Nucleic acid-mediated autoinflammation and autoimmunity—type I interferonopathies

Lee‐Kirsch, Min Ae; Günther, Claudia; Roers, Axel

doi:10.1007/s00109-016-1467-3

Cited by 6 publications

(4 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Defects in clearance of NA through mutations in cellular nucleases such as RNase H2 or TREX1 can lead to accumulation of NA and finally to unwanted immune reactions . Autoimmune diseases in which the recognition of endogenous NAs is involved include systemic lupus erythematosus (SLE) and type I interferonopathies . Nevertheless, NA‐specific receptors have been shown to play a crucial role in immune responses against a variety of different pathogens including bacteria, viruses, and protozoa .…”

Section: Introductionmentioning

confidence: 99%

RNA is taking its Toll: Impact of RNA‐specific Toll‐like receptors on health and disease

Vierbuchen

Stein

Heine

2018

Allergy

View full text Add to dashboard Cite

RNA-sensing Toll-like receptors (TLRs) are often described as antiviral receptors of the innate immune system. However, the past decade has shown that the function and relevance of these receptors are far more complex. They were found to be essential for the detection of various bacterial, archaeal, and eukaryotic microorganisms and facilitate the discrimination between dead and living microbes. The cytokine and interferon response profile that is triggered has the potential to improve the efficacy of next-generation vaccines and may prevent the development of asthma and allergy. Nevertheless, the ability to recognize foreign RNA comes with a cost as also damaged host cells can release nucleic acids that might induce an inappropriate immune response. Thus, it is not surprising that RNA-sensing TLRs play a key role in various autoimmune diseases. However, promising new inhibitors and antagonists are on the horizon to improve their treatment. K E Y W O R D Sarchaea, infection, RNA, TLR8, vaccines

show abstract

Section: Introductionmentioning

confidence: 99%

RNA is taking its Toll: Impact of RNA‐specific Toll‐like receptors on health and disease

Vierbuchen

Stein

Heine

2018

Allergy

View full text Add to dashboard Cite

show abstract

“…The capacity of differentiation between self and foreign nucleic acids is limited. If the amount of self nucleic acids reaches a certain level in the cytosol, nucleic acid sensors can be activated, resulting in type 1 IFN secretion ( 34 ). To deteriorate the amount of nucleic acids, human cells exhibit cytosolic exonucleases such as TREX1 (three prime repair exonuclease 1), lysosomal DNase2, and extracellular DNase1 ( 35 , 36 ).…”

Section: Type I Ifn—activation and Secretionmentioning

confidence: 99%

Type I Interferon Induction in Cutaneous DNA Damage Syndromes

Klein

Günther

2021

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

Type I interferons (IFNs) as part of the innate immune system have an outstanding importance as antiviral defense cytokines that stimulate innate and adaptive immune responses. Upon sensing of pattern recognition particles (PRPs) such as nucleic acids, IFN secretion is activated and induces the expression of interferon stimulated genes (ISGs). Uncontrolled constitutive activation of the type I IFN system can lead to autoinflammation and autoimmunity, which is observed in autoimmune disorders such as systemic lupus erythematodes and in monogenic interferonopathies. They are caused by mutations in genes which are involved in sensing or metabolism of intracellular nucleic acids and DNA repair. Many authors described mechanisms of type I IFN secretion upon increased DNA damage, including the formation of micronuclei, cytosolic chromatin fragments and destabilization of DNA binding proteins. Hereditary cutaneous DNA damage syndromes, which are caused by mutations in proteins of the DNA repair, share laboratory and clinical features also seen in autoimmune disorders and interferonopathies; hence a potential role of DNA-damage-induced type I IFN secretion seems likely. Here, we aim to summarize possible mechanisms of IFN induction in cutaneous DNA damage syndromes with defects in the DNA double-strand repair and nucleotide excision repair. We review recent publications referring to Ataxia teleangiectasia, Bloom syndrome, Rothmund–Thomson syndrome, Werner syndrome, Huriez syndrome, and Xeroderma pigmentosum. Furthermore, we aim to discuss the role of type I IFN in cancer and these syndromes.

show abstract

“…viruses), but chronic IFN activation can lead to several autoimmune diseases (Di Domizio & Cao, 2013;Psarras et al, 2017;Crow et al, 2019). A fine homeostatic balance of type I interferons needs to be maintained to avoid autoimmune diseases, including interferonopathies (Di Domizio & Cao, 2013;Niewold, 2014;Lee-Kirsch et al, 2016;Crow et al, 2019). The knowledge of the master switches and the mechanisms that suppress the type I IFN response will be beneficial for generating therapeutics against autoimmune diseases.…”

Section: Introductionmentioning

confidence: 99%

Autoimmunity gene IRGM suppresses cGAS ‐ STING and RIG ‐I‐ MAVS signaling to control interferon response

Jena¹,

Mehto

Nath³

et al. 2020

EMBO Reports

View full text Add to dashboard Cite

Activation of the type 1 interferon response is extensively connected to the pathogenesis of autoimmune diseases. Loss of function of Immunity Related GTPase M (IRGM) has also been associated to several autoimmune diseases, but its mechanism of action is unknown. Here, we found that IRGM is a master negative regulator of the interferon response. Several nucleic acid‐sensing pathways leading to interferon‐stimulated gene expression are highly activated in IRGM knockout mice and human cells. Mechanistically, we show that IRGM interacts with nucleic acid sensor proteins, including cGAS and RIG‐I, and mediates their p62‐dependent autophagic degradation to restrain interferon signaling. Further, IRGM deficiency results in defective mitophagy leading to the accumulation of defunct leaky mitochondria that release cytosolic DAMPs and mtROS. Hence, IRGM deficiency increases not only the levels of the sensors, but also those of the stimuli that trigger the activation of the cGAS‐STING and RIG‐I‐MAVS signaling axes, leading to robust induction of IFN responses. Taken together, this study defines the molecular mechanisms by which IRGM maintains interferon homeostasis and protects from autoimmune diseases.

show abstract

Nucleic acid-mediated autoinflammation and autoimmunity—type I interferonopathies

Cited by 6 publications

References 31 publications

RNA is taking its Toll: Impact of RNA‐specific Toll‐like receptors on health and disease

RNA is taking its Toll: Impact of RNA‐specific Toll‐like receptors on health and disease

Type I Interferon Induction in Cutaneous DNA Damage Syndromes

Autoimmunity gene IRGM suppresses cGAS ‐ STING and RIG ‐I‐ MAVS signaling to control interferon response

Contact Info

Product

Resources

About