Autoinflammatory encephalopathy due to PTPN1 haploinsufficiency: a case series

The Lancet Neurology, Journal Year: 2025, Volume and Issue: 24(3), P. 218 - 229

Published: Feb. 19, 2025

Through the agnostic screening of patients with uncharacterised disease phenotypes for an upregulation type I interferon (IFN) signalling, we identified a cohort individuals heterozygous mutations in PTPN1, encoding protein-tyrosine phosphatase 1B (PTP1B). We aimed to describe clinical phenotype and molecular cellular pathology this new disease. In case series, collected neuroradiological data through collaboration paediatric neurology genetics colleagues across Europe (Czechia, France, Germany, Italy, Slovenia, UK) Israel. Variants PTPN1 were by exome directed Sanger sequencing. The expression IFN-stimulated genes was determined quantitative (q) PCR or NanoString technology. Experiments assess RNA protein investigate 1 IFN signalling undertaken patient fibroblasts, hTERT-immortalised BJ-5ta RPE-1 cells using CRISPR-Cas9 editing standard cell biology techniques. Between Dec 20, 2013, Jan 11, 2023, 12 from 11 families who PTPN1. found ten novel very rare variants (frequency on gnomAD version 4.1.0 <1·25 × 10:sup>-6). Six predicted as STOP mutations, two involved canonical splice-site nucleotides, missense substitutions. three patients, variant occurred de novo, whereas nine affected individuals, inherited asymptomatic parent. characterised subacute onset (age range 1-8 years) loss motor language skills absence seizures after initially normal development, leading spastic dystonia bulbar involvement. Neuroimaging variably demonstrated cerebral atrophy (sometimes unilateral initially) high T2 white matter signal. Neopterin CSF elevated all tested, probands whole blood. Although stabilisation improvement seen both treated untreated six eight high-dose corticosteroids judged clinically result neurological status. Of four parents blood (three patients) minimally (one patient). Analysis fibroblasts showed that tested led reduced levels mRNA PTP1B protein, in-vitro assays function associated impaired negative regulation signalling. haploinsufficiency causes IFN-driven autoinflammatory encephalopathy. Notably, some stabilisation, even recovery, treatment, others, appeared be responsive immune suppression. Prospective studies are needed safety efficacy specific suppression approaches population. UK Medical Research Council, European Agence Nationale la Recherche.

Language: Английский

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Human immunity

Published: Feb. 26, 2025

Due to the burden of infectious diseases, human life expectancy at birth remained about 20–25 years until end 19th century, implying that host defense—which operates individual level, and only poorly that—is barely sufficient population level. Microbes preceded us by three billion evolve much more rapidly. Moreover, protective immunity has been selected evolutionary cost allergy, autoinflammation, autoimmunity. It is therefore no exaggeration predict almost all humans carry inborn errors immunity, with insufficient or excessive responses some environmental triggers, otherwise. Thanks remarkable power its concepts recent progress in methods, genetics finally made it possible investigate mechanisms molecular cellular levels. Human provide countless opportunities analyze derailments natural conditions, an unprecedented scale, are thus a unique asset from both biological medical perspectives. Hence, Journal Immunity.

Language: Английский

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CNS disease associated with enhanced type I interferon signalling

The Lancet Neurology, Journal Year: 2024, Volume and Issue: 23(11), P. 1158 - 1168

Published: Oct. 16, 2024

Language: Английский

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Cellular RNA interacts with MAVS to promote antiviral signaling

Science, Journal Year: 2024, Volume and Issue: 386(6728)

Published: Dec. 19, 2024

Antiviral signaling downstream of RIG-I–like receptors (RLRs) proceeds through a multi-protein complex organized around the adaptor protein mitochondrial antiviral (MAVS). Protein function can be modulated by RNA molecules that provide allosteric regulation or act as molecular guides scaffolds. We hypothesized plays role in organizing MAVS platforms. found MAVS, its central intrinsically disordered domain, directly interacted with 3′ untranslated regions cellular messenger RNAs. Elimination ribonuclease treatment disrupted signalosome, including RNA-modulated interactors regulate RLR and viral restriction, inhibited phosphorylation transcription factors induce interferons. This work uncovered for promoting highlights generalizable principles regulatory control immune complexes.

Language: Английский

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Gene regulatory logic of the interferon-β enhancer contains multiple selectively deployed modes of transcription factor synergy

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

ABSTRACT Type I interferon IFNβ is a key regulator of the immune response, and its dysregulated expression causes disease. The regulation promoter activity has been touchpoint mammalian gene control research since discovery functional synergy between two stimulus-responsive transcription factors (TFs) nuclear factor kappa B (NFκB) regulatory (IRF). However, subsequent knockout studies revealed that this condition-dependent such either NFκB or IRF activation can be dispensable, leaving precise logic an open question. Here, we developed series quantitative enhancer states models evaluated them with stimulus-response data from TF knockouts. Our analysis confirmed hallmark but it need not involve NFκB, as adjacent dimers sufficient. We found sigmoidal binding curve at distal site renders dual mode ultrasensitive, allowing only in conditions high upon viral infection. In contrast, proximal affinity enables response to bacterial exposure through NFκB. accessibility controlled by competitive repressor p50:p50, which prevents basal levels synergizing NFκB-only stimuli do activate expression. model identifies multiple modes are accessed differentially different threats, enabling highly stimulus-specific also versatile for SIGNIFICANCE Precise cytokine essential human health. Classic established function synergistically activating more recent may dispensable certain conditions, study, several determine what account available data. exhibits specific capabilities deployed manner. resulting reveals how stimulus-specificity achieved, tuned, thereby overcoming bottleneck predictive modeling innate responses.

Language: Английский

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How (Ultra‐)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases

ACR Open Rheumatology, Journal Year: 2025, Volume and Issue: 7(2)

Published: Feb. 1, 2025

The aim of this study was to explore the impact rare and ultra‐rare genetic variants on understanding treatment autoimmune autoinflammatory diseases with a focus systemic lupus erythematosus (SLE) Behçet syndrome. This review summarizes current research monogenic causes SLE syndrome, highlighting various pathways that can be responsible for these unique phenotypes. In SLE, identification complement DNASE1L3 deficiencies has elucidated mechanisms apoptotic body accumulation extracellular nucleic acid sensing. Type I interferonopathies underline specific role DNA/RNA sensing interferon overexpression in development autoimmunity. Other significant defects include Toll‐like receptor hypersignaling JAK/STATopathies, which contribute breakdown immune tolerance. To date, directly affecting B T cell biology only account minority identified lupus, importance tight regulation mechanistic target rapamycin RAS (Rat sarcoma GTPase)/MAPK (mitogen‐activated protein kinase) signaling lupus. TNFAIP3, RELA , NFKB1 genes have been identified, underscoring NF‐κB overactivation. Additional such as ELF4, WDR1 mutations trisomy 8 further illustrate complexity condition. Observations from studies syndrome highlight inflammatory distinct molecular caused by single‐gene promote or syndromes, often unrecognizable their genetically complex “classical” forms. Insights gained studying enhance our function health disease, paving way targeted therapies personalized medicine.

Language: Английский

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NF-κB signaling directs a program of transient amplifications at innate immune response genes

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 13, 2025

The cellular response to pathogens involves an intricate directed by key innate immune signaling pathways which is characterized cell-to-cell heterogeneity. How this heterogeneity established and regulated remains unclear. We describe a program of transient site-specific gains (TSSG) producing extrachromosomal DNA (ecDNA) immune-related genes in signaling. Activation NF-κB drives TSSG the interferon receptor gene cluster through inducible recruitment transcription factor RelA pre-replication complex member MCM2 epigenetically control element. Targeted or p300 are sufficient induce formation. specify for at least six as many 179 regions enriched genes. Identification reveals production ecDNA mechanism host response.

Language: Английский

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ACOD1-mediated lysosomal membrane permeabilization contributes to Mycobacterium tuberculosis –induced macrophage death

Proceedings of the National Academy of Sciences, Journal Year: 2025, Volume and Issue: 122(12)

Published: March 18, 2025

Mycobacterium tuberculosis (Mtb) primarily infects macrophages. In vitro without antibiotics, wild-type Mtb hastens death of the macrophages, but processes leading to rapid cell are not well understood. Our earlier work indicated that Mtb-infected mouse macrophages in is markedly exacerbated by induction interferon-β (IFN-β) [L. Zhang et al., J. Exp. Med. 18 , e20200887 (2021)]. Here, we identified a key downstream response IFN-β context infection as massive cis-aconitate decarboxylase (ACOD1), only its canonical subcellular localization mitochondria also cytosol, where it bound lysosome-stabilizing protein HSP70. ACOD1’s product, itaconate, protected However, contrasting and predominant effect high-level ACOD1 expression was act noncatalytic manner promote HSP70’s degradation, lysosomal membrane permeabilization (LMP). Mtb-induced macrophage diminished inhibitors cysteine proteases, consistent with lysosome-mediated death. Neither nor protease suitable for potential host-directed therapy (HDT) tuberculosis. Instead, this directs attention how acts nonenzymatically degradation

Language: Английский

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Type I interferon autoantibody footprints reveal neutralizing mechanisms and allow inhibitory decoy design

The Journal of Experimental Medicine, Journal Year: 2025, Volume and Issue: 222(6)

Published: March 20, 2025

Autoantibodies neutralizing type I interferons (IFN-Is; IFNα or IFNω) exacerbate severe viral disease, but specific treatments are unavailable. With footprint profiling, we delineate two dominant IFN-I faces commonly recognized by autoantibody–containing plasmas from aged individuals with HIV-1 and COVID-19. These overlap regions independently essential for engaging the IFNAR1/IFNAR2 heterodimer, efficiently block interaction of both receptor subunits in vitro. In contrast, non-neutralizing limit only one subunit display relatively low IFN-I–binding avidities, thus likely hindering function. Iterative engineering signaling-inert mutant IFN-Is (simIFN-Is) retaining autoantibody targets created potent decoys that prevent neutralization autoantibody-containing restore IFN-I–mediated antiviral activity. Additionally, microparticle-coupled simIFN-Is were effective at depleting autoantibodies plasmas, leaving antibodies unaffected. Our study reveals mechanisms action demonstrates a proof-of-concept strategy to alleviate pathogenic effects.

Language: Английский

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TRIM21 promotes type I interferon by inhibiting the autophagic degradation of STING via p62/SQSTM1 ubiquitination in systemic lupus erythematosus

Acta Biochimica et Biophysica Sinica, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

The cGAS-STING signaling pathway serves as a pivotal surveillance mechanism for cytosolic double-stranded DNA (dsDNA) detection in mammalian systems. While STING-mediated type I interferon production is crucial host defense, sustained activation of this contributes to autoimmune pathologies, including systemic lupus erythematosus (SLE). Maintaining immune homeostasis requires precise regulation STING activity prevent hyperactivation. Our study identifies TRIM21 novel positive regulator SLE pathogenesis. results demonstrate that overexpression stabilizes by suppressing autophagic degradation, whereas depletion accelerates clearance process. Mechanistically, catalyzes the K63-linked polyubiquitylation selective autophagy receptor p62/SQSTM1, disrupting its interaction with STING. This post-translational modification prevents sequestration into autophagosomes, thereby stabilizing adaptor protein and amplifying downstream responses. findings reveal previously unrecognized regulatory circuit which orchestrates cross-talk between ubiquitin control turnover. TRIM21-p62 axis represents potential therapeutic target attenuating pathological STING-dependent disorders. work advances our understanding demonstrating how E3 ligase-mediated modifications modulate cargo recognition pathways. identified provides new insights molecular interplay ubiquitylation degradation maintaining innate balance, offering perspectives developing targeted therapies against interferonopathies associated hyperactivity.

Language: Английский

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