Knockdown of RSAD2 attenuates B cell hyperactivity in patients with primary Sjögren’s syndrome (pSS) via suppressing NF-κb signaling pathway

Zhu, Hong; Zheng, Jiayi; Zhou, Yan; Wu, Tong; Zhu, Tiantian

doi:10.1007/s11010-021-04070-z

Cited by 21 publications

(14 citation statements)

References 30 publications

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“…The involvement of B cells in the pathogenesis of pSS has long been well‐established, including hyperactivation of B cells and plasma cells with augmented antibody production. Previous studies have explored the genes including RSAD2 and ESPT11 in promoting B cell hyperactivity in pSS patients [10, 11]. To the best of our knowledge, we are the first to demonstrate the association of B cell metabolic patterns with pathogenic functions in pSS patients.…”

Section: Discussionmentioning

confidence: 86%

mTORC1‐GLUT1‐mediated glucose metabolism drives hyperactivation of B cells in primary Sjogren's syndrome

Luo

Wang

et al. 2022

Immunology

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Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by B cell hyperactivation and hypergrammaglobulinemia. Currently, the role of metabolic pathways in the B cells of pSS patients is poorly defined. Here, we showed that upon cytosine phosphate-guanine (CpG)/sCD40L/IL-4 stimulation, B cells proportionally increased glycolysis and oxygen consumption, and compared with B cells from healthy controls (HCs), B cells from pSS patients exhibited higher glycolysis capacity and maximal oxidative respiration (OXPHOS).We also found that glucose transporter 1 (GLUT1) expression in B cells from pSS patients was significantly higher than that in B cells from HCs. Treatment with 2-deoxy-D-glucose (2-DG) inhibited the activation of B cells in pSS patients. Both 2-DG and Metformin inhibited the proliferation, formation of plasma/ plasmablasts and decreased the IgG and IgM levels in the supernatants of B cells from pSS patients. Furthermore, inhibition of mTORC1 by rapamycin had an effect similar to that of 2-DG, suppressing B cell activation, proliferation and antibody production. Taken together, we demonstrated that B cells from pSS patients are more metabolically active than those from HCs and suggested that the mTORC1-GLUT1 glycolysis pathways were the major drivers of B cell hyperactivation and autoantibody production in pSS patients.

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Section: Discussionmentioning

confidence: 86%

mTORC1‐GLUT1‐mediated glucose metabolism drives hyperactivation of B cells in primary Sjogren's syndrome

Luo

Wang

et al. 2022

Immunology

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“…RSAD2, also known as Viperin, is a highly induced ISG and plays an intermediary role in inducing pDCs to generate IFN-I by mediating TLR7 and TLR9 ( 36 ). Silencing RASD2 can reduce the viability and promote the apoptosis of CD19 + B cells by inhibiting NF-κB pathway, as well as reduce the expression of IL-10 ( 37 ). RSAD2 has been identified as a key gene of SLE frequently, not only its transcriptional levels but also serum protein levels were significantly up-regulated in SLE patients ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of key interferon-stimulated genes for indicating the condition of patients with systemic lupus erythematosus

et al. 2022

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with highly heterogeneous clinical symptoms and severity. There is complex pathogenesis of SLE, one of which is IFNs overproduction and downstream IFN-stimulated genes (ISGs) upregulation. Identifying the key ISGs differentially expressed in peripheral blood mononuclear cells (PBMCs) of patients with SLE and healthy people could help to further understand the role of the IFN pathway in SLE and discover potential diagnostic biomarkers.The differentially expressed ISGs (DEISG) in PBMCs of SLE patients and healthy persons were screened from two datasets of the Gene Expression Omnibus (GEO) database. A total of 67 DEISGs, including 6 long noncoding RNAs (lncRNAs) and 61 messenger RNAs (mRNAs) were identified by the “DESeq2” R package. According to Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, those DEISGs were mainly concentrated in the response to virus and immune system processes. Protein-protein interaction (PPI) network showed that most of these DEISGs could interact strongly with each other. Then, IFIT1, RSAD2, IFIT3, USP18, ISG15, OASL, MX1, OAS2, OAS3, and IFI44 were considered to be hub ISGs in SLE by “MCODE” and “Cytohubba” plugins of Cytoscape, Moreover, the results of expression correlation suggested that 3 lncRNAs (NRIR, FAM225A, and LY6E-DT) were closely related to the IFN pathway.The lncRNA NRIR and mRNAs (RSAD2, USP18, IFI44, and ISG15) were selected as candidate ISGs for verification. RT-qPCR results showed that PBMCs from SLE patients had substantially higher expression levels of 5 ISGs compared to healthy controls (HCs). Additionally, statistical analyses revealed that the expression levels of these ISGs were strongly associated to various clinical symptoms, including thrombocytopenia and facial erythema, as well as laboratory indications, including the white blood cell (WBC) count and levels of autoantibodies. The Receiver Operating Characteristic (ROC) curve demonstrated that the IFI44, USP18, RSAD2, and IFN score had good diagnostic capabilities of SLE.According to our study, SLE was associated with ISGs including NRIR, RSAD2, USP18, IFI44, and ISG15, which may contribute to the future diagnosis and new personalized targeted therapies.

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“…Radical S-adenosyl methionine domain-containing protein 2 (RASD2) expression is closely related to the degree of differentiation of podocytes, and its regulatory expression gradually decreases with the development of the kidney [46]. In addition, silencing of RSAD2 inhibits the NF-κb signaling pathway and attenuates B-cell hyperactivity [47]. Overall, we inferred that the 5 key genes might be considered diagnostic biomarkers in MCD.…”

Section: Discussionmentioning

confidence: 99%

Identification of key biomarkers and immune infiltration in Minimal Change Disease: Novel Insights from bioinformatics analysis

Tang

Yang

et al. 2022

Preprint

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Background Minimal change disease (MCD) is not a simple immune disease, and its pathogenesis has not been elucidated because of its complexity in terms of the glomerular microenvironment and genetic susceptibility. Hence the therapeutic approach is equally imprecise. Methods We downloaded GSE108109 from the Gene Expression Omnibus (GEO) database for bioinformatic analyses. Genome-wide expression analysis (GSEA) and functional enrichment analysis of differentially expressed genes (DEGs) were performed. Single sample gene set enrichment analysis (ssGSEA) was applied to assess the level of immune infiltration patterns of diseases. Protein-Protein Interaction (PPI) network was constructed to identify hub genes. Hub genes were intersected with immune-related genes downloaded from the Immunology Database and Analysis Portal (ImmPort) to obtain key genes. In addition, the expression levels of key genes were validated in the Kidney Interactive Transcriptomics webpage and Nephroseq database. Receiver operating characteristic (ROC) analysis and principal component analysis (PCA) was performed to explore the value of key genes for MCD diagnosis. Results 1029 DEGs were screened, of which 493 were up-regulated, and 536 were down-regulated. GSEA analysis revealed that DEGs were significantly enriched in three pathways, including T-cell receptor signaling pathway, natural killer cell-mediated cytotoxicity, and B-cell receptor signaling pathway. In addition, 17 of the 21 immune cell types were significantly different in MCD compared to the normal group. A total of five key genes (ISG15, IRF1, OAS1, RSAD2, BST2) were shown to play essential roles in the immune response. Among them, IRF1, OAS1, RSAD2, and BST2 were highly expressed in podocytes. Conclusions In this study, bioinformatics analysis revealed new insights into MCD: (1) Immune cell infiltration analysis provided new evidence and clues to the molecular mechanisms of MCD. (2) Key genes such as ISG15, IRF1, OAS1, RSAD2 and BST2 may contribute to the immunopathological process of MCD development.

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Knockdown of RSAD2 attenuates B cell hyperactivity in patients with primary Sjögren’s syndrome (pSS) via suppressing NF-κb signaling pathway

Cited by 21 publications

References 30 publications

mTORC1‐GLUT1‐mediated glucose metabolism drives hyperactivation of B cells in primary Sjogren's syndrome

mTORC1‐GLUT1‐mediated glucose metabolism drives hyperactivation of B cells in primary Sjogren's syndrome

Identification of key interferon-stimulated genes for indicating the condition of patients with systemic lupus erythematosus

Identification of key biomarkers and immune infiltration in Minimal Change Disease: Novel Insights from bioinformatics analysis

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