01414377-550f-40be-9ce1-63e4d17a20b4 - samples
Ontology highlight
ABSTRACT:
PROVIDER: EGAD00001008534 | EGA |
REPOSITORIES: EGA
Similar Datasets
Project description:Set of 133 bam files from patients affected with Lupus. BAM alignments for exonic variants present in 76 Lupus-related genes. VCF file describing the variants.
| EGAD00001004859 | EGA
Project description:Set of 8 bam files from patients affected with Lupus. BAM alignments for exonic variants present in P2RY8 gene. VCF file describing the variants.
| EGAD00001008330 | EGA
Project description:While circumstantial evidence supports enhanced TLR7 signaling as a mechanism of human systemic autoimmune disease, we have lacked the proof afforded by lupus-causing TLR7 gene variants. Here we undertook a whole exome sequencing (WES) approach to identify novel TLR7 variants in human lupus patients. We establish the importance of TLR7 for human SLE pathogenesis, which paves the way for therapeutic TLR7 or MyD88 inhibition.
| EGAS00001005965 | EGA
Project description:While circumstantial evidence supports enhanced TLR7 signaling as a mechanism of human systemic autoimmune disease, we have lacked the proof afforded by lupus-causing TLR7 gene variants. Here we describe human systemic lupus erythematosus (SLE) caused by TLR7 gain-of-function (GoF). We identified a de novo, novel, missense TLR7 Y264H variant in a child with severe lupus. The de novo TLR7 Y264H variant selectively increased sensing of guanosine and was sufficient to cause lupus when introduced in mice (kika mice). We performed RNA-seq of kika and wild type B cells cultured for 20 hours with anti-IgM and found a decreased tendency to apoptosis in kika B cells, including decreased expression of active Caspase 3 and also a small decrease in proliferation. Overall, these results suggest that hypersensitive TLR7 signaling allows the survival of B cells that are binding self-antigen through their surface BCR.
2022-02-10 | GSE196316 | GEO
Project description:Hyperactive TLR7 signaling has long been appreciated as a driver of autoimmune disease in mouse models by breaking tolerance to self-nucleic acids1-5. Recently, the first monogenic mutations within TLR7 or its associated regulator Unc93b16,7 have been identified as causative agents of human lupus. The unifying feature of these mutations is TLR7 gain-of-function resulting from increased ligand binding. TLR7 is an intracellular transmembrane receptor, localized to late endosomes, that senses RNA breakdown products within these hydrolytic compartments8,9. Hence, its function depends on a complex interplay between specialized organelles, transport mechanisms and membrane interactions. Whether perturbations of any of these endosome-related processes can give rise to TLR7 gain-of-function and facilitate self-reactivity has not been investigated. Here we show that a dysregulated endosomal compartment can result in TLR7 gain-of-function and lupus disease in humans. Mechanistically, the late endosomal protein complex BORC-Arl8b controls TLR7 protein levels by mediating the receptor's final sorting step towards lysosomal degradation. A direct interaction between Arl8b and Unc93b1 is required to regulate the turnover of TLR7. We identified an amino acid insertion in Unc93b1 in a patient with childhood-onset lupus, which results in loss of interaction with the BORC-Arl8b complex and an accumulation of functional TLR7. Our results highlight the importance of an intact endomembrane system to prevent autoimmune disease. Disrupting the proper progression of TLR7 through its endocytic life cycle is sufficient to break immunological tolerance to nucleic acids. Our work expands the repertoire of cellular mechanisms important to restrict pathological TLR7 activity. Identifying and stratifying lupus patients based on a TLR7-driven pathology opens the way for precision medicine specifically targeting TLR7.
2023-11-22 | PXD039263 | Pride
Project description:Hyperactive TLR7 signaling has long been appreciated as a driver of autoimmune disease in mouse models by breaking tolerance to self-nucleic acids1-5. Recently, the first monogenic mutations within TLR7 or its associated regulator Unc93b16,7 have been identified as causative agents of human lupus. The unifying feature of these mutations is TLR7 gain-of-function resulting from increased ligand binding. TLR7 is an intracellular transmembrane receptor, localized to late endosomes, that senses RNA breakdown products within these hydrolytic compartments8,9. Hence, its function depends on a complex interplay between specialized organelles, transport mechanisms and membrane interactions. Whether perturbations of any of these endosome-related processes can give rise to TLR7 gain-of-function and facilitate self-reactivity has not been investigated. Here we show that a dysregulated endosomal compartment can result in TLR7 gain-of-function and lupus disease in humans. Mechanistically, the late endosomal protein complex BORC-Arl8b controls TLR7 protein levels by mediating the receptor's final sorting step towards lysosomal degradation. A direct interaction between Arl8b and Unc93b1 is required to regulate the turnover of TLR7. We identified an amino acid insertion in Unc93b1 in a patient with childhood-onset lupus, which results in loss of interaction with the BORC-Arl8b complex and an accumulation of functional TLR7. Our results highlight the importance of an intact endomembrane system to prevent autoimmune disease. Disrupting the proper progression of TLR7 through its endocytic life cycle is sufficient to break immunological tolerance to nucleic acids. Our work expands the repertoire of cellular mechanisms important to restrict pathological TLR7 activity. Identifying and stratifying lupus patients based on a TLR7-driven pathology opens the way for precision medicine specifically targeting TLR7.
2023-11-22 | PXD040042 | Pride
Project description:UNC93B1 is critical for trafficking and function of nucleic acid-sensing Toll-like receptors (TLRs) TLR3, TLR7, TLR8, and TLR9, which are essential for antiviral immunity. Overactive TLR7 signaling induced by recognition of self-nucleic acids has been implicated in systemic lupus erythematosus (SLE). Here, we report UNC93B1 variants (E92G and R336L) in four patients with early-onset SLE. Patient cells or mouse macrophages carrying the UNC93B1 variants produced high amounts of TNF-α and IL-6 and upon stimulation with TLR7/TLR8 agonist, but not with TLR3 or TLR9 agonists. E92G causes UNC93B1 protein instability and reduced interaction with TLR7, leading to selective TLR7 hyperactivation with constitutive type I IFN signaling. Thus, UNC93B1 regulates TLR subtype-specific mechanisms of ligand recognition. Our findings establish a pivotal role for UNC93B1 in TLR7-dependent autoimmunity and highlight the therapeutic potential of targeting TLR7 in SLE.
2023-12-14 | GSE250223 | GEO
Project description:Genome-wide association studies implicate multiple loci in risk for systemic lupus erythematosus (SLE), but few contain exonic variants, rendering systematic identification of non-coding variants essential to decoding SLE genetics. We utilized SNP-seq and bioinformatic enrichment to interrogate 2180 single-nucleotide polymorphisms (SNPs) from 87 SLE risk loci for potential binding of transcription factors and related proteins from B cells. 52 SNPs that passed initial screening were tested by electrophoretic mobility shift (EMSA) and luciferase reporter assays. To identify binding of transcription factors and/or other nuclear proteins in an allele-determined manner, we employed pulldown using nuclear extract from Daudi cells and silver staining in SNPs that had exhibited allele-specific differential binding by EMSA. Each pulldown product for each allele of the five high-probability SNPs (rs2297550 C/G, rs13213604 C/G, rs276461 T/C, rs9907955 C/T, rs7302634 T/C) was evaluated by mass spectrometry (MS) to identify binding nuclear proteins, yielding a set of candidate proteins for each.
2024-08-02 | PXD048367 | Pride
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