Autoimmunity最新文献

Background: Juvenile idiopathic arthritis (JIA), superseding juvenile rheumatoid arthritis (JRA), is a chronic autoimmune disease affecting children and characterized by various types of childhood arthritis. JIA manifests clinically with joint inflammation, swelling, pain, and limited mobility, potentially leading to long-term joint damage if untreated. This study aimed to identify genes associated with the progression and prognosis of JIA polyarticular to enhance clinical diagnosis and treatment.

Methods: We analyzed the gene expression omnibus (GEO) dataset GSE1402 to screen for differentially expressed genes (DEGs) in peripheral blood single nucleated cells (PBMCs) of JIA polyarticular patients. Weighted gene co-expression network analysis (WGCNA) was applied to identify key gene modules, and protein-protein interaction networks (PPIs) were constructed to select hub genes. The random forest model was employed for biomarker gene screening. Functional enrichment analysis was conducted using David's online database, gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to annotate and identify potential JIA pathways. Hub genes were validated using the receiver operating characteristic (ROC) curve.

Results: PHLDA1, EGR3, CXCL2, and PF4V1 were identified as significantly associated with the progression and prognosis of JIA polyarticular phenotype, demonstrating high diagnostic and prognostic assessment value.

Conclusion: These genes can be utilized as potential molecular biomarkers, offering valuable insights for the early diagnosis and personalized treatment of JIA polyarticular patients.

Graves' ophthalmopathy (GO) obvious manifestation is the imbalance of Th17/Treg. N6-methyladenosine (m6A) methylation is an important regulator of Th17/Treg balance. However, few reports narrate how m6A regulators mediate the role of genes in GO progression. We explored the m6A modification of THBS1 mediated by WTAP, and the mechanism by which THBS1 regulated glycolysis and Th17/Treg balance. A total of 12 peripheral blood (4 GO samples, 4 GH samples, and 4 health samples) were collected to measure the percentage of Th17/Treg in monocytes by flow cytometry. RNA sequencing (RNA-seq) combined with MeRIP sequencing (MeRIP-seq) was used to screen differentially expressed and methylated genes. MeRIP-qPCR was performed to evaluate the m6A abundance of THBS1 after WTAP silencing. Glycolysis of CD4⁺ T cells was reflected by the lactate content and glucose uptake. The number of Th17 cells was increased in GO peripheral blood, whereas the Treg cells decreased. RNA-seq acquired 679 differentially expressed genes (308 up-regulated, and 371 down-regulated) in the CD4⁺ T cells of GO compared to healthy control. MeRIP-seq identified 3277 m6A peaks between the GO group and the healthy control group, corresponding with 2744 genes (1143 hypermethylated and 1601 hypomethylated). Combined analysis of RNA-seq and MeRIP-seq showed 81 hypermethylated and up-regulated genes. Among the six candidate genes in the PI3K-signaling pathway, THBS1 was the most significantly differentially expressed and hypermethylated. THBS1 silencing resulted in decreased lactate content and glucose uptake in CD4⁺ T cells. WTAP was significantly upregulated in CD4⁺ T cells of GO, and WTAP silencing significantly reduced m6A abundance and expression of THBS1. Upregulated and hypermethylated THBS1 mediated by WTAP promoted glycolysis of CD4⁺ T cells, affected Th17/Treg balance, and facilitated GO progression. We provided a novel potential target for GO treatment and revealed the molecular mechanism of WTAP and THBS1 in GO under the m6A perspective.

Systemic lupus erythematosus (SLE) is an extremely heterogenous autoimmune disorder. A key biomarker, the double stranded (ds) DNA autoantibody, provides diagnostic specificity for SLE. We analyzed anti-dsDNA by mass spectrometry (MS) to determine if ascertaining the autoantibody's heavy chain variable region (IGHV) may hold any clinical relevance. A cross-sectional study of 32 SLE patients (75% female) in a single center was performed. Serum anti-dsDNA was subjected to MS analyses. Obtained IGHV subfamilies were correlated with active clinical features of SLE, as determined by medical record reviews. We established significant associations with the presence of IGHV3-15 and active neuropsychiatric lupus (relative risk [RR] 5.71); IGHV3-21, IGHV3-23 and IGHV4-34 and leukopenia (RR 13.70, 2.14 and 10.29 respectively); and IGHV3-23 and serositis (RR 2.41) and cutaneous lesions (RR 2.82). This study provides the first evidence for the clinical benefits of deep anti-dsDNA profiling through MS, and provides an avenue for improving predictive medicine for SLE patients. Future studies with a greater number of patients, and to determine if these subfamilies have direct pathogenic properties are required.

Recent studies have implied an increased incidence of autoimmune diseases following the SARS-CoV-2 pandemic. The objective was to determine if SARS-CoV-2 infections were associated with celiac disease (CD), type 1 diabetes (T1D), and autoimmune thyroid disease (AITD) autoantibodies in a population-based screening when the pandemic hit the South of Sweden during 2021 and 2022. Between August 2021 and June 2022 self-obtained capillary plasma samples were collected from 1088 children at 6-9 years of age and 1185 adolescents at 13-16 years of age, who were randomly invited from the general population to a screening for CD, T1D, AITD, and SARS-CoV-2 antibodies. Among children and adolescents screened for autoantibodies associated with CD, T1D and AITD, the SARS-CoV-2 infection rate was increased in tissue transglutaminase autoantibody (tTGA) positive (13/17; 76.5%) compared with tTGA negative (492/1168; 42.1%) 13-16-year-old individuals (p = 0.0057). There was no association between SARS-CoV-2 infection rate and AITD- or T1D autoantibodies. Our findings indicate a potential association between prior SARS-CoV-2 infection and screening-detected CD autoimmunity in adolescents aged 13-16 years. Further research is needed to elucidate whether ongoing CD autoimmunity increases susceptibility to infection or if SARS-CoV-2 may act as a trigger for CD autoimmunity in genetically and environmentally predisposed individuals.

The prevalence of inflammatory bowel disease (IBD) has increased recently and lacks curative treatments. The involvement of the N6-methyladenosine (m⁶A) reader YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) in ulcerative colitis (UC)-like model was studied in this study. DSS was employed to induce the UC-like condition both in vitro and in vivo. TNF-α, IL-1β, IL-6, and IL-8 secretion levels were analyzed by ELISA assay. Cell vitality was determined by CCK8 assay. FOXO1 mRNA m⁶A level was examined using methylated RNA binding protein immunoprecipitation (Me-RIP) assay. The interactions between YTHDF1 and FOXO1 were analyzed by RIP assay. ChIP and dual luciferase reporter assays were used to explore the relationship between FOXO1 and FBW7. YTHDF1, FOXO1, and FBW7 were overexpressed in DSS-induced colon epithelial cells. YTHDF1 downregulation alleviated DSS-induced inflammation and NF-κB signal activation in colon epithelial cells. Mechanically, YTHDF1 increased FOXO1 mRNA stability in an m⁶A manner. YTHDF1 overexpression prevented the inhibition of FOXO1 knockdown on DSS-induced inflammation in colon epithelial cells. In addition, FOXO1 transcriptionally activated FBW7. Moreover, FOXO1 upregulation abolished the inhibitory effect of FBW7 knockdown on DSS-induced inflammation in colon epithelial cells. Animal experiments also showed that YTHDF1 deletion alleviated inflammatory response in UC-like mice. YTHDF1 promoted inflammatory response in the UC-like model by transcriptionally activating FBW7 through regulating m⁶A-dependent FOXO1.

Lupus nephritis (LN) is the most common complication of systemic lupus erythematosus (SLE) affecting the kidneys. Receptor-interacting protein kinase 1 (RIPK1) is involved in necroptosis and inflammatory signaling. Here, we investigate the role of RIPK1 kinase activity in the pathogenesis of LN. Immunofluorescent colocalization of necroptosis with podocyte, endothelial cells, and mesangial cells was detected in the kidney of MRL/lpr mice. In vivo studies used ZJU37 (a RIPK1 inhibitor) to treat MRL/lpr mice to evaluate LN pathological alterations. In vitro, mouse mesangial cells were stimulated with DMSO, serum from MRL/lpr mice, and serum + ZJU37 to detect cell viability, cell death status, expression of necroptosis-related molecular proteins, and significant pathway alterations accompanied by necroptosis. We also conducted functional assay to validate the biological significance of the pathway changed. Firstly, the involvement of RIPK1/RIPK3/MLKL-dependent necroptosis was shown in the mesangial cells of MRL/lpr mice. Secondly, we found that ZJU37 inhibited glomerulonephritis, tubulointerstitial lesions, and vasculitis by reducing the necroptosis of mesangial cells in MRL/lpr mice. Moreover, we discovered that mesangial cells are susceptible to necroptosis when stimulated with serum from MRL/lpr animals and identified the primary altered pathways, including cytokine-cytokine receptor interaction and the PI3K-Akt signaling pathway, which could be abolished by ZJU37. Functional assay showed ZJU37 could significantly increase the migration and cell proliferation ability of mesangial cells. RIPK1 activation triggered mesangial cell necroptosis was identified in the kidneys of MRL/lpr mice and Inhibition of RIPK1 could alleviate LN by reducing the necroptosis of mesangial cells.

To examine the differences in the proportions of circulating peripheral helper T cells (Tph), follicular helper T cells (Tfh), regulatory T cells (Treg), and Treg subtypes between patients with rheumatoid arthritis positive for Hashimoto thyroiditis antibodies (RA-HT) and those with rheumatoid arthritis alone (RA). To investigate the correlations between these cell types and clinical indicators, and evaluate their potential as biomarkers for diagnosing and predicting RA-HT, thereby providing directions for more detailed mechanistic studies. The study enrolled 50 RA-HT patients, 53 RA patients, and 10 healthy controls. Fresh peripheral blood was collected for flow cytometry analysis, and clinical data were gathered for correlation studies. The diagnostic performance of the cells was analyzed using the receiver operating characteristic (ROC) curve. In the RA-HT group, there were significant increases in circulating Tph, Tfh, Treg, and memory Treg cells compared to the RA group (p < 0.0001, p < 0.01, p < 0.05, p < 0.05), while activated Treg cells decreased significantly (p < 0.0001). ROC curve analysis showed that the area under the curve of the combined prediction model of Tph, Tfh, Treg, and activated Treg cells was 0.905, with a sensitivity of 78.00% and a specificity of 90.57%. The increase in the proportions of Tph and Tfh cells and the imbalance in the proportions of Treg cell subtypess, may contribute to the pathogenesis of RA-HT. The combined prediction model of Tph, Tfh, Treg, and activated Treg cells demonstrates diagnostic potential for RA-HT.

Systemic lupus erythematosus (SLE) is an autoimmune disease with complex clinical manifestations and no current cure. Alternative splicing (AS) plays a key role in SLE by regulating immune-related genes, but its genome-wide regulatory mechanisms remain unclear. To investigate the involvement of abnormal splicing regulators and AS events in the immune regulation of SLE. Transcriptome data from the SLE dataset GSE162828 were analyzed for differential gene expression and AS events using bioinformatics tools. Immune infiltration analysis was conducted with CIBERSORT, and co-expression of key splicing factors (SFs) and AS events was assessed using SUVA software. A total of 5144 differentially expressed genes and 73 SFs were identified. Significant immune cell differences were observed between SLE and controls, highlighting SFs such as HNRNPDL, RBM47, TIA1, SSB, and DHX15. Eighty-three AS events were identified, with IRF9 and PTPRC emerging as key regulatory events linked to SLE. Dysregulated SFs influence AS in immune-related genes, affecting immune cell composition and SLE progression. These findings offer potential new therapeutic targets for modulating the immune microenvironment in SLE.

Cryptorchidism, a common male reproductive disorder characterized by undescended testes, is associated with infertility and increased cancer risk. While its etiology remains incompletely understood, accumulating evidence suggests that immune-inflammatory responses contribute to disease progression. This study investigated the role of carboxypeptidase N subunit 2 (CPN2) in modulating immune activation and testicular pathology via the NF-κB signaling pathway. Key regulatory genes were identified through transcriptomic analysis, weighted gene co-expression network analysis (WGCNA), and machine learning approaches. A di-n-butyl phthalate (DBP)-induced rat model of cryptorchidism and CRISPR/Cas9-mediated CPN2 knockout rats were employed, alongside histological, immunohistochemical, Western blotting, and co-culture assays to explore immune activation and spermatogonial cell fate. CPN2 was identified as a pivotal factor that suppresses NF-κB activation and plasma cell infiltration. Its overexpression alleviated inflammatory cytokine production, preserved spermatogonial stem cell proliferation, and reduced apoptosis in both in vivo and in vitro models. These effects were reversed upon NF-κB activation, confirming the regulatory role of the CPN2/NF-κB axis. Our findings reveal that CPN2 mitigates cryptorchidism progression by modulating immune-inflammatory responses, highlighting it as a promising molecular target for non-surgical intervention in this condition.

The advent of chimeric antigen receptor (CAR) T cell therapy has yielded transformative efficacy in hematological malignancies, yet its application in solid tumors remains constrained by the immunosuppressive tumor microenvironment (TME). Characterized by hypoxia, acidosis, and nutrient deprivation, the TME critically compromises CAR-T cell infiltration, persistence, and effector functions. Hypoxia-inducible factor 1α (HIF-1α), a central regulator of cellular adaptation to hypoxia within the TME, modulates T cell metabolism and functionality-presenting a strategic framework for enhancing CAR-T cell efficacy in solid malignancies. This review characterizes the role of HIF-1α in reprogramming the tumor-immune microenvironment, with specific emphasis on its metabolic regulation of T cells and translational implications for CAR-T therapy. Under hypoxic stress, HIF-1α orchestrates a metabolic shift toward glycolysis in effector T cells by suppressing oxidative phosphorylation (OXPHOS) while upregulating key glycolytic enzymes (e.g. GLUT1, HK2, LDHA). This adaptation sustains ATP production while attenuating mitochondrial reactive oxygen species (ROS) accumulation, thereby mitigating T cell exhaustion and augmenting cytotoxic persistence. This HIF-1α-mediated metabolic reprogramming provides critical insights for overcoming barriers to CAR-T cell efficacy in solid tumors.