Multiplexed scRNA-seq reveals the cellular and genetic correlates of systemic lupus erythematosus
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE174188 | GEO | 2021/12/01
REPOSITORIES: GEO
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Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease defined by a broad range of symptoms that disproportionately affects women Our knowledge of which immune cells mediate the etiology and pathogenesis of the disease remains incomplete Identifying pathogenic cells using bulk gene expression analysis is confounded by the functional overlap and frequency variation of immune cell types Here, we used multiplexed single-cell RNA-seq (scRNA-seq) to profile ~1 million peripheral blood mononuclear cells from 134 SLE cases and 58 healthy controls Cases were marked by a reduction of naive CD4+ T cells, clonal restriction of effector memory CD8+ T cells, and elevated expression of interferon-stimulated genes in classical monocytes An additional 15 cases experiencing active disease flares displayed increased expansion of effector memory CD8+ T cells and the presence of macrophages not seen in managed disease Although cell-type-specific expression contributed most to inter-individual expression variability across all cells, cell composition accounted for more variability in genes differentially expressed in cases We integrated dense genotyping data to map thousands of genetic variants, including SLE-associations, whose effects on expression are modified by cell type or interferon activation Population-scale scRNA-seq analysis reveals changes in cell composition and state associated with SLE, and when integrated with genetic data, ascribes function to disease-associated and disease-modified variants
2019-11-10 | GSE137029 | GEO
Project description:Background/Purpose: Systemic lupus erythematosus (SLE) is a complex multi-system autoimmune disease of uncertain etiology. Patients from different ancestral backgrounds demonstrate differences in clinical manifestations and autoantibody profiles. In this study we examined genome-wide transcriptional patterns in major immune cell subsets across different ancestral backgrounds. Methods: Peripheral blood was collected from 21 African-American (AA) and 21 European-American (EA) SLE patients, 5 AA controls, and 5 EA controls. CD4+ T-cells, CD8+ T-cells, monocytes and B cells were purified by flow sorting. Each cell subset from each subject was run on an Illumina HumanHT-12 V4 expression BeadChip array (n=208 arrays). Differentially expressed genes (DEGs) were determined by comparing cases and controls of the same ancestral background. Results: The overlap in DEG lists between different cell types from the same ancestral background was very modest (<1%). Typically between 5-10% of DEGs were shared when comparing the same cell type between different ancestral backgrounds (for ex. CD20 AA vs. CD20 EA). Quantitative measurement of global IFN-stimulated gene (ISG) expression revealed that AA subjects demonstrated more concordance across all studied cell types. Two subgroups of patients were identified based on the ISG expression profiles. One subgroup showed higher ISGs expression in all cell types, and the other subgroup had higherISG expression only in T and B lymphocytes but not in monocytes. The correlation of ISG expression with medication data revealed that only the B cells had lower ISG expression in patients taking immunosuppressants, while ISG expression in the other cell types did not differ based upon medication use. Conclusion: We find striking differences in gene expression between different immune cell subsets and between ancestral backgrounds in SLE patients. The IFN signature is diverse, with different transcripts represented in different cell populations, and signature-positive cell subsets differed in EA vs. AA patients. We also find that treatment with the immunosuppressive agents correlates with the down-regulation of B cell ISG expression, and this was not observed in other cell types. Peripheral blood was collected from 21 African-American (AA) and 21 European-American (EA) SLE patients, 5 AA controls, and 5 EA controls. CD4+ T-cells, CD8+ T-cells, monocytes and B cells were purified by flow sorting. Each cell subset from each subject was run on an Illumina HumanHT-12 V4 expression BeadChip array (n=208 arrays).
2015-05-15 | E-GEOD-55447 | biostudies-arrayexpress
Project description:Background/Purpose: Systemic lupus erythematosus (SLE) is a complex multi-system autoimmune disease of uncertain etiology. Patients from different ancestral backgrounds demonstrate differences in clinical manifestations and autoantibody profiles. In this study we examined genome-wide transcriptional patterns in major immune cell subsets across different ancestral backgrounds. Methods: Peripheral blood was collected from 21 African-American (AA) and 21 European-American (EA) SLE patients, 5 AA controls, and 5 EA controls. CD4+ T-cells, CD8+ T-cells, monocytes and B cells were purified by flow sorting. Each cell subset from each subject was run on an Illumina HumanHT-12 V4 expression BeadChip array (n=208 arrays). Differentially expressed genes (DEGs) were determined by comparing cases and controls of the same ancestral background. Results: The overlap in DEG lists between different cell types from the same ancestral background was very modest (<1%). Typically between 5-10% of DEGs were shared when comparing the same cell type between different ancestral backgrounds (for ex. CD20 AA vs. CD20 EA). Quantitative measurement of global IFN-stimulated gene (ISG) expression revealed that AA subjects demonstrated more concordance across all studied cell types. Two subgroups of patients were identified based on the ISG expression profiles. One subgroup showed higher ISGs expression in all cell types, and the other subgroup had higherISG expression only in T and B lymphocytes but not in monocytes. The correlation of ISG expression with medication data revealed that only the B cells had lower ISG expression in patients taking immunosuppressants, while ISG expression in the other cell types did not differ based upon medication use. Conclusion: We find striking differences in gene expression between different immune cell subsets and between ancestral backgrounds in SLE patients. The IFN signature is diverse, with different transcripts represented in different cell populations, and signature-positive cell subsets differed in EA vs. AA patients. We also find that treatment with the immunosuppressive agents correlates with the down-regulation of B cell ISG expression, and this was not observed in other cell types.
2015-05-15 | GSE55447 | GEO
Project description:Genome-wide alternative splice analysis of RNA from lupus and its severe form lupus nephritis We aimed to explore the genome-wide peripheral blood transcriptome of lupus (SLE) and its severe form lupus nephritis (LN) cases compared to healthy subjects (HC) using high density Affymetrix Human Exon1.0.ST arrays. Analysis revealed 15 splice variants that are differentially expressed between SLE/HC and 99 variants between LN/HC (p≤0.05,SI>or≤0.5,Benjamin Hochberg-False discovery rate correction). Comparison between LN/SLE revealed 7 variants that are differentially expressed with p≤0.05,SI>0.5,Benjamin Hochberg-FDR correction. Pathway analysis of differentially spliced genes revealed 11 significant pathways in SLE and 12 in LN (p<0.05). Analysis of peripheral blood transcriptome revealed signature causative genes that are alternatively spliced, signifying their clinical relevance in the pathophysiology of disease. The extent of differential splicing was found to be higher in LN than in SLE, signifying the need for further in-depth research in the same domain. Present study is the first to reveal the significance of alternative variants in susceptibility to SLE and LN.
2016-01-06 | GSE62764 | GEO
Project description:Genome-wide alternative splice analysis of RNA from lupus and its severe form lupus nephritis We aimed to explore the genome-wide peripheral blood transcriptome of lupus (SLE) and its severe form lupus nephritis (LN) cases compared to healthy subjects (HC) using high density Affymetrix Human Exon1.0.ST arrays. Analysis revealed 15 splice variants that are differentially expressed between SLE/HC and 99 variants between LN/HC (pâ¤0.05,SI>orâ¤0.5,Benjamin Hochberg-False discovery rate correction). Comparison between LN/SLE revealed 7 variants that are differentially expressed with pâ¤0.05,SI>0.5,Benjamin Hochberg-FDR correction. Pathway analysis of differentially spliced genes revealed 11 significant pathways in SLE and 12 in LN (p<0.05). Analysis of peripheral blood transcriptome revealed signature causative genes that are alternatively spliced, signifying their clinical relevance in the pathophysiology of disease. The extent of differential splicing was found to be higher in LN than in SLE, signifying the need for further in-depth research in the same domain. Present study is the first to reveal the significance of alternative variants in susceptibility to SLE and LN. We analyzed blood from 11 female subjects (5 lupus, 3 lupus nephritis and 3 healthy control) using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Alt Analyze and Genespring software. No techinical replicates were performed. One of the outiler sample (HC2) was excluded from further analysis.
2016-01-06 | E-GEOD-62764 | biostudies-arrayexpress
Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease, and affects all parts of the human body. Genome-wide association studies have been employed to identify susceptibility genes of SLE. However, most of the SLE associated variants are located in the noncoding regions of the human genome.We characterized SLE risk variants in Chinese populations. One of the most significant validated SNP was located in a gene which we named SLEAR. We found SLEAR was enriched in the nucleus and could regulate apoptosis. Apoptosis is a highly regulated process. And misregulation of the process could lead to autoimmune diseases, especially SLE. Our results suggest that the SLEAR plays a key role in apoptosis regulation and is associated with SLE predisposition.
2018-04-09 | GSE104479 | GEO
Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease, and affects all parts of the human body. Genome-wide association studies have been employed to identify susceptibility genes of SLE. However, most of the SLE associated variants are located in the noncoding regions of the human genome. We characterized SLE risk variants in Chinese populations. One of the most significant validated SNP was located in a gene which we named SLEAR. We found SLEAR was enriched in the nucleus and could regulate apoptosis. Apoptosis is a highly regulated process. And misregulation of the process could lead to autoimmune diseases, especially SLE. Our results suggest that SLEAR plays a key role in apoptosis regulation and is associated with SLE predisposition.
2018-04-09 | GSE104382 | GEO
Project description:Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variant found in patients, but not those found exclusively in controls, impair suppression of IRF and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
2019-05-01 | GSE126307 | GEO
Project description:Background: Patients with paediatric-onset systemic lupus erythematosus (SLE) often present with more severe clinical courses than adult-onset patients. Although genome-wide DNA methylation (DNAm) profiling has been performed in adult-onset SLE patients, parallel data on paediatric-onset SLE are not available. Therefore, we undertook a genome-wide DNAm study in paediatric-onset SLE patients across multiple blood cell lineages. Methods: The DNAm profiles of four purified immune cell lineages were compared in 16 Chinese patients with paediatric-onset SLE and 13 healthy controls using the Illumina HumanMethylationEPIC BeadChip. The DNAm dataset consisted of 145 samples, including data from CD4+ T cells, CD8+ T cells, B cells, neutrophils and whole blood. Results: Genome-wide DNAm analysis revealed considerable variation in DNAm levels across samples, and as expected, clustering occurred by cell type rather than disease status. Comparison of DNAm in whole blood and within each independent cell lineage identified a consistent pattern of loss of DNAm at 21 CpG sites overlapping 15 genes, which represented a robust, disease-specific DNAm signature for paediatric-onset SLE in our cohort. This DNAm signature shows considerable overlap with that identified in our adult-onset SLE patient cohort, predominantly showing a loss of DNAm and enrichment in genes involved in type I interferon signalling in SLE, regardless of the age of onset. In addition, cell lineage-specific changes, involving both loss and gain of DNAm, were observed in both novel genes and genes with well-described roles in SLE pathogenesis. Conclusion: The SLE-specific DNAm signature has the potential to develop into a diagnostic biomarker for SLE, which is particularly important for paediatric-onset patients, as diagnosing SLE in children can be challenging. This study also highlights the importance of studying DNAm changes in different immune cell lineages rather than only whole blood, since cell type-specific DNAm changes facilitated the elucidation of the cell type-specific molecular pathophysiology of SLE.
2019-02-19 | GSE118144 | GEO
Project description:Type I interferon (IFN-I) neutralizing autoantibodies have been found in some critical COVID-19 patients; however, their prevalence and longitudinal dynamics across the disease severity scale, and functional effects on circulating leukocytes remain unknown. Here, in 284 COVID-19 patients, we found IFN-I autoantibodies in 19% of critical, 6% of severe and none of the moderate cases. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single- cell epitope and transcriptome sequencing from 54 COVID-19 patients, 15 non-COVID-19 patients and 11 non-hospitalized healthy controls, revealed a lack of IFN-I stimulated gene (ISG-I) response in myeloid cells from critical cases, including those producing anti-IFN-I autoantibodies. Moreover, surface protein analysis showed an inverse correlation of the inhibitory receptor LAIR-1 with ISG-I expression response early in the disease course. This aberrant ISG-I response in critical patients with and without IFN-I autoantibodies, supports a unifying model for disease pathogenesis involving ISG-I suppression via convergent mechanisms.
2021-03-09 | GSE168453 | GEO