risk in Egyptian Children and Adolescents.

PurposeSystemic lupus erythematosus (SLE) is a multifactorial autoimmune inflammatory disease that is influenced by both genetic and environmental factors and associated with dysregulation of type I interferon (INF) response. This study aimed to investigate the effects of single nucleotide polymorphisms (SNPs) of the IFIH1, TNFAIP3, and STAT4 genes in the type I INF system on SLE risk in Egyptian children and adolescents.Patients and MethodsWe recruited 94 SLE individuals and 94 healthy subjects. SNPs of IFIH1 rs3747517 C/T, TNFAIP3 rs610604 G/T, and STAT4 rs7574865 G/T were evaluated using TaqMan™ SNP genotyping assay.ResultsIndividuals with the TT, CT+TT genotypes, and T allele of rs3747517 in the IFIH1 gene were protective for SLE patients (OR = 0.429, 95% CI = 0.191–0.962, P = 0.040), (OR = 0.685, 95% CI = 0.477–0.984, P = 0.041), and (OR = 0.705, 95% CI = 0.527–0.944, P = 0.019), respectively. Also, individuals with the TT, GT+TT genotypes, and T allele of rs7574865 in the STAT4 gene were associated with SLE risk (OR = 3.945, 95% CI = 1.303–11.947, P = 0.015), (OR = 1.536, 95% CI = 1.058–2.231, P = 0.024), and (OR = 1.522, 95% CI = 1.113–2.082, P = 0.009), respectively. In the case of TNFAIP3 rs610604, no significant association of genotypes or alleles with SLE were detected, while the three SNPs did not show any significant association with the SLE clinical or laboratory features.ConclusionOur findings indicated that rs3747517 in IFIH1 was protective for SLE in Egyptian children and adolescents. Moreover, rs7574865 in STAT4 not rs610604 in TNFAIP3 was associated with SLE risk.

Association of tumor necrosis factor alpha-induced protein 3 gene polymorphism and systemic lupus erythematosus

Background Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) is a negative regulator of the activity of NF-κB in the cells and genetic variations in TNFAIP3 may be implicated in the risk of systemic lupus erythematosus (SLE) development. Objective The purpose of this paper is to evaluate TNFAIP3 gene polymorphism in SLE and its relationship with autoimmune parameters. Methods The study was carried out on 94 children suffering from SLE and 94 healthy controls of matched age and sex. TNFAIP3 polymorphism by RT-PCR using TaqMan assay, and levels of serum antinuclear and serum anti-double-stranded DNA were measured by ELISA technique. Complement C3 and C4 were estimated by using turbidimetric assay. Results The results showed that there is no significant correlation of TNFAIP3 alleles or genotypes with risk of development of SLE (P&gt;0.05). In addition, the authors did not detect any significant correlation between alleles or genotypes of TNFAIP3 with SLE clinical features and immune disorders (P&gt;0.05). Conclusion The authors concluded that TNFAIP3 polymorphism is not associated with SLE risk. In addition, these results suggested no significant association between the TNFAIP3 SNP and autoimmune parameters, or any complications among SLE individuals.

IFN-γ Mediates the Development of Systemic Lupus Erythematosus.

Objective Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect all organs in the body. It is characterized by overexpression of antibodies against autoantigen. Although previous bioinformatics analyses have identified several genetic factors underlying SLE, they did not discriminate between naive and individuals exposed to anti-SLE drugs. Here, we evaluated specific genes and pathways in active and recently diagnosed SLE population. Methods GSE46907 matrix downloaded from Gene Expression Omnibus (GEO) was analyzed using R, Metascape, STRING, and Cytoscape to identify differentially expressed genes (DEGs), enrichment pathways, protein-protein interaction (PPI), and hub genes between naive SLE individuals and healthy controls. Results A total of 134 DEGs were identified, in which 29 were downregulated, whereas 105 were upregulated in active and newly diagnosed SLE cases. GO term analysis revealed that transcriptional induction of the DEGs was particularly enhanced in response to secretion of interferon-γ and interferon-α and regulation of cytokine production innate immune responses among others. KEGG pathway analysis showed that the expression of DEGs was particularly enhanced in interferon signaling, IFN antiviral responses by activated genes, class I major histocompatibility complex (MHC-I) mediated antigen processing and presentation, and amyloid fiber formation. STAT1, IRF7, MX1, OASL, ISG15, IFIT3, IFIH1, IFIT1, OAS2, and GBP1 were the top 10 DEGs. Conclusions Our findings suggest that interferon-related gene expression and pathways are common features for SLE pathogenesis, and IFN-γ and IFN-γ-inducible GBP1 gene in naive SLE were emphasized. Together, the identified genes and cellular pathways have expanded our understanding on the mechanism underlying development of SLE. They have also opened a new frontier on potential biomarkers for diagnosis, biotherapy, and prognosis for SLE.