Comprehensive analysis of epigenetic modifications and immune-cell infiltration in tissues from patients with systemic lupus erythematosus

Epigenomics ◽  
2021 ◽  
Author(s):  
Zhenghao He ◽  
Shihang Zhou ◽  
Ming Yang ◽  
Zhidan Zhao ◽  
Yang Mei ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dna Methylation ◽  
Lupus Erythematosus ◽  
Immune Cell ◽  
Epigenetic Modifications ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Methylation Analysis ◽  
Systemic Lupus ◽  
Dna Methylation Analysis

Aim: To explore potential abnormal epigenetic modifications and immune-cell infiltration in tissues from systemic lupus erythematosus (SLE) patients. Materials & methods: To utilize bioinformatics analysis and ‘wet lab' methods to identify and verify differentially expressed genes in multiple targeted organs in SLE. Results: Seven key genes, IFI44, IFI44L, IFIT1, IFIT3, PLSCR1, RSAD2 and OAS2, which are regulated by epigenetics and may be involved in the pathogenesis of SLE, are identified by combined long noncoding RNA–miRNA–mRNA network analysis and DNA methylation analysis. The results of quantitative reverse transcription PCR, immunohistochemistry and DNA methylation analysis confirmed the potential of these genes as biomarkers. Conclusion: This study reveals the potential mechanisms in SLE from epigenetic modifications and immune-cell infiltration, providing diagnostic biomarkers and therapeutic targets for SLE.

scholarly journals Identification of key biomarkers and immune infiltration in systemic lupus erythematosus by integrated bioinformatics analysis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xingwang Zhao ◽  
Longlong Zhang ◽  
Juan Wang ◽  
Min Zhang ◽  
Zhiqiang Song ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Erythematosus ◽  
Immune Cell ◽  
Expression Profiles ◽  
Gene Set Enrichment Analysis ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Tissue Destruction ◽  
Systemic Lupus ◽  
Ppi Networks

Abstract Background Systemic lupus erythematosus (SLE) is a multisystemic, chronic inflammatory disease characterized by destructive systemic organ involvement, which could cause the decreased functional capacity, increased morbidity and mortality. Previous studies show that SLE is characterized by autoimmune, inflammatory processes, and tissue destruction. Some seriously-ill patients could develop into lupus nephritis. However, the cause and underlying molecular events of SLE needs to be further resolved. Methods The expression profiles of GSE144390, GSE4588, GSE50772 and GSE81622 were downloaded from the Gene Expression Omnibus (GEO) database to obtain differentially expressed genes (DEGs) between SLE and healthy samples. The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments of DEGs were performed by metascape etc. online analyses. The protein–protein interaction (PPI) networks of the DEGs were constructed by GENEMANIA software. We performed Gene Set Enrichment Analysis (GSEA) to further understand the functions of the hub gene, Weighted gene co‐expression network analysis (WGCNA) would be utilized to build a gene co‐expression network, and the most significant module and hub genes was identified. CIBERSORT tools have facilitated the analysis of immune cell infiltration patterns of diseases. The receiver operating characteristic (ROC) analyses were conducted to explore the value of DEGs for SLE diagnosis. Results In total, 6 DEGs (IFI27, IFI44, IFI44L, IFI6, EPSTI1 and OAS1) were screened, Biological functions analysis identified key related pathways, gene modules and co‐expression networks in SLE. IFI27 may be closely correlated with the occurrence of SLE. We found that an increased infiltration of moncytes, while NK cells resting infiltrated less may be related to the occurrence of SLE. Conclusion IFI27 may be closely related pathogenesis of SLE, and represents a new candidate molecular marker of the occurrence and progression of SLE. Moreover immune cell infiltration plays important role in the progession of SLE.

scholarly journals N-Acetyl-Seryl-Aspartyl-Lysyl-Proline: mechanisms of renal protection in mouse model of systemic lupus erythematosus

2015 ◽  
Vol 308 (10) ◽  
pp. F1146-F1154 ◽  
Author(s):  
Tang-Dong Liao ◽  
Pablo Nakagawa ◽  
Branislava Janic ◽  
Martin D'Ambrosio ◽  
Morel E. Worou ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Immune Cell ◽  
Organ Damage ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Renal Protection ◽  
Systemic Lupus ◽  
Autoimmune Myocarditis

Systemic lupus erythematosus is an autoimmune disease characterized by the development of auto antibodies against a variety of self-antigens and deposition of immune complexes that lead to inflammation, fibrosis, and end-organ damage. Up to 60% of lupus patients develop nephritis and renal dysfunction leading to kidney failure. N-acetyl-seryl-aspartyl-lysyl-proline, i.e., Ac-SDKP, is a natural tetrapeptide that in hypertension prevents inflammation and fibrosis in heart, kidney, and vasculature. In experimental autoimmune myocarditis, Ac-SDKP prevents cardiac dysfunction by decreasing innate and adaptive immunity. It has also been reported that Ac-SDKP ameliorates lupus nephritis in mice. We hypothesize that Ac-SDKP prevents lupus nephritis in mice by decreasing complement C5-9, proinflammatory cytokines, and immune cell infiltration. Lupus mice treated with Ac-SDKP for 20 wk had significantly lower renal levels of macrophage and T cell infiltration and proinflammatory chemokine/cytokines. In addition, our data demonstrate for the first time that in lupus mouse Ac-SDKP prevented the increase in complement C5-9, RANTES, MCP-5, and ICAM-1 kidney expression and it prevented the decline of glomerular filtration rate. Ac-SDKP-treated lupus mice had a significant improvement in renal function and lower levels of glomerular damage. Ac-SDKP had no effect on the production of autoantibodies. The protective Ac-SDKP effect is most likely achieved by targeting the expression of proinflammatory chemokines/cytokines, ICAM-1, and immune cell infiltration in the kidney, either directly or via C5-9 proinflammatory arm of complement system.

scholarly journals POS0736 IDENTIFICATION OF MOLECULAR PHENOTYPES AND IMMUNE CELL INFILTRATION IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS ACCORDING TO LONGITUDINAL GENE EXPRESSION

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 619.1-619
Author(s):  
S. Song ◽  
S. X. Zhang ◽  
J. Qiao ◽  
R. Zhao ◽  
J. Shi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
Lupus Erythematosus ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Systemic Lupus ◽  
Signature Genes

Background:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with highly heterogeneous clinical presentation characterized by disease unpredictable flares and multi-systemic involvement1 2. This clinical heterogeneity calls for design a molecular stratification to improve clinical trial design and formulate personalization treatment therapies.Objectives:This research was conducted to develop a reliable method to stratify SLE patients combined gene expression information and disease status.Methods:The mRNA expression profile of GSE138458 (contained 307 patients and 23 controls) and GSE49454 (contained 111 patients and 16 controls) were downloaded from the publicly GEO databases. After background adjustment, batch correction, and other pre-procession, obtaining a big gene matrix to identify the differentially expressed genes (DEGs) in SLE compared with healthy controls, which were screened by P value < 0.01. SLE subtypes were identified by non-negative matrix factorization (NMF) based on DEGs. Acquired signature genes in different SLE subtypes were conducted to process pathway enrichment analysis in Metascape. SLEDAI score and immune cell infiltration was also performed between subtypes by software package R (version 4.0.3).Results:Total 1202 DEGs were imputed to NMF unsupervised machine learning method. Patients with SLE were stratified into two subsets based on 184 signature genes derived from obtained DEGs(Fig.1A, 1B). GO and KEGG enrichment analysis showed that signature genes were mainly involved in negative regulation of innate immune response, toll-like receptor signaling pathway, regulation of immune effector process and so on(Fig.1C). Patients in Sub1 group had severe disease activity measures compared with those in Sub2(Fig.1D). SLEDAI scores from GSE49454 dataset were also higher in Sub1 compare with Sub2(Fig.1E). Further, immune cell infiltration results revealed an insufficient of regulatory T cell, CD8 T cells and naive CD4 T cells in Sub1 and neutrophils cells in Sub2(P<0.05)(Fig.1F).Conclusion:Our findings indicate that patients with SLE could be stratified into 2 subtypes which had different lymphocyte status and closely related to disease activity. This phenotyping may help us understand the etiology of the disease, inform patient in the design of clinical trials and guide treatment decision.References:[1]Dorner T, Furie R. Novel paradigms in systemic lupus erythematosus. Lancet 2019;393(10188):2344-58. doi: 10.1016/S0140-6736(19)30546-X [published Online First: 2019/06/11].[2]Fanouriakis A, Tziolos N, Bertsias G, et al. Update οn the diagnosis and management of systemic lupus erythematosus. Annals of the rheumatic diseases 2021;80(1):14-25. doi: 10.1136/annrheumdis-2020-218272 [published Online First: 2020/10/15].Acknowledgements:This project was supported by National Science Foundation of China (82001740), Open Fund from the Key Laboratory of Cellular Physiology (Shanxi Medical University) (KLCP2019) and Innovation Plan for Postgraduate Education in Shanxi Province (2020BY078).Disclosure of Interests:None declared

scholarly journals Methyl donor micronutrients, CD40-ligand methylation and disease activity in systemic lupus erythematosus: A cross-sectional association study

Lupus ◽  
2021 ◽  
pp. 096120332110345
Author(s):  
Stefan Vordenbäumen ◽  
Alexander Sokolowski ◽  
Anna Rosenbaum ◽  
Claudia Gebhard ◽  
Johanna Raithel ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dna Methylation ◽  
T Cells ◽  
Disease Activity ◽  
Lupus Erythematosus ◽  
Cd40 Ligand ◽  
Systemic Lupus ◽  
Methyl Donors ◽  
Methyl Donor ◽  
The Mean

Objective Hypomethylation of CD40-ligand (CD40L) in T-cells is associated with increased disease activity in systemic lupus erythematosus (SLE). We therefore investigated possible associations of dietary methyl donors and products with CD40L methylation status in SLE. Methods Food frequency questionnaires were employed to calculate methyl donor micronutrients in 61 female SLE patients (age 45.7 ± 12.0 years, disease duration 16.2 ± 8.4 years) and compared to methylation levels of previously identified key DNA methylation sites (CpG17 and CpG22) within CD40L promotor of T-cells using quantitative DNA methylation analysis on the EpiTYPER mass spectrometry platform. Disease activity was assessed by SLE Disease Activity Index (SLEDAI). Linear regression modelling was used. P values were adjusted according to Benjamini & Hochberg. Results Amongst the micronutrients assessed (g per day), methionine and cysteine were associated with methylation of CpG17 (β = 5.0 (95%CI: 0.6-9.4), p = 0.04; and β = 2.4 (0.6-4.1), p = 0.02, respectively). Methionine, choline, and cysteine were additionally associated with the mean methylation of the entire CD40L (β = 9.5 (1.0-18.0), p = 0.04; β = 1.6 (0.4-3.0), p = 0.04; and β = 4.3 (0.9-7.7), p = 0.02, respectively). Associations of the SLEDAI with hypomethylation were confirmed for CpG17 (β=-32.6 (-60.6 to -4.6), p = 0.04) and CpG22 (β=-38.3 (-61.2 to -15.4), p = 0.004), but not the mean methylation of CD40L. Dietary products with the highest impact on methylation included meat, ice cream, white bread, and cooked potatoes. Conclusions Dietary methyl donors may influence DNA methylation levels and thereby disease activity in SLE.

scholarly journals Epigenetic Contribution and Genomic Imprinting Dlk1-Dio3 miRNAs in Systemic Lupus Erythematosus

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 680
Author(s):  
Rujuan Dai ◽  
Zhuang Wang ◽  
S. Ansar Ahmed
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Dna Methylation ◽  
Lupus Erythematosus ◽  
Critical Role ◽  
Methylation Status ◽  
Transcriptional Level ◽  
Dna Hypomethylation ◽  
Systemic Lupus ◽  
Multiple Organs ◽  
Genetic Imprinting

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that afflicts multiple organs, especially kidneys and joints. In addition to genetic predisposition, it is now evident that DNA methylation and microRNAs (miRNAs), the two major epigenetic modifications, are critically involved in the pathogenesis of SLE. DNA methylation regulates promoter accessibility and gene expression at the transcriptional level by adding a methyl group to 5′ cytosine within a CpG dinucleotide. Extensive evidence now supports the importance of DNA hypomethylation in SLE etiology. miRNAs are small, non-protein coding RNAs that play a critical role in the regulation of genome expression. Various studies have identified the signature lupus-related miRNAs and their functional contribution to lupus incidence and progression. In this review, the mutual interaction between DNA methylation and miRNAs regulation in SLE is discussed. Some lupus-associated miRNAs regulate DNA methylation status by targeting the DNA methylation enzymes or methylation pathway-related proteins. On the other hand, DNA hyper- and hypo-methylation are linked with dysregulated miRNAs expression in lupus. Further, we specifically discuss the genetic imprinting Dlk1-Dio3 miRNAs that are subjected to DNA methylation regulation and are dysregulated in several autoimmune diseases, including SLE.

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