Aicardi–Goutières syndrome and the type I interferonopathies

@article{Crow2015AicardiGoutiresSA,
  title={Aicardi–Gouti{\`e}res syndrome and the type I interferonopathies},
  author={Yanick J. Crow and Nicolas Manel},
  journal={Nature Reviews Immunology},
  year={2015},
  volume={15},
  pages={429-440}
}
Dissection of the genetic basis of Aicardi–Goutières syndrome has highlighted a fundamental link between nucleic acid metabolism, innate immune sensors and type I interferon induction. This had led to the concept of the human interferonopathies as a broader set of Mendelian disorders in which a constitutive upregulation of type I interferon activity directly relates to disease pathology. Here, we discuss the molecular and cellular basis of the interferonopathies, their categorization, future… 

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References

SHOWING 1-10 OF 113 REFERENCES
Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response
TLDR
Mutations in SAMHD1 are described as the cause of Aicardi-Goutières syndrome at the AGS5 locus and data is presented to show that SAM HD1 may act as a negative regulator of the cell-intrinsic antiviral response.
Therapies in Aicardi–Goutières syndrome
TLDR
The clinical phenotype of AGS is outlined, paying particular attention to factors relevant to therapeutic intervention, and possible treatment strategies are suggested in light of emerging insights.
Type I interferonopathies: a novel set of inborn errors of immunity
  • Y. Crow
  • Medicine
    Annals of the New York Academy of Sciences
  • 2011
TLDR
A group of conditions, including Aicardi–Goutières syndrome, spondyloenchondrodysplasia, and cases of systemic lupus erythematosus with complement deficiency, are discussed, in which an upregulation of type I interferons is apparently central to their pathogenesis.
Aicardi-Goutieres syndrome and related phenotypes: linking nucleic acid metabolism with autoimmunity.
TLDR
Evidence is emerging to show that the nucleases defective in AGS are involved in removing endogenously produced nucleic acid species, and that a failure of this removal results in activation of the immune system, which explains the phenotypic overlap of AGS with congenital infection and some aspects of SLE, where an equivalent type I interferon-mediated innate immune response is triggered by viral and self NAs.
Aicardi-Goutières syndrome is caused by IFIH1 mutations.
Cree encephalitis is allelic with Aicardi-Goutiéres syndrome: implications for the pathogenesis of disorders of interferon alpha metabolism
TLDR
The data show that a CSF lymphocytosis is not necessary for the diagnosis of Aicardi-Goutiéres syndrome and strongly suggest that AGS and pseudo-TORCH syndrome are the same disorder.
Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature
TLDR
It is shown that mutations in ADAR1 cause the autoimmune disorder Aicardi-Goutières syndrome (AGS), and it is speculated that ADar1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.
Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection
TLDR
It is shown that AGS can result from mutations in the genes encoding any one of its three subunits, demonstrating a role for ribonuclease H in human neurological disease and suggesting an unanticipated relationship between ribonUClease H2 and the antiviral immune response that warrants further investigation.
Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling
TLDR
It is demonstrated that aberrant sensing of nucleic acids can cause immune upregulation and heterozygous mutations in the cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmunological features consistently associated with an enhanced interferon state.
An autoimmune disease prevented by anti-retroviral drugs
TLDR
It is shown that two other FDA-approved drugs that inhibit reverse transcriptase can ameliorate the myocarditis in Trex1-null mouse, suggesting that retroelements contribute to this hereditary form of autoimmunity, and that treatment with retroelement inhibitors might amelIORate Aicardi-Goutières syndrome in humans.
...
1
2
3
4
5
...