cyclic-guanosine-monophosphate-adenosine-monophosphate has been researched along with Autoimmune-Diseases-of-the-Nervous-System* in 3 studies
3 other study(ies) available for cyclic-guanosine-monophosphate-adenosine-monophosphate and Autoimmune-Diseases-of-the-Nervous-System
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Development of novel highly sensitive methods to detect endogenous cGAMP in cells and tissue.
Intracellular DNA triggers interferon release during the innate immune response. Cyclic GMP-AMP synthase (cGAS) senses intracellular double-stranded DNA not only in response to viral infection but also under autoimmune conditions. Measuring the levels of cyclic GMP-AMP (cGAMP) as a second messenger of cGAS activation is important to elucidate the physiological and pathological roles of cGAS. Therefore, we generated monoclonal antibodies against cGAMP using hybridoma technology to test antibody specificity and establish methods to detect intracellular cGAMP. The resulting cGAMP-specific antibody enabled the development of a time-resolved fluorescence energy transfer assay with a quantifiable range of 0.1 nM to 100 nM cGAMP. Using this assay, we detected cellular and tissue cGAMP. We confirmed that the cGAMP antibody successfully targeted intracellular cGAMP through immunocytochemical analyses. These results demonstrated that the cGAMP antibody is a powerful tool that allows determining cGAS involvement in autoimmunity and disease pathology at the cell and tissue levels. Topics: Animals; Antibodies, Monoclonal; Antibody Specificity; Autoimmune Diseases of the Nervous System; Autoimmunity; Biomarkers; Caco-2 Cells; Disease Models, Animal; Enzyme Activation; Exodeoxyribonucleases; Fluorescence Resonance Energy Transfer; HEK293 Cells; High-Throughput Screening Assays; HL-60 Cells; Humans; Immunohistochemistry; Mice, Inbred C57BL; Mice, Knockout; Neoplasms; Nervous System Malformations; Nucleotides, Cyclic; Nucleotidyltransferases; Phosphoproteins; Predictive Value of Tests; Reproducibility of Results | 2020 |
cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing.
Inappropriate stimulation or defective negative regulation of the type I interferon response can lead to autoinflammation. In genetically uncharacterized cases of the type I interferonopathy Aicardi-Goutières syndrome, we identified biallelic mutations in LSM11 and RNU7-1, which encode components of the replication-dependent histone pre-mRNA-processing complex. Mutations were associated with the misprocessing of canonical histone transcripts and a disturbance of linker histone stoichiometry. Additionally, we observed an altered distribution of nuclear cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and enhanced interferon signaling mediated by the cGAS-stimulator of interferon genes (STING) pathway in patient-derived fibroblasts. Finally, we established that chromatin without linker histone stimulates cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) production in vitro more efficiently. We conclude that nuclear histones, as key constituents of chromatin, are essential in suppressing the immunogenicity of self-DNA. Topics: Autoimmune Diseases of the Nervous System; Cell Line; Chromatin; DNA; Gene Expression Regulation; HCT116 Cells; HEK293 Cells; Hereditary Autoinflammatory Diseases; Histones; Humans; Interferon Type I; Membrane Proteins; Nervous System Malformations; Nucleotides, Cyclic; Nucleotidyltransferases; Ribonucleoprotein, U7 Small Nuclear; RNA Precursors; RNA-Binding Proteins | 2020 |
Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi-Goutières Syndrome.
Detection of intracellular DNA triggers activation of the stimulator of IFN genes-dependent IFN-stimulatory DNA (ISD) pathway, which is essential for antiviral immune responses. However, chronic activation of this pathway is implicated in autoimmunity. Mutations in TREX1, a 3' repair exonuclease that degrades cytosolic DNA, cause Aicardi-Goutières syndrome and chilblain lupus. Trex1 (-/-) mice develop lethal, IFN-driven autoimmune disease that is dependent on activation of the ISD pathway, but the DNA sensors that detect the endogenous DNA that accumulates in Trex1 (-/-) mice have not been defined. Multiple DNA sensors have been proposed to activate the ISD pathway, including cyclic GMP-AMP synthase (cGAS). In this study, we show that Trex1 (-/-) mice lacking cGAS are completely protected from lethality, exhibit dramatically reduced tissue inflammation, and fail to develop autoantibodies. These findings implicate cGAS as a key driver of autoimmune disease and suggest that cGAS inhibitors may be useful therapeutics for Aicardi-Goutières syndrome and related autoimmune diseases. Topics: Animals; Autoantibodies; Autoimmune Diseases of the Nervous System; Cells, Cultured; Disease Models, Animal; Embryo, Mammalian; Exodeoxyribonucleases; Fibroblasts; Gene Expression; Humans; Immunoblotting; Inflammation; Interferon-beta; Interferons; Macrophages; Mice, Inbred C57BL; Mice, Knockout; Nervous System Malformations; Nucleotides, Cyclic; Nucleotidyltransferases; Phosphoproteins; Reverse Transcriptase Polymerase Chain Reaction | 2015 |