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Mapping the heterogeneity of pDCs and Monocytes of systemic sclerosis at single cell level [scRNA-seq]

ABSTRACT: Systemic sclerosis (SSc) is an uncommon disease characterized by elevated autoantibody production, vasculopathy and fibrosis of the skin and internal organs. pDCs are the core cell type to produce type I IFN and contributes to the ISG signature and SSc progression. Using single-cell RNA sequencing, we profiled 32529 pDCs enriched and T cell depleted peripheral blood mononuclear cells (PBMCs) from 4 patients with SSc and 4 matched controls. Increased CD16+ monocytes and decreased cDCs are the major changes in the cell composition between SSc and heathy controls. Increased expression of interferon-stimulated genes (ISGs) and apoptotic genes distinguished cells from patients with SSc from healthy control cells. The high ISG expression signature (ISGhi) derived from a small number of transcriptionally defined subpopulations within major cell types, including monocytes, natural killer cells, conventional and plasmacytoid dendritic cells, B cells. Profiling of 10976 pDCs revealed a newly identified PTGDS+ population and a clear increased ISG hi clusters in SSc pDCs. Profiling of 13317 Monocytes revealed increased CD16+ Monocytes and a clear increased ISG hi clusters in SSc monocytes. We then compared the TLRs-IFN response of the pDCs from SSc and Healthy control. RNASeq revealed SSc pDCs enables an unexpected TLR8-IFN signaling to increase the IFN signature. This study lays the groundwork for resolving the origin of the SSc transcriptional signatures and the disease heterogeneity towards precision medicine applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE210395 | GEO | 2024/08/10

REPOSITORIES: GEO

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Project description:To identify potential dysregulation of miRNA expression in plasmacytoid dendritic cells from Systemic Sclerosis patients (SSc), miRNA profiling was performed in pDCs from healthy donors or patients with the most severe fibrotic cutaneous form of SSc, namely in dcSSc, with either disease duration shorter (edcSSc) or longer than two years (ldcSSc). Plasmacytoid dendritic cells (pDCs) are a critical source of type I interferons (IFNs) that can contribute to the onset and maintenance of autoimmunity. Molecular mechanisms leading to pDC dysregulation and persistent type I IFN signature are largely unexplored, especially in systemic sclerosis (SSc), a disease in which pDCs infiltrate fibrotic skin lesions and produce higher levels of IFNa as compared to healthy controls. To investigate potential microRNA–mediated epigenetic mechanisms underlying pDC dysregulation and type I IFN production in SSc. microRNA expression profiling and validation was performed in highly purified pDCs obtained from the peripheral blood of 3 independent cohorts of healthy controls and SSc patients. Possible functions of miR-618 on pDC biology were identified by overexpression in healthy pDCs. miR-618 expression was upregulated in pDCs of SSc patients, including those in the early stage of disease onset and not presenting with skin fibrosis. IRF8, a crucial transcription factor for pDC development and activation, was identified as a target of miR-618. miR-618 overexpression reduced the development of pDCs from CD34+ cells in-vitro and enhanced their ability to secrete IFNα, mimicking the pDC phenotype observed in SSc patients. miR-618 upregulation suppresses pDC development and increases their ability to secrete IFNα, potentially contributing to the type I IFN signature observed in SSc patients. Considering the importance of pDCs in the pathogenesis of SSc and other diseases characterized by a type I IFN signature, miR-618 potentially represents an important epigenetic target to regulate immune system homeostasis in these conditions.

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).

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Mapping the heterogeneity of pDCs and Monocytes of systemic sclerosis at single cell level [scRNA-seq]

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