scholarly journals Nucleic acid-mediated autoinflammation and autoimmunity—type I interferonopathies

2016 ◽  
Vol 94 (10) ◽  
pp. 1081-1084 ◽  
Author(s):  
Min Ae Lee-Kirsch ◽  
Claudia Günther ◽  
Axel Roers
Keyword(s):  
Nucleic Acid ◽  
Type I ◽  
Type I Interferonopathies

scholarly journals Self-Awareness: Nucleic Acid–Driven Inflammation and the Type I Interferonopathies

2019 ◽  
Vol 37 (1) ◽  
pp. 247-267 ◽  
Author(s):  
Carolina Uggenti ◽  
Alice Lepelley ◽  
Yanick J. Crow
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Evolutionary Strategy ◽  
Type I ◽  
Self Awareness ◽  
Inborn Errors ◽  
Biological Challenge ◽  
Disease States ◽  
Dna And Rna ◽  
Type I Interferonopathies

Recognition of foreign nucleic acids is the primary mechanism by which a type I interferon–mediated antiviral response is triggered. Given that human cells are replete with DNA and RNA, this evolutionary strategy poses an inherent biological challenge, i.e., the fundamental requirement to reliably differentiate self–nucleic acids from nonself nucleic acids. We suggest that the group of Mendelian inborn errors of immunity referred to as the type I interferonopathies relate to a breakdown of self/nonself discrimination, with the associated mutant genotypes involving molecules playing direct or indirect roles in nucleic acid signaling. This perspective begs the question as to the sources of self-derived nucleic acids that drive an inappropriate immune response. Resolving this question will provide fundamental insights into immune tolerance, antiviral signaling, and complex autoinflammatory disease states. Here we develop these ideas, discussing type I interferonopathies within the broader framework of nucleic acid–driven inflammation.

scholarly journals RIG-I-Like Receptors and Type I Interferonopathies

2017 ◽  
Vol 37 (5) ◽  
pp. 207-213 ◽  
Author(s):  
Hiroki Kato ◽  
Seong-Wook Oh ◽  
Takashi Fujita
Keyword(s):  
Type I ◽  
Type I Interferonopathies

scholarly journals Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Amanda L. Gavin ◽  
Deli Huang ◽  
Tanya R. Blane ◽  
Therese C. Thinnes ◽  
Yusuke Murakami ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Inflammatory Diseases ◽  
Type I ◽  
Multiple Sensors ◽  
Dna And Rna ◽  
Elevated Type ◽  
Minor Contribution ◽  
Ifn Γ ◽  
A Minor ◽  
Rna And Dna

AbstractPhospholipase D3 (PLD3) and PLD4 polymorphisms have been associated with several important inflammatory diseases. Here, we show that PLD3 and PLD4 digest ssRNA in addition to ssDNA as reported previously. Moreover, Pld3−/−Pld4−/− mice accumulate small ssRNAs and develop spontaneous fatal hemophagocytic lymphohistiocytosis (HLH) characterized by inflammatory liver damage and overproduction of Interferon (IFN)-γ. Pathology is rescued in Unc93b13d/3dPld3−/−Pld4−/− mice, which lack all endosomal TLR signaling; genetic codeficiency or antibody blockade of TLR9 or TLR7 ameliorates disease less effectively, suggesting that both RNA and DNA sensing by TLRs contributes to inflammation. IFN-γ made a minor contribution to pathology. Elevated type I IFN and some other remaining perturbations in Unc93b13d/3dPld3−/−Pld4−/− mice requires STING (Tmem173). Our results show that PLD3 and PLD4 regulate both endosomal TLR and cytoplasmic/STING nucleic acid sensing pathways and have implications for the treatment of nucleic acid-driven inflammatory disease.

Therapeutic Approaches to Type I Interferonopathies

2018 ◽  
Vol 20 (6) ◽  
Author(s):  
Marc Bienias ◽  
Normi Brück ◽  
Constanze Griep ◽  
Christine Wolf ◽  
Stefanie Kretschmer ◽  
...  
Keyword(s):  
Type I ◽  
Therapeutic Approaches ◽  
Type I Interferonopathies

Detection of Microbial Infections Through Innate Immune Sensing of Nucleic Acids

2018 ◽  
Vol 72 (1) ◽  
pp. 447-478 ◽  
Author(s):  
Xiaojun Tan ◽  
Lijun Sun ◽  
Jueqi Chen ◽  
Zhijian J. Chen
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Immune Defense ◽  
Innate Immune ◽  
Type I Interferons ◽  
Microbial Pathogens ◽  
Type I ◽  
Immune Recognition ◽  
Microbial Infection ◽  
Microbial Infections

Microbial infections are recognized by the innate immune system through germline-encoded pattern recognition receptors (PRRs). As most microbial pathogens contain DNA and/or RNA during their life cycle, nucleic acid sensing has evolved as an essential strategy for host innate immune defense. Pathogen-derived nucleic acids with distinct features are recognized by specific host PRRs localized in endolysosomes and the cytosol. Activation of these PRRs triggers signaling cascades that culminate in the production of type I interferons and proinflammatory cytokines, leading to induction of an antimicrobial state, activation of adaptive immunity, and eventual clearance of the infection. Here, we review recent progress in innate immune recognition of nucleic acids upon microbial infection, including pathways involving endosomal Toll-like receptors, cytosolic RNA sensors, and cytosolic DNA sensors. We also discuss the mechanisms by which infectious microbes counteract host nucleic acid sensing to evade immune surveillance.

Clinical case of type I interferonopathy: homozygous STAT2 gain-of-function mutation

2021 ◽  
Vol 20 (3) ◽  
pp. 132-139
Author(s):  
А. L. Kozlova ◽  
М. Е. Leonteva ◽  
V. I. Burlakov ◽  
Z. А. Nesterenko ◽  
О. М. Laba ◽  
...  
Keyword(s):  
Side Effects ◽  
Clinical Case ◽  
Kinase Inhibitor ◽  
Genetic Defect ◽  
Type I ◽  
Gain Of Function ◽  
The World ◽  
Key Aspects ◽  
Methods Of Treatment ◽  
Type I Interferonopathies

The article is devoted to an extremely rare variant of type I interferonopathies associated with a homozygous gain of function (GOF) mutation in the STAT2 gene in a 5-year-old child. This genetic defect was first described in 2019, and so far only 3 cases are known in the world with a similar pathology. Here we present the fourth clinical case and our experience in managing a patient with STAT2 GOF. The article presents the key aspects of the pathogenesis, clinical picture based on the analysis of all known cases of the disease. The absence of established criteria and methods of treatment for this disease is due to the rarity and relative novelty of the described nosology. We present the experience of treatment using a JAK kinase inhibitor, followed by an assessment of the effectiveness of the therapy and side effects. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.

scholarly journals Detection of spacer precursors formed in vivo during primed CRISPR adaptation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Anna A. Shiriaeva ◽  
Ekaterina Savitskaya ◽  
Kirill A. Datsenko ◽  
Irina O. Vvedenskaya ◽  
Iana Fedorova ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Nucleic Acid ◽  
High Throughput Sequencing ◽  
Dna Degradation ◽  
Type I ◽  
Dna Fragments ◽  
Crispr Array ◽  
Foreign Dna ◽  
And Function

Abstract Type I CRISPR-Cas loci provide prokaryotes with a nucleic-acid-based adaptive immunity against foreign DNA. Immunity involves adaptation, the integration of ~30-bp DNA fragments, termed prespacers, into the CRISPR array as spacers, and interference, the targeted degradation of DNA containing a protospacer. Interference-driven DNA degradation can be coupled with primed adaptation, in which spacers are acquired from DNA surrounding the targeted protospacer. Here we develop a method for strand-specific, high-throughput sequencing of DNA fragments, FragSeq, and apply this method to identify DNA fragments accumulated in Escherichia coli cells undergoing robust primed adaptation by a type I-E or type I-F CRISPR-Cas system. The detected fragments have sequences matching spacers acquired during primed adaptation and function as spacer precursors when introduced exogenously into cells by transformation. The identified prespacers contain a characteristic asymmetrical structure that we propose is a key determinant of integration into the CRISPR array in an orientation that confers immunity.

scholarly journals Rapid simultaneous detection of multiple retroviral DNA sequences using the polymerase chain reaction and capillary DNA chromatography

Blood ◽  
1991 ◽  
Vol 77 (4) ◽  
pp. 879-886 ◽  
Author(s):  
FJ Sunzeri ◽  
TH Lee ◽  
RG Brownlee ◽  
MP Busch
Keyword(s):  
Polymerase Chain Reaction ◽  
Nucleic Acid ◽  
Blood Supply ◽  
Virus Type ◽  
Automated System ◽  
Type I ◽  
Chain Reaction ◽  
Polymerase Chain ◽  
Target Sequences ◽  
Nucleic Acid Sequences

Abstract The polymerase chain reaction (PCR) technique is a powerful new tool for amplifying target DNA, thus allowing for sensitive detection of specific nucleic acid sequences. One important potential use of PCR involves screening the donated blood supply for transfusion-transmitted viruses. Realization of this goal has been limited by (1) the requirement for multiple, discrete PCR reactions to amplify and detect target sequences of more than one virus, and (2) the lack of a rapid, nonhazardous means for specific detection of one or more PCR-amplified products. We report the simultaneous amplification of three distinct target sequences without discernable loss in sensitivity toward any single target sequence. We also demonstrate very rapid separation and detection of PCR-amplified viral DNA through the use of automated capillary DNA chromatography. Amplified DNA peaks were initially identified by scanning the capillary effluent at ultraviolet wavelengths, while discrimination of human immunodeficiency virus type 1 and human T-cell leukemic virus type I PCR-amplified DNA was accomplished through use of virus-specific, fluorescently labeled primers and probes. These results indicate progress toward an automated system for screening the blood supply for nucleic acid sequences of multiple pathogens.

scholarly journals Biochemical Characterization of Mycobacterium smegmatis RnhC (MSMEG_4305), a Bifunctional Enzyme Composed of Autonomous N-Terminal Type I RNase H and C-Terminal Acid Phosphatase Domains

2015 ◽  
Vol 197 (15) ◽  
pp. 2489-2498 ◽  
Author(s):  
Agata Jacewicz ◽  
Stewart Shuman
Keyword(s):  
Acid Phosphatase ◽  
Nucleic Acid ◽  
Mycobacterium Smegmatis ◽  
Excision Repair ◽  
Rnase H ◽  
Type I ◽  
Duplex Dna ◽  
Phosphatase Domain ◽  
Content Type ◽  
Acid Substrate

ABSTRACTMycobacterium smegmatisencodes several DNA repair polymerases that are adept at incorporating ribonucleotides, which raises questions about how ribonucleotides in DNA are sensed and removed. RNase H enzymes, of whichM. smegmatisencodes four, are strong candidates for a surveillance role. Here, we interrogate the biochemical activity and nucleic acid substrate specificity ofM. smegmatisRnhC, a bifunctional RNase H and acid phosphatase. We report that (i) the RnhC nuclease is stringently specific for RNA:DNA hybrid duplexes; (ii) RnhC does not selectively recognize and cleave DNA-RNA or RNA-DNA junctions in duplex nucleic acid; (iii) RnhC cannot incise an embedded monoribonucleotide or diribonucleotide in duplex DNA; (iv) RnhC can incise tracts of 4 or more ribonucleotides embedded in duplex DNA, leaving two or more residual ribonucleotides at the cleaved 3′-OH end and at least one or two ribonucleotides on the 5′-PO4end; (v) the RNase H activity is inherent in an autonomous 140-amino-acid (aa) N-terminal domain of RnhC; and (vi) the C-terminal 211-aa domain of RnhC is an autonomous acid phosphatase. The cleavage specificity of RnhC is clearly distinct from that ofEscherichia coliRNase H2, which selectively incises at an RNA-DNA junction. Thus, we classify RnhC as a type I RNase H. The properties of RnhC are consistent with a role in Okazaki fragment RNA primer removal or in surveillance of oligoribonucleotide tracts embedded in DNA but not in excision repair of single misincorporated ribonucleotides.IMPORTANCERNase H enzymes help cleanse the genome of ribonucleotides that are present either as ribotracts (e.g., RNA primers) or as single ribonucleotides embedded in duplex DNA.Mycobacterium smegmatisencodes four RNase H proteins, including RnhC, which is characterized in this study. The nucleic acid substrate and cleavage site specificities of RnhC are consistent with a role in initiating the removal of ribotracts but not in single-ribonucleotide surveillance. RnhC has a C-terminal acid phosphatase domain that is functionally autonomous of its N-terminal RNase H catalytic domain. RnhC homologs are prevalent inActinobacteria.

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