318 research outputs found
NOTCH1-related leukoencephalopathy: a novel variant and literature review
No full textBackground: NOTCH1-related leukoencephalopathy is a new diagnostic entity linked to heterozygous gain-of-function variants in NOTCH1 that neuroradiologically shows some overlap with the inflammatory microangiopathy Aicardi-Goutières syndrome (AGS). Aim: To report a 16-year-old boy harbouring a novel NOTCH1 mutation who presented neuroradiological features suggestive of enhanced type I interferon signalling. We describe 5-years of follow-up and review the current literature on NOTCH1-related leukoencephalopathy. Methods: Clinical evaluation, standardized scales (SPRS, SARA, CBCL, CDI-2:P, WISCH-IV and VABS-2) and neuroradiological studies were performed, as well as blood DNA analysis. For the literature review, a search was performed on Pubmed, Scopus and Web of Science, up to December 2023 using the following text word search strategy: (NOTCH1) AND (leukoencephalopathy). Results: Our patient presents clinical features consistent with other reported cases with NOTCH1 mutations but is among the minority of patients with an onset after infancy. During the 5-year follow-up, we observed an increase in the severity of spasticity and ataxia. However, at the age of 16 years, our proband is still ambulatory. As for other reported patients, he manifests psychiatric features, ranging from hyperactivity during childhood, to anxiety and depression during adolescence. The neuroradiological picture remained essentially stable over 5 years. In addition to the typical findings of leukoencephalopathy with cysts and calcifications already described, we report the presence of T2-hyperintensity and T1-hypotensity of the transverse pontine fibres, enhancement in the periventricular white matter after gadolinium administration, and decreased NAA and Cho peaks in the periventricular white matter on MRS. We identified a novel heterozygous variant in NOTCH1 (c.4788_4799dup), a frame insertion located in extracellular negative regulatory region (NRR)-domain as in previously published cases. Blood interferon signalling was not elevated compared to controls. Conclusions: This case provides further data on a new diagnostic entity i.e. NOTCH1-related leukoencephalopathy. By describing a standardized 5-year follow-up in one case, and reviewing the other patients described to date, we outline recommendations relating to monitoring in this illness, emphasizing the importance of psychiatric and gastroenterological surveillance alongside neurological and neuropsychological management. Studies are needed to better understand the factors influencing disease onset and severity, which are heterogeneous
Novel mutations in the gene SALL4 provide further evidence for acro-renal-ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum.
No full textConséquences pathologiques d’un excès d’interféron
No full textDans cette brève revue, nous montrons les liens entre les différentes recherches qui ont conduit à la mise en évidence d’un rôle délétère d’un excès d’interféron de type 1, depuis la découverte de son activité antivirale en 1957 par A. Isaacs et J. Lindemann jusqu’au concept d’interféronopathie introduit par Y. Crow en 2011
Type I interferonopathies: A novel set of inborn errors of immunity
No full textThe concept of grouping Mendelian disorders associated with an upregulation of type I interferon is not currently recognized in the medical literature. Here, we argue that such a concept has scientific validity and clinical utility. Specifically, we discuss a group of conditions, including Aicardi-Goutières syndrome, spondyloenchondrodysplasia, and cases of systemic lupus erythematosus with complement deficiency, in which an upregulation of type I interferons is apparently central to their pathogenesis. We believe that these diseases can usefully be considered to represent a novel set of inborn errors of immunity, and that the recognition of such diseases as type I interferonopathies will have significance in the development and use of targeted therapies. © 2011 New York Academy of Sciences
Caractérisation clinique et moléculaire des interféronopathies de type I
No full textLes interférons de type I (IFN I) sont des cytokines antivirales aux propriétés puissantes. L’induction, la transmission et la résolution de la réponse immunitaire engendrée par les IFN I est minutieusement régulée. Le concept d’interféronopathie de type I, récemment individualisé par notre équipe, repose sur l’hypothèse que certaines pathologies seraient secondaires au déséquilibre de ces voies de signalisation complexes et à la sécrétion excessive et inappropriée d’IFN I. L’inhibition de celle-ci par des thérapeutiques ciblées permettrait de valider cette hypothèse, si les symptômes allégués s’amélioraient, voire disparaissaient. Ce travail de thèse s’est initialement concentré sur la caractérisation clinique et biologique des interféronopathies monogéniques et polygéniques, et secondairement sur l’identification moléculaire de nouvelles mutations du gène TMEM173 à l’origine de l’interféronopathie liée à STING, également appelée SAVI (STING associated vasculopathy with onset in infancy), syndrome auto-inflammatoire associant une atteinte sévère cutanée et pulmonaire. De nouvelles techniques ont permis la sélection de patients présentant une augmentation de l’IFN I en comparaison à des contrôles sains : la signature IFN I, qPCR de 6 gènes stimulés par l’IFN (IFN stimulated genes – ISGs) et le dosage d’IFN alpha sérique ou plasmatique par méthode du SIMOA (single molecule array) permettant la détection de molécules d’IFN de l’ordre du femtogramme (10-18g). Ces méthodes nous ont ainsi permis d’élargir le spectre clinique phénotypique des interféronopathies de type I, initialement considéré comme essentiellement neurologique. Les patients atteints du syndrome d’Aicardi-Goutières, première interféronopathie monogénique décrite, présentaient les signes suivants : dystonie, spasticité, décalage des acquisitions, calcifications intra-cérébrales et anomalies de la substance blanche. Cependant, l’utilisation systématique de nos méthodes de criblage associée à l’avènement des technologies de séquençage à haut débit (next generation sequencing – NGS) a permis de révéler un phénotype plus large, caractéristique des interféronopathies de type I : sur le plan cutané (engelures, vascularite nécrosante des extrémités, sclérodermie), pulmonaire (pneumopathie interstitielle isolée ou non), musculo-squelettique (arthralgies, arthrites, arthropathie de Jaccoud, myalgies et myosites), ophtalmologique (glaucome), néphrologique (néphropathies lupiques), gastro-entérologique (maladies inflammatoires chroniques intestinales précoces), associées à de l’auto-immunité ou un déficit immunitaire inconstants. Notre méthode de sélection nous a notamment permis d’identifier des patients présentant de manière variable des signes cardinaux de SAVI et une de trois nouvelles mutations activatrices dans une région spécifique du gène TMEM173 (codant pour STING). Ces mutations circonscrivent une région de la protéine à ce jour encore jamais impliquée dans le contrôle de la voie de l’IFN I. STING est une protéine du réticulum endoplasmique qui agit comme adaptateur cytosolique de senseurs intracellulaires d’ADN viral dans une voie de signalisation de l’IFN I. STING active TBK1 (TANK-binding kinase) et permet la transcription des IFN I par la phosphorylation d’IRF3. La Janus Kinase 1 (JAK1) et la tyrosine kinase 2 (TYK2) sont activées suite à la stimulation des récepteurs de l’IFN I et phosphorylent les facteurs de transcription STAT1 et STAT2, conduisant à l’expression de nombreux ISGs. Les analyses génétiques, de conformation tridimensionnelle, sur un modèle cellulaire in vitro (HEK293T) et ex vivo sur cellules mononuclées périphériques des patients nous ont ainsi permis de mettre en évidence pour ces mutations un caractère constitutionnellement activé, indépendant de la liaison au ligand cGAMP, mais transmettant ce signal à travers la voie d’aval par TBK1. (...)Type I interferons (IFN I) are antiviral cytokines with potent properties. Hence, the induction, transmission and resolution of the immune response generated by IFN I is tightly regulated. The concept of the type I interferonopathies, recently formulated by our team, rests on the assumption that some diseases arise from a disturbance of this complex signalling pathway, leading to excessive and inappropriate IFN I secretion. On this basis, targeted therapeutics should improve or cure features of such type I interferonopathies, thereby providing a validation of the underlying hypothesis. This PhD project initially focused on the clinical and biological characterisation of monogenic and polygenic interferonopathies, and secondarily on the molecular identification of novel mutations in the gene TMEM173 causing the interferonopathy called STING associated vasculopathy with onset in infancy (SAVI), an auto-inflammatory syndrome with severe cutaneous and pulmonary features. Our selection of patients in comparison to healthy controls was made possible through the use of novel screening tools: IFN signature (qPCR of 6 IFN stimulated genes – ISGs), and measurement of IFN alpha protein levels in serum or plasma (SIMOA-single molecule array - enabling the detection of molecules of IFN in the femtogram [10-18g]) range. In this way, we have been able to expand the phenotypic spectrum of the interferonopathies, which was initially considered as primarily neurological. Patients with Aicardi-Goutières syndrome (AGS), the first described of the monogenic interferonopathies, exhibit dystonia, spasticity, developmental delay, intra-cranial calcifications and white matter abnormalities. However, the systematic use of our interferon screening assays, plus the advent of next-generation sequencing technology, has revealed a much broader set of features relevant to this novel disease grouping – involving the skin (chilblains, necrotising vasculitis, scleroderma), lungs (isolated lung interstitial disease or associated with other signs), musculoskeletal system (joint pain, arthritis, Jaccoud’s arthropathy, muscle pain and myositis), eyes (glaucoma), kidneys (lupus nephritis) and gastro-intestinal tract (early inflammatory bowel disease), as well features of autoimmunity and immunodeficiency. Using our screening assays enabled us to identify three patients variably exhibiting the core features of SAVI, all of whom were found to harbour distinct novel activating mutations in STING. These mutations highlight a protein domain not previously implicated in the control of IFN I signalling. STING is an endoplasmic reticulum protein, acting as a cytosolic adaptor of intracellular sensors of viral DNA in the type I IFN signalling pathway. STING activates TANK-binding kinase (TBK1), allowing transcription of IFN I through phosphorylation of IRF3. Janus kinase 1 (JAK1) and tyrosine kinase 2 (TYK2) are activated following stimulation of the IFN I receptor, leading to phosphorylation of the transcription factors STAT1 and STAT2 and the subsequent induction of a large number of ISGs. Genetic analysis, conformational studies, an in vitro cellular model (HEK293T) and ex vivo experimental data (using patient peripheral blood mononuclear cells - PBMCs) enabled us to confirm the constitutive activating nature of these variants, and show that this activation did not require binding with cGAMP, but was dependent on signalling through TBK1. Ruxolitinib, a JAK1/2 inhibitor, could antagonise this constitutive activation ex vivo. These results indicate a promising therapeutic approach in such patients, and more widely in the monogenic, and perhaps even, polygenic, interferonopathy context
Caractéristiques cliniques et moléculaires et approches thérapeutiques des interféronopathies de type I
No full textLe concept d'interféronopathie de type I émerge en 2011 et fait référence à un ensemble de pathologies Mendéliennes caractérisées par une hyperactivation des interférons (IFN) de type I. Tous les gènes associés au syndrome d'Aicardi-Goutières (SAG), la première interféronopathie de type I décrite, sont impliqués dans la détection ou le métabolisme des acides nucléiques. Les autres protéines mutées associées aux interféronopathies de type I modifient toutes la voie de signalisation des acides nucléiques, de manière directe, indirecte ou encore non définie. Les IFN de type I se fixent à un récepteur unique et activent la Janus kinase 1 (JAK1) et la tyrosine kinase 2 conduisant à l'expression de gènes stimulés par les IFN (IFN-stimulated genes, ISGs) via la phosphorylation des facteurs de transcription STAT1 et STAT2. Notre équipe a développé des outils diagnostiques des interféronopathies de type I, comprenant la signature IFN, analyse combinée de l'expression de 6 ISGs, et, plus récemment, une méthode de détection de l'IFN alpha à l'aide de la technologie «single molecule array». Les mutations monogéniques associées jusqu'à présent aux interféronopathies de type I causent des phénotypes variables. Leurs points communs sont une morbidité et une mortalité importantes, notamment en raison de leur réponse faible aux immunomodulateurs classiques. Les mutations activatrices de TMEM173 codant pour STING (Stimulator of IFN genes) sont responsables d'une inflammation sévère, connue sous le nom de STING-associated vasculopathy with onset in infancy (SAVI), et caractérisée par une vascularite cutanée et une atteinte interstitielle pulmonaire conduisant à une insuffisance respiratoire terminale. STING, une protéine du réticulum endoplasmique (RE), agit comme un adaptateur cytosolique de la détection de l'ADN, permettant la synthèse d'IFN de type I via la phosphorylation d'IRF3. Une cohorte internationale de 20 patients SAVI est décrite dans cette thèse soulignant l'hétérogénéité clinique de cette maladie. Nous avons également étudié le lien entre des mutations hétérozygotes de COPA et une activation de la voie des IFN de type I. COPA code pour la sous-unité alpha du complexe du coatomère I, impliqué dans le transport rétrograde entre le RE et le Golgi. Les mutations hétérozygotes de COPA sont à l'origine d'un phénotype proche du SAVI et entraînent une hausse du stress du RE et une réponse immunitaire de type Th17. Cependant, la physiopathologie de cette maladie reste peu connue. Nous avons étudié un groupe de 8 patients qui illustre l'hétérogénéité phénotypique de cette affection nouvellement décrite. Nous avons observé des similitudes entre l'histologie pulmonaire du syndrome COPA et du SAVI, ainsi qu'une signature IFN, des taux élevés d'IFN alpha dans le sérum et une phosphorylation de STAT1 dans les lymphocytes des patients. Dans un modèle cellulaire, la coexpression de COPA muté et de STING sauvage entraîne la phosphorylation d'IRF3 et à une induction d'ISGs, suggérant que les mutations de COPA conduisent à une activation dépendante de STING de la voie des IFN de type I. Nous avons mené avec succès le premier essai clinique d'un inhibiteur de JAK1, le ruxolitinib, dans le contexte du SAVI. L'amélioration clinique remarquable a été confirmée in vitro et ex vivo. La gravité de la maladie nous a également poussé à chercher des alternatives thérapeutiques pour contrôler la voie des IFN de type I. Nous avons montré que l'inhibition d'IKK bloquait efficacement la production et la signalisation des IFN de type I dans les cellules de patients STING in vitro. Devant les résultats prometteurs de l'inhibition de JAK1 dans le SAVI, nous avons ensuite testé le ruxolitinib dans le cadre d'autres interféronopathies de type I monogéniques (COPA, TREX1) mais aussi chez une enfant ayant une dermatomyosite sévère, une maladie pour laquelle le rôle pathogénique de l'IFN de type I a été suggéré.The term 'type I interferonopathies', first coined in 2011, refers to a set of Mendelian disorders associated with constitutive up-regulation of type I interferon (IFN) signalling. All of the genes associated with Aicardi-Goutières syndrome (AGS), the first Mendelian type I interferonopathy described, have been implicated in either the processing or sensing of nucleic acids. Beyond AGS, the other mutated proteins associated with type I interferonopathies have a direct, indirect, or currently undefined action on nucleic acid signalling. Type I IFNs drive the expression of IFN-stimulated genes (ISGs) through the engagement of a common receptor and the subsequent activation of Janus kinase 1 (JAK1) and tyrosine kinase 2, and phosphorylation of STAT1 and STAT2. Our team has developed diagnostic tools to identify type I interferonopathies, comprising a so-called IFN signature, involving the assessment of mRNA expression of 6 ISGs and, more recently, a high sensitivity assay of IFN alpha protein using single molecule array technology. Monogenic mutations so far recognised as type I interferonopathies are associated with a wide spectrum of phenotype. The hallmark of these diseases is their significant morbidity and mortality, associated with an apparent absence of response to conventional immunosuppressive therapies. Activating mutations in TMEM173, encoding stimulator of IFN genes (STING), cause a severe inflammatory condition referred to as STING-associated vasculopathy with onset in infancy (SAVI), characterised by skin vasculopathy and interstitial lung disease leading to end-stage respiratory failure. The endoplasmic reticulum (ER) protein STING is a central component of DNA sensing that induces type I IFNs through phosphorylation of IRF3. An international cohort of 20 STING patients is reported in this thesis, emphasising the clinical heterogeneity of this condition. We also investigated the link between heterozygous mutations in COPA and type I IFN signalling. COPA encodes the alpha subunit of the 7 member coatomer complex I, involved in retrograde transport from the golgi to the ER. Heterozygous mutations in COPA cause a phenotype showing some overlap with SAVI, and are associated with increased ER stress and priming of a Th17 response. However, the precise pathophysiology of this disease is so far undefined. We have studied a group of 8 patients illustrating the phenotypic variability of this emerging disease. We observed commonalities in the lung pathology in COPA and SAVI, as well as an IFN signature, raised levels of IFN alpha in the serum and phosphorylation of STAT1 in patient T cells. In a cellular model, phosphorylation of IRF3 and increased ISG expression were observed in cells co-transfected with wild type STING and mutant COPA plasmids, suggesting that mutations in COPA lead to constitutive activation of type IFN signalling through STING. We reported, for the first time, the successful use of a JAK1 inhibitor, ruxolitinib, in the context of SAVI. We observed a marked clinical effect, which was mirrored by the results of in vitro and ex vivo experiments. Because of the severity of SAVI, we also aimed to evaluate alternative therapeutic approaches to block type I IFN signalling and showed that IKK inhibition efficiently abrogated in vitro constitutive activation of type I IFN production and signalling in cells from STING patients. Considering the promising results of JAK1 blockade in SAVI, we then trialled ruxolitinib in other monogenic type I interferonopathies (TREX1, COPA) and in a child with severe dermatomyositis, a disease where type I IFN has been suggested to play a key pathogenic role
Neuroradiologic patterns and novel imaging findings in Aicardi-Goutières syndrome.
No full textOBJECTIVE: To perform an updated characterization of the neuroradiologic features of Aicardi-Goutières syndrome (AGS). METHODS: The neuroradiologic data of 121 subjects with AGS were collected. The CT and MRI data were analyzed with a systematic approach. Moreover, we evaluated if an association exists between the neuroradiologic findings, clinical features, and genotype. RESULTS: Brain calcifications were present in 110 subjects (90.9%). Severe calcification was associated with TREX1 mutations and early age at onset. Cerebral atrophy was documented in 111 subjects (91.8%). Leukoencephalopathy was present in 120 children (99.2%), with 3 main patterns: frontotemporal, diffuse, and periventricular. White matter rarefaction was found in 54 subjects (50.0%), strongly associated with mutations in TREX1 and an early age at onset. Other novel radiologic features were identified: deep white matter cysts, associated with TREX1 mutations, and delayed myelination, associated with RNASEH2B mutations and early age at onset. CONCLUSIONS: We demonstrate that the AGS neuroradiologic phenotype is expanding by adding new patterns and findings to the classic criteria. The heterogeneity of neuroradiologic patterns is partly explained by the timing of the disease onset and reflects the complexity of the pathogenic mechanisms
Type I interferonopathies: mendelian type I interferon up-regulation.
No full textThe concept of grouping Mendelian disorders associated with an up-regulation of type I interferon has only recently been suggested. Here we discuss the progress being made in the delineation and understanding of this novel set of inborn errors of immunity, the human type I interferonopathies
- …
