A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE161476 | GEO | 2020/12/08
REPOSITORIES: GEO
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Project description:Recent literature has shown that neutrophils exert significant influence on the course of disease progression in lupus, but there is currently controversy in the lupus field regarding a) whether neutrophils are predominantly protective or deleterious toward the propagation of auto-reactivity, b) the specific mechanism of neutrophil influence on adaptive immune dysregulation, and c) identity and origin of functionally abnormal neutrophil subsets in lupus. Here we used RNA sequencing of splenic neutrophils isolated from a murine lupus model (NZB/W) to characterize changes in the transcriptional program of neutrophils over the course of lupus progression. We find that the transcription of immunologically relevant genes change over the course of disease, and that lupus neutrophils early in disease show enrichment for transcripts associated with neutrophil precursors. These data provide the first detailed profile of the splenic neutrophil transcriptional program changes during the progression of lupus.
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Project description:Neutrophils are understudied in lupus. We performed RNA-sequencing of neutrophils from patients with lupus and healthy controls.
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Project description:Our group has proposed that low-density granulocytes (LDGs) play an important role in lupus pathogenesis, as they can damage endothelial cells and synthesize increased levels of proinflammatory cytokines and type I interferons. LDGs have a heightened capacity to synthesize neutrophil extracellular traps (NETs). NETs from LDGs display increased levels of bactericidal and immunostimulatory proteins, such as the cathelicidin LL37 and externalize double-stranded DNA (dsDNA). Lupus netting LDGs have increased capacity to kill endothelial cells and expose IL-17. Through NETosis, lupus neutrophils stimulate plasmacytoid DCs to synthesize IFN-?. Our results further expand the potential pathogenic role of aberrant lupus neutrophils through a NET-mediated effect. We used microarrays to analyze the gene expression of neutrophils in healthy and lupus patients, and of low-density granulocytes in lupus patients. Human neutrophils and LDGs were isolated from PBMCs. RNA from healthy neutrophils, lupus neutrophils and lupus LDGs was extracted and processed for hybridization on Affymetrix microarrays.
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Project description:Lupus neutrophils transcriptome
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Project description:Our group has proposed that low-density granulocytes (LDGs) play an important role in lupus pathogenesis, as they can damage endothelial cells and synthesize increased levels of proinflammatory cytokines and type I interferons. LDGs have a heightened capacity to synthesize neutrophil extracellular traps (NETs). NETs from LDGs display increased levels of bactericidal and immunostimulatory proteins, such as the cathelicidin LL37 and externalize double-stranded DNA (dsDNA). Lupus netting LDGs have increased capacity to kill endothelial cells and expose IL-17. Through NETosis, lupus neutrophils stimulate plasmacytoid DCs to synthesize IFN-α. Our results further expand the potential pathogenic role of aberrant lupus neutrophils through a NET-mediated effect. We used microarrays to analyze the gene expression of neutrophils in healthy and lupus patients, and of low-density granulocytes in lupus patients.
2011-06-22 | GSE26975 | GEO
Project description:We identified genome-wide DNA methylation patterns within neutrophils and low-density granulocytes of Lupus patients and demographically matched controls Comparison of 15 Lupus patients vs 15 age-, sex-, and ethnicity-matched controls using the Illumina HumanMethylation 450 beadchip array
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Project description:Lupus nephritis (LN) is characterized by immune-complex deposition in kidney glomeruli and has been classified according to histological features, but has not been characterized on a molecular level. This study aimed to characterize the relationship between histological and molecular phenotypes in LN. Renal compartmental mRNA expression was measured in 54 kidney biopsy specimens from patients with LN and correlated to histological phenotypes. The top identified transcripts were compared to a separate longitudinal cohort of 36 patients with paired kidney biopsies obtained at the time of flare and at follow up. Unsupervised clustering based on mRNA abundance resulted in clear separation by renal compartment, but did not demonstrate a relationship with LN class based on the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification, or the NIH activity and chronicity indices. A strong interferon gene signature was observed in both cohorts. FN1, SPP1, and LGALS-3 correlated with disease activity in both cohorts. The relationship between mRNA expression and ISN/RPS classification is modest. However, correlation of mRNA expression with individual histologic lesions identifies transcripts that change with resolution of disease flare, and provide insights into the molecular pathways potentially responsible for pathologic kidney lesions. Combining molecular and pathologic kidney biopsy phenotype may hold promise to better classify disease and identify actionable treatment targets.
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Project description:A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients
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Project description:The highly heterogeneous clinical presentation of lupus is characterized by the unpredictable appearance of flares of disease activity and important organ damage. Attempts to stratify lupus patients have been limited to clinical information, leading to unsuccessful clinical trials and controversial research results. Our aim was to develop and validate a robust method to stratify patients with lupus according to longitudinal disease activity and whole-genome gene expression data in order to establish subgroups of patients who share disease progression mechanisms. We applied a clustering-based approach to stratify SLE patients based on the correlation between disease activity scores and longitudinal gene expression information. Clustering robustness was evaluated by bootstrapping and the clusters were characterized in terms of clinical and functional features.Using two independent sets of patients, one pediatric and another adult, our results show a clear partition into three different disease clusters not influenced by treatment, race or other source of bias. Two of the clusters differentiate into a neutrophil correlated disease group and a lymphocyte correlated disease group, while the third that correlated to a lesser extent with neutrophils, was functionally more heterogeneous. The neutrophil-driven clusters were associated with increased development towards proliferative nephritis. We found three subgroups of patients that show different mechanisms of disease progression and are clinically differentiated. Our results have important implications for treatment options, the design of clinical trials, the etiology of the disease, and the prediction of severe glomerulonephritis.
2018-10-15 | GSE121239 | GEO
Project description:An important pathogenic role for neutrophils in systemic lupus erythematosus (SLE) has been proposed. Neutrophils that lack brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (Bmal1), one of the clock genes, are defective in aging and proinflammatory responses. We assessed the role of Bmal1 in clinical and immunologic manifestations of murine lupus and in human SLE neutrophils. We used myeloid-conditional Bmal1 knockout mice (Bmal1Mye−/−) and wild type (WT) that were treated with epicutaneous TLR7/8 agonist (imiquimod; IMQ) for 6 weeks to induce a lupus phenotype. Upon euthanasia, immune responses, autoantibodies and renal manifestations were evaluated. NET formation and gene expression of bone marrow (BM)-derived murine neutrophils were evaluated. BMAL1 expression was quantified in SLE neutrophils and compared with clinical disease. IMQ-treated Bmal1Mye−/− and WT displayed comparable systemic inflammation. While renal function did not differ, serum anti-dsDNA levels and renal immune complex deposition were significantly increased in Bmal1Mye−/−. While no differences were observed in NET formation, expression levels of April in BM neutrophils were significantly higher in Bmal1Mye−/−. Bulk RNA-sequence data showed that BM neutrophils in IMQ-treated Bmal1Mye−/− were relatively immature when compared to IMQ-treated WT. BM showed enhanced April protein expression in Bmal1Mye−/− mice. BMAL1 levels in human SLE peripheral blood neutrophils correlated positively with serum C3 and negatively with serum anti-dsDNA levels. Taken toghether, Bmal1 is associated with lower disease activity in SLE. These results indicate that perturbation in the circadian rhythm of neutrophils can have pathogenic consequences in SLE.
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