TLR7 gain-of-function genetic variation causes human lupus
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PROVIDER: PRJNA804244 | ENA |
REPOSITORIES: ENA
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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: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: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:Interferon lambdas share important functional similarities with type I interferons, but their role in inflammation and autoimmune disease remains controversial and is not well studied. Here, we present the first evidence that interferon lambda is pathogenic and has nonredundant functions in TLR7-associated lupus inflammation. Most notably, we found that interferon lambda promotes systemic immune dysregulation through localized effects in the skin and kidneys. These data identify a novel role for interferon lambda in lupus immunobiology and tissue-specific pathology.
2020-05-15 | GSE142637 | 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:The debilitating autoimmune disease Systemic Lupus Erythematosus (SLE) is closely associated with Toll-like receptor (TLR) 7 and type I interferon (IFN) activity in humans and in murine SLE-like disease. Two central manifestations of SLE affect the myeloid lineage of the immune system, myeloid expansion and anemia. Yet, whether these symptoms are linked and the role of TLR7 and/or type I IFN in these processes is unclear. Here we show that TLR7 signaling promotes cell-autonomous, phosphoinositide 3-kinase (PI3K)- and mammalian target of rapamycin (mTOR)-dependent macrophage development from the common myeloid progenitor (CMP). Strikingly, this TLR7-driven macrophage development requires and is enhanced by type I IFN. Genome-wide transcriptional profiling and functional studies demonstrated that TLR7 promoted the expression of Spic, the master regulator of splenic red pulp macrophages (RPM) and preferential development of hemophagocytic RPM-like cells from CMP in vitro. We found increased incidence of RPM-like cells in vivo in a mouse model of SLE caused by TLR7 overexpression, which correlated with decreased red blood cell (RBC) count and anemia. These findings demonstrate a mechanism by which TLR7 signaling promotes anemia that is of clinical significance in SLE, other rheumatological diseases and chronic viral infections. This work also identifies a previously unknown molecular pathway by which TLR signaling and type I IFN synergize to promote myeloid development from hematopoietic progenitors. CMP were sorted from the bone marrow of wild-type C57BL/6 mice, cultured with SCF+R848 or SCFr+MCSF, and CD11b+F4/80+ macrophages sorted after 5 days, n=3 per group
2016-07-01 | E-GEOD-70520 | biostudies-arrayexpress
Project description:Abstract Introduction Several environmental stimuli may influence lupus, especially viral infection. We utilize an imiquimod-induced lupus mouse model focusing on TLR7 pathway and use proteomics analysis to figure out the specific pathway related to viral infection and its related protein expressions in splenic B cells, hoping to get an insight on B cell responses to viral infection in lupus model. Material and methods. FVB/N wild type mouse was used treated with imiquimod for 8 weeks to induce lupus symptoms and signs, and splenocytes were retrieved, and B cells were selected and conducted proteomic analysis. The B cells were co-cultured with CD40L+ feeder cells for another one week before Western blot analysis. Panther pathway analysis was used to disclose the pathways activated and protein-protein interactome analyzed by STRING database in this lupus murine model. Results. The lupus model is well established and well demonstrated with serology evidence and pathology proof of lupus-mimic organ damage. Proteomics data of splenic B cells revealed the most important pathways activated (fold enrichment >100) were positive regulation of MDA-5 signaling pathway, negative regulation of IP-10 production, negative regulation of chemokine (C-X-C motif) ligand 2 production and positive regulation of RIG-I signaling pathway. A unique protein-protein interactome containing 10 genes was discovered, within which ISG15, IFIH1, IFIT1, DDX60, and DHX58 have been demonstrated to be downstream effectors of MDA5 signaling. Finally, B cells intracellular cytosolic proteins were determined with Western blot experiment and the MDA5-related pathway activation is still evident. Conclusion. In this experiment, we confirmed that the B cells in lupus murine model focusing on TLR7 pathway were activated through MDA5 signaling pathway, an important RNA sensor implicated in the detection of viral infections and autoimmune. The MDA5 agonists/antagonist RNAs and detailed molecular interactions inside B cells are worthy further investigation for lupus therapy.
2023-03-10 | PXD034855 | Pride
Project description:Systemic autoimmune diseases such as lupus and scleroderma are characterized by the loss of tolerance to nuclear antigens, but the mechanisms by which specific autoantibodies are selected are unclear. Here we report that B cells containing the Y-linked autoimmune accelerator (Yaa) locus are intrinsically biased towards nucleolar antigens due to a duplication of TLR genes in the pseudoautosomal region that makes them more responsive to TLR7 ligands and augments the Btk-dependent signaling pathway. These findings provide genetic evidence that naturally occurring differences in expression of TLR7 have a dramatic impact on antigen selection in autoimmunity. Follicular B cells were isolated from spleen of C57BL/6 male and C57BL/6.Yaa male. Four mice from each group using in this analysis were 2 months old. Dye swab labeled RNA had been done in one mice from each group.
2010-07-01 | E-GEOD-4445 | biostudies-arrayexpress
Project description:Exosomes from the brains of rhesus macaques were isolated and characterized, both with and without simian immunodeficiency virus (SIV) induced central nervous system (CNS) disease. Small RNA sequencing revealed that exosomes from the brains of animals with CNS disease contained significantly increased miR-21, a microRNA we have previously shown to be significantly increased in both SIV and HIV induced CNS disease. In addition to neurons in the brain, macrophage/microglial cells/nodules also express miR-21 during SIV induced CNS disease. In vitro culture of macrophages revealed that miR-21 is released into exosomes, and exosomes from macrophage cultures produced from WT, but not miR-21-/- KO, animals are neurotoxic. We find this neurotoxicity is dependent upon exosome carriage of miR-21, and mutation of the sequence within miR-21 predicted to bind TLR7 eliminates this neurotoxicity. Indeed exosomal miR-21 activates TLR7 in a reporter cell line, and the neurotoxicity of exosomal miR-21 is dependent upon TLR7, as neurons isolated from TLR7-/- KO mice are protected from neurotoxicity. Finally, we show that exosomes isolated from the brains of monkeys with SIV induced CNS disease both activate TLR7 and are neurotoxic when compared to exosomes from control animals.
2018-01-29 | GSE109414 | GEO