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1.
J Clin Immunol ; 41(3): 603-609, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33411153

RESUMO

Whilst upregulation of type I interferon (IFN) signaling is common across the type I interferonopathies (T1Is), central nervous system (CNS) involvement varies between these disorders, the basis of which remains unclear. We collected cerebrospinal fluid (CSF) and serum from patients with Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with onset in infancy (SAVI), presumed monogenic T1Is (pT1I), childhood systemic lupus erythematosus with neuropsychiatric features (nSLE), non-IFN-related autoinflammation (AI) and non-inflammatory hydrocephalus (as controls). We measured IFN-alpha protein using digital ELISA. Eighty-two and 63 measurements were recorded respectively in CSF and serum of 42 patients and 6 controls. In an intergroup comparison (taking one sample per individual), median CSF IFN-alpha levels were elevated in AGS, SAVI, pT1I, and nSLE compared to AI and controls, with levels highest in AGS compared to all other groups. In AGS, CSF IFN-alpha concentrations were higher than in paired serum samples. In contrast, serum IFN was consistently higher compared to CSF levels in SAVI, pT1I, and nSLE. Whilst IFN-alpha is present in the CSF and serum of all IFN-related diseases studied here, our data suggest the primary sites of IFN production in the monogenic T1I AGS and SAVI are, respectively, the CNS and the periphery. These results inform the diagnosis of, and future therapeutic approaches to, monogenic and multifactorial T1Is.


Assuntos
Suscetibilidade a Doenças , Regulação da Expressão Gênica , Interferon Tipo I/genética , Interferon-alfa/genética , Especificidade de Órgãos/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Interferon Tipo I/líquido cefalorraquidiano , Interferon Tipo I/metabolismo , Interferon-alfa/líquido cefalorraquidiano , Interferon-alfa/metabolismo , Masculino , Mutação , Fenótipo , Estudos Retrospectivos , Adulto Jovem
2.
Rheumatology (Oxford) ; 59(8): 1927-1937, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31755959

RESUMO

OBJECTIVES: JDM and juvenile overlap myositis represent heterogeneous subtypes of juvenile idiopathic inflammatory myopathy (JIIM). Chronic evolution can occur in up to 60% of cases, and morbidity/mortality is substantial. We aimed to describe the clinical, biological, histological and type I IFN status in JIIM associated with anti-melanoma differentiation-associated protein 5 (anti-MDA5) autoantibodies at presentation (group 1) in comparison with other JIIM (group 2). METHODS: This was a retrospective and prospective study of patients with JIIM ascertained from three French paediatric rheumatology reference centres between 2013 and 2019. Muscle biopsies were reviewed. Type I interferon pathway activity was assessed by dosage of IFNα serum protein and the expression of IFN-stimulated genes. RESULTS: Sixty-four patients were included, 13 in group 1 (54% JDM and 46% juvenile overlap myositis) and 51 in group 2 (76% JDM and 24% juvenile overlap myositis). Group 1 patients demonstrated more arthritis, skin ulcerations, lupus features and interstitial lung disease, and a milder muscular involvement. Serum IFNα levels were higher in group 1 than 2, and decreased after treatment or improvement in both groups. Outcome was similar in both groups. Unconventional treatment (more than two lines) was required in order to achieve remission, especially when skin ulceration was reported. CONCLUSION: This study indicates a higher frequency of arthritis, skin ulcerations and interstitial lung disease, but milder muscular involvement, in JIIM with positive anti-MDA5 autoantibodies compared with other JIIM. Our data support an important role of systemic IFNα in disease pathology, particularly in the anti-MDA5 auto-antibody-positive subgroup. In severe and refractory forms of JIIM, IFNα may represent a therapeutic target.


Assuntos
Autoanticorpos/imunologia , Helicase IFIH1 Induzida por Interferon/imunologia , Interferon-alfa/metabolismo , Músculo Esquelético/metabolismo , Miosite/metabolismo , Transdução de Sinais/fisiologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Miosite/imunologia , Miosite/patologia , Estudos Prospectivos , Estudos Retrospectivos
3.
Cell Rep ; 32(3): 107942, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32698007

RESUMO

A large share of the non-coding transcriptome in yeast is controlled by the Nrd1-Nab3-Sen1 (NNS) complex, which promotes transcription termination of non-coding RNA (ncRNA) genes, and by the nuclear exosome, which limits the steady-state levels of the transcripts produced. How unconstrained ncRNA levels affect RNA metabolism and gene expression are long-standing and important questions. Here, we show that degradation of ncRNAs by the exosome is required for freeing Nrd1 and Nab3 from the released transcript after termination. In exosome mutants, these factors are sequestered by ncRNAs and cannot be efficiently recycled to sites of transcription, inducing termination defects at NNS targets. ncRNA-dependent, genome-wide termination defects can be recapitulated by the expression of a degradation-resistant, circular RNA containing a natural NNS target in exosome-proficient cells. Our results have important implications for the mechanism of termination, the general impact of ncRNAs abundance, and the importance of nuclear ncRNA degradation.


Assuntos
Estabilidade de RNA/genética , RNA não Traduzido/genética , Saccharomyces cerevisiae/genética , Fatores de Transcrição/metabolismo , Terminação da Transcrição Genética , Núcleo Celular/metabolismo , Exossomos/metabolismo , Regulação Fúngica da Expressão Gênica , Genoma Fúngico , Modelos Genéticos , RNA Fúngico/genética , RNA não Traduzido/metabolismo , Saccharomyces cerevisiae/crescimento & desenvolvimento , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/genética , Transcriptoma/genética
4.
J Exp Med ; 217(11)2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32725128

RESUMO

Heterozygous missense mutations in coatomer protein subunit α, COPA, cause a syndrome overlapping clinically with type I IFN-mediated disease due to gain-of-function in STING, a key adaptor of IFN signaling. Recently, increased levels of IFN-stimulated genes (ISGs) were described in COPA syndrome. However, the link between COPA mutations and IFN signaling is unknown. We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients. In vitro, both overexpression of mutant COPA and silencing of COPA induced STING-dependent IFN signaling. We detected an interaction between COPA and STING, and mutant COPA was associated with an accumulation of ER-resident STING at the Golgi. Given the known role of the coatomer protein complex I, we speculate that loss of COPA function leads to enhanced type I IFN signaling due to a failure of Golgi-to-ER STING retrieval. These data highlight the importance of the ER-Golgi axis in the control of autoinflammation and inform therapeutic strategies in COPA syndrome.


Assuntos
Proteína Coatomer/genética , Proteína Coatomer/metabolismo , Complexo de Golgi/metabolismo , Interferon Tipo I/metabolismo , Proteínas de Membrana/metabolismo , Mutação de Sentido Incorreto , Transdução de Sinais/genética , Adolescente , Adulto , Criança , Retículo Endoplasmático/metabolismo , Feminino , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Transporte Proteico/genética , Células THP-1 , Transfecção , Adulto Jovem
5.
Nat Genet ; 52(12): 1364-1372, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33230297

RESUMO

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.


Assuntos
Cromatina/metabolismo , Histonas/metabolismo , Interferon Tipo I/biossíntese , Precursores de RNA/metabolismo , Proteínas de Ligação a RNA/genética , Ribonucleoproteína Nuclear Pequena U7/genética , Doenças Autoimunes do Sistema Nervoso/genética , Doenças Autoimunes do Sistema Nervoso/imunologia , Linhagem Celular , DNA/imunologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Células HCT116 , Células HEK293 , Doenças Hereditárias Autoinflamatórias/genética , Doenças Hereditárias Autoinflamatórias/imunologia , Humanos , Proteínas de Membrana/metabolismo , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/imunologia , Nucleotídeos Cíclicos/biossíntese , Nucleotidiltransferases/metabolismo
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