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Results for “Type I interferonopathy”

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3 recordsLinked to original sources
PubMed2025

Identification of Potential Therapeutic Agents for Type I Interferonopathy Using iPSC-Based Disease Modeling.

PURPOSE: Type I interferonopathy encompasses disorders marked by systemic inflammation and neurological involvement, arising from genetic mutations that result in the upregulation of type I IFN signaling through various mechanisms. Currently, therapeutic options are limited, and no standard therapy exists. This study aims to develop a strategy for identifying new therapeutic targets for type I interferonopathy using induced pluripotent stem cells (iPSCs). METHODS: The IFIH1 R779H variant was introduced into iPSCs through genome editing. RNA sequencing of iPSC-derived dendritic cells (DCs) was performed, and differentially expressed genes (DEGs) were identified. IFN-α secretion, reactive oxygen species (ROS), and mitochondrial oxygen consumption rate (OCR) were analyzed in iPSC-derived DCs. An in silico prediction of compounds binding to the OAS-like domain was conducted. Candidate compounds were evaluated for their ability to inhibit IFN secretion from IFIH1 R779H-mutated iPSC-derived DCs. RESULTS: Transcriptome analysis indicated upregulation of the IFN-related and metabolic pathways. IFIH1 R779H-mutated iPSC-derived DCs exhibited increased OCR and ROS generation, and blocking mitochondrial metabolism significantly reduced excessive IFN-α secretion. Among the DEGs, PML was upregulated, and targeting this gene with arsenic trioxide (ATO), a PML antagonist, suppressed IFN-α secretion from IFIH1 R779H-mutated iPSC-derived DCs. Additionally, bisantrene, phthalylsulfathiazole and ganaplacide were predicted to bind to the RNA binding groove of OAS-like domain of human OASL in silico, effectively inhibiting IFN-α secretion from IFIH1 R779H-mutated DCs. CONCLUSION: Our iPSC-based disease modeling and drug investigation approach provides a robust platform for validating the efficacy and toxicity of candidate therapeutic agents for rare and intractable human diseases such as type I interferonopathy.

Humans↗
PubMed2026

Neonatal Aicardi-Goutières syndrome presenting with macrophage activation syndrome-like hyperinflammation and severe congenital glaucoma: a case report.

BACKGROUND: Neonatal-onset Aicardi-Goutières syndrome (AGS) is a rare monogenic type I interferonopathy that may mimic congenital infection and can present with severe multisystem inflammation. The distinction between primary hemophagocytic lymphohistiocytosis (HLH) and AGS-associated macrophage activation syndrome (MAS)-like hyperinflammation can be challenging in neonates. CASE PRESENTATION: We report a term neonate presenting with cholestatic jaundice, a generalized blueberry muffin-like ecchymotic-purpuric rash, cytopenias, hyperferritinemia, hepatosplenomegaly, intracranial calcifications, and severe bilateral congenital glaucoma. Extensive infectious evaluation was negative. The patient fulfilled five of eight HLH-2004 criteria, consistent with a severe MAS-like hyperinflammatory phenotype. Dexamethasone and intravenous immunoglobulin had been initiated at the referring center for presumed virus-associated HLH but were not continued after transfer to our unit. With persistent disease activity, negative microbiological studies, and neuroimaging strongly suggestive of a type I interferonopathy, ruxolitinib was initiated on day of life (DOL) 34 before molecular confirmation. Exome sequencing subsequently identified homozygous pathogenic variants in RNASEH2B and CYP1B1, supporting AGS type 2 and primary congenital glaucoma (glaucoma 3 A), respectively. Serial laboratory data showed sustained improvement after initiation of JAK1/2 inhibition, although the observational nature of a single case and other immunomodulatory exposures limit causal attribution. CONCLUSIONS: This case illustrates the clinical overlap between neonatal AGS and MAS-like hyperinflammation, underscores the potential role of early mechanism-based therapy in selected critically ill neonates with suspected interferonopathy, and emphasizes the importance of comprehensive genomic evaluation when severe ocular disease accompanies AGS. The identified CYP1B1 variant provides a strong molecular explanation for the patient's congenital glaucoma.

Humans↗
PubMed2026

NAP1 switches from an activator to a limiter of interferon induction by trapping TBK1 in condensates.

TBK1 kinase is a central regulator of type I IFN production. Upon activation of the IFN-β induction pathway, TBK1-adaptor proteins (NAP1, SINTBAD, TANK) form liquid condensates. We show that NAP1 condensates concentrate TBK1. Using NAP1KO cell lines, we demonstrate that NAP1 exerts a dual effect on TBK1 activity. Initially, NAP1 binds TBK1 and increases its activity, promoting IFN pathway activation. Subsequently, TBK1-mediated phosphorylation of NAP1 induces the formation of condensates. These NAP1 condensates concentrate both TBK1 and the phosphatase PP2A, which dephosphorylates and consequently deactivates TBK1, thus limiting IFN induction. Additionally, in patients with lupus or interferonopathies, we identify NAP1 variants unable to form condensates upon danger signal exposure, which sustain TBK1 activation without limiting its activity. This study reveals a mode of regulating a signaling pathway through condensate formation and provides a potential molecular explanation for immune dysregulation associated with NAP1 variants in certain patients with interferonopathies.

Protein Serine-Threonine Kinases↗