Defective removal of ribonucleotides from DNA promotes systemic autoimmunity
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE63755 | GEO | 2014/12/15
SECONDARY ACCESSION(S): PRJNA268979
REPOSITORIES: GEO
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Project description:Constitutive low level DNA damage in RNASEH2 deficiency is linked to innate immune activation. Hierarchical clustering of over 16000 transcripts revealed remarkably similar profiles in patients with lupus erythematosus and patients with AGS with up-regulation of genes involved in DNA damage signaling and type I-IFN signaling. Comparison of transcriptional profiles of native RNASEH2-deficient patient fibroblasts with wild type cells.
2014-12-15 | E-GEOD-63755 | biostudies-arrayexpress
Project description:Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE- and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.
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Project description:Constitutive low level DNA damage is linked to innate immune activation. Hierarchical clustering of over 9000 transcripts revealed remarkably similar profiles in a patient with lupus erythematosus and a patient with AGS with up-regulation of genes involved in DNA damage signaling, p53-inducible genes, senescence-associated genes as well as up-regulation of interferon-stimulated genes. Transcriptional profiling of fibroblasts exposed to oxidative stress showed a marked up-regulation of genes involved in DNA replication/repair and replication licensing in TREX1-deficient cells compared to wild type cells suggesting massive replication stress. Comparison of transcriptional profiles of unstressed patient fibroblasts with wild type cells as well as fibroblasts exposed to oxidative stress
2016-05-30 | E-GEOD-59233 | biostudies-arrayexpress
Project description:Constitutive low level DNA damage is linked to innate immune activation. Hierarchical clustering of over 9000 transcripts revealed remarkably similar profiles in a patient with lupus erythematosus and a patient with AGS with up-regulation of genes involved in DNA damage signaling, p53-inducible genes, senescence-associated genes as well as up-regulation of interferon-stimulated genes. Transcriptional profiling of fibroblasts exposed to oxidative stress showed a marked up-regulation of genes involved in DNA replication/repair and replication licensing in TREX1-deficient cells compared to wild type cells suggesting massive replication stress.
2016-05-30 | GSE59233 | GEO
Project description:Biallelic defects of the gene encoding for the intracellular enzyme 3â repair exonuclease (Trex)1 cause Aicardi-Goutières syndrome (AGS), a rare monogenic, lupus-like autoimmune disease, while heterozygous Trex1 loss of function alleles are associated with systemic lupus erythematosus (SLE). Trex1-/- mice develop lethal autoimmune multi-organ inflammation, which results from a chronic type I IFN response triggered by intracellular accumulation of a putative nucleic acid substrate of Trex1. This pathogenic nucleic acid is detected by the broadly, but not ubiquitously, expressed cytosolic DNA sensor cGAS, raising the question whether there are specific cell types that respond to Trex1 deficiency by production of IFN and induce autoimmunity. We generated mice with conditional knock out of the Trex1 gene and demonstrated that loss of Trex1 throughout the hematopoietic system and even selective loss in dendritic cells is sufficient to cause IFN release and autoimmunity. B cells showed no transcriptional response to Trex1 deficiency. Trex1-/- keratinocytes produced IFN but did not induce skin inflammation, whereas loss of Trex1 in cardiomyocytes triggered neither IFN response nor pathology. Trex1-deficient neurons and astrocytes did not release IFN in the CNS. In contrast, mice with selective inactivation of Trex1 in long-living CNS macrophages such as microglia locally produced IFN but did not reproduce the mild encephalitis seen in Trex1-/- mice. Collectively, individual cell types differentially respond to the loss of Trex1 and dendritic cells seem promising candidates for experiments addressing the molecular pathomechanism in Trex1 deficiency. We sorted CD19-positive B cells from spleens of Trex1fl/fl CD19-Cre+ and Trex1fl/fl CD19-Cre- mice and isolated total RNA for library construction to perform mRNA deep sequencing.
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Project description:Lupus, a server and complex autoimmune disease, is clinically divided into cutaneous lupus erythematosus (CLE) which featured in skin damage, and systemic lupus erythematosus (SLE) which characterized in systemic multi-organ damage. The distinction of these two types of lupus is widely unknown. Here, we collected 23 skin biopsies of healthy control(HC), DLE (discoid lupus erythematosus, a main type of CLE) and SLE, separated epidermis and dermis and performed single cell RNA sequencing through microfluidics based 10x genomics system. Our results demonstrated larger numbers of immune cells infiltrated in skin lesions of DLE than SLE, which may help to distinguish them. Then, non-immune cells such as keratinocytes and fibroblasts were showed functions like immune cells. Moreover, ISGs(interferon stimulated genes), HSP70 coding genes were found to be overexpressed in multi expanded subclusters. Some biological progresses such as autophagy and neutrophil activation were enriched in expanded subclusters.
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Project description:Aicardi-Goutières syndrome (AGS) is a severe childhood inflammatory disorder that shows clinical and genetic overlap with systemic lupus erythematosus (SLE). AGS is thought to arise from the accumulation of incompletely metabolized endogenous nucleic acid species owing to mutations in nucleic acid degrading enzymes TREX1 (AGS1), RNase H2 (AGS2, 3 and 4) and SAMHD1 (AGS5). However, the identity and source of such immunogenic nucleic acid species remain undefined. Using genome-wide approaches, we show that fibroblasts from AGS patients with AGS1-5 mutations are burdened by excessive loads of RNA:DNA hybrids. Using MethylC-seq, we show that AGS fibroblasts display pronounced and global loss of DNA methylation and demonstrate that AGS-specific RNA:DNA hybrids often occur within DNA hypomethylated regions. Altogether, our data suggest that RNA:DNA hybrids may represent a common immunogenic form of nucleic acids in AGS and provide the first evidence of epigenetic perturbations in AGS, furthering the links between AGS and SLE.
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Project description:Biallelic defects of the gene encoding for the intracellular enzyme 3’ repair exonuclease (Trex)1 cause Aicardi-Goutières syndrome (AGS), a rare monogenic, lupus-like autoimmune disease, while heterozygous Trex1 loss of function alleles are associated with systemic lupus erythematosus (SLE). Trex1-/- mice develop lethal autoimmune multi-organ inflammation, which results from a chronic type I IFN response triggered by intracellular accumulation of a putative nucleic acid substrate of Trex1. This pathogenic nucleic acid is detected by the broadly, but not ubiquitously, expressed cytosolic DNA sensor cGAS, raising the question whether there are specific cell types that respond to Trex1 deficiency by production of IFN and induce autoimmunity. We generated mice with conditional knock out of the Trex1 gene and demonstrated that loss of Trex1 throughout the hematopoietic system and even selective loss in dendritic cells is sufficient to cause IFN release and autoimmunity. B cells showed no transcriptional response to Trex1 deficiency. Trex1-/- keratinocytes produced IFN but did not induce skin inflammation, whereas loss of Trex1 in cardiomyocytes triggered neither IFN response nor pathology. Trex1-deficient neurons and astrocytes did not release IFN in the CNS. In contrast, mice with selective inactivation of Trex1 in long-living CNS macrophages such as microglia locally produced IFN but did not reproduce the mild encephalitis seen in Trex1-/- mice. Collectively, individual cell types differentially respond to the loss of Trex1 and dendritic cells seem promising candidates for experiments addressing the molecular pathomechanism in Trex1 deficiency.
2016-08-01 | GSE77693 | GEO
Project description:The role of gut microbiota dysbiosis in systemic lupus erythematosus (SLE) pathogenesis remains elusive. Here, we show that fecal microbiota transplantation (FMT) from healthy mice to lupus mice ameliorated lupus-like symptoms. Microbiota reconstitution effectively reduced systemic class switch recombination and elevated IGH naïve isotype. Microbiota profiling revealed an enrichment of Lactobacillus johnsonii post-FMT, with a significant correlation to purine metabolites. Importantly, the Lactobacillus johnsonii-derived inosine, an intermediate metabolite in purine metabolism, effectively alleviated lupus-like symptoms by impeding B cell differentiation and reducing renal B cell infiltration. We further demonstrated that inosine reprograms B cells through the ERK-HIF-1α signaling pathway. Overall, our study highlights the discovery of a novel microbial metabolite modulating autoimmunity and suggests its potential for innovative microbiome-based therapeutic approaches.
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Project description:RNA-seq analysis of nonlesional skin, whole blood, and cultured primary keratinocytes of wild-type and autoimmunity-prone K5-Vgll3 mice, which overexpress the female-biased transcription cofactor VGLL3 in the epidermis and develop a progressive lupus-like rash and systemic autoimmune disease with features of systemic lupus erythematosus. These skin and blood data demonstrate that skin-directed overexpression of VGLL3 results in gene expression changes strikingly similar to those seen in skin and blood of patients with cutaneous and systemic lupus, respectively.
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