Inborn errors of OAS-RNase L in SARS-CoV-2-related multisystem inflammatory syndrome in children

Funding Information: The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R21AI160576), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the Yale Center for Mendelian Genomics and the GSP Coordinating Center funded by the National Human Genome Research Institute (NHGRI) (UM1HG006504 and U24HG008956), the Yale High-Performance Computing Center (S10OD018521), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JBP Foundation, the French National Research Agency (ANR) under the "Investments for the Future" program (ANR-10-IAHU-01), the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), the French Foundation for Medical Research (FRM) (EQU201903007798), the ANR GenMISC (ANR-21-COVR-039), the ANRS-COV05, ANR GENVIR (ANR-20-CE93-003) and ANR AABIFNCOV (ANR-20-CO11-0001) projects, the ANR-RHU program (ANR-21-RHUS-08), the European Union's Horizon 2020 research and innovation program under grant agreement 824110 (EASI-genomics), the HORIZON-HLTH-2021-DISEASE-04 program under grant agreement 01057100 (UNDINE), the ANR-RHU Program ANR-21-RHUS-08 (COVIFERON), the Square Foundation, Grandir - Fonds de solidarité pour l'enfance, the Fondation du Souffle, the SCOR Corporate Foundation for Science, the French Ministry of Higher Education, Research, and Innovation (MESRI-COVID-19), Institut National de la Santé et de la Recherche Médicale (INSERM), and Paris Cité University. We acknowledge support from the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH under award R01AI104887 to R.H.S. and S.R.W. The Laboratory of Human Evolutionary Genetics (Institut Pasteur) is supported by the Institut Pasteur, the Collège de France, the French Government's Investissement d'Avenir program, Laboratoires d'Excellence "Integrative Biology of Emerging Infectious Diseases" (ANR-10-LABX-62-IBEID) and "Milieu Intérieur" (ANR-10-LABX-69-01), the Fondation de France (no. 00106080), the FRM (Equipe FRM DEQ20180339214 team), and the ANR COVID-19-POPCELL (ANR-21-CO14-0003-01). A. Puj. is supported by ACCI20-759 CIBERER, EasiGenomics H2020 Marató TV3 COVID 2021-31-33, the HORIZON-HLTH-2021-ID: 101057100 (UNDINE), the Horizon 2020 program under grant no. 824110 (EasiGenomics grant no. COVID-19/PID12342), and the CERCA Program/Generalitat de Catalunya. The Canarian Health System sequencing hub was funded by the Instituto de Salud Carlos III (COV20-01333 and COV20-01334), the Spanish Ministry of Science and Innovation (RTC-2017-6471-1; AEI/FEDER, UE), Fundación MAPFRE Guanarteme (OA21/131), and Cabildo Insular de Tenerife (CGIEU0000219140 and "Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19"). The CoV-Contact Cohort was funded by the French Ministry of Health and the European Commission (RECOVER project). Our studies are also funded by the Ministry of Health of the Czech Republic Conceptual Development of Research Organization (FNBr, 65269705) and ANID COVID0999 funding in Chile. G. Novelli and A. Novelli are supported by Regione Lazio (Research Group Projects 2020) No. A0375-2020-36663, GecoBiomark. A.M.P., M.L.D., and J.P.-T. are supported by the Inmungen-CoV2 project of CSIC. This work was supported in part by the Intramural Research Program of the NIAID, NIH. The research work of A.M.P, M.L.D., and J.P.-T. was funded by the European Commission-NextGenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global). I.M. is a senior clinical investigator at FWO Vlaanderen supported by a VIB GC PID grant, by FWO grants G0B5120N (DADA2) and G0E8420N, and by the Jeffrey Modell Foundation. I.M. holds an ERC-StG MORE2ADA2 grant and is also supported by ERN-RITA. A.Y. is supported by fellowships from the European Academy of Dermatology and Venereology and the Swiss National Science Foundation and by an Early Career Award from the Thrasher Research Fund. Y.-H.C. is supported by an A*STAR International Fellowship (AIF). M.O. was supported by the David Rockefeller Graduate Program, the New York Hideyo Noguchi Memorial Society (HNMS), the Funai Foundation for Information Technology (FFIT), the Honjo International Scholarship Foundation (HISF), and the National Cancer Institute (NCI) F99 Award (F99CA274708). A.A.A. was supported by Ministerio de Ciencia Tecnología e Innovación MINCIENCIAS, Colombia (111584467551/CT 415-2020). D.L. is supported by a fellowship from the FRM for medical residents and fellows. E.H. received funding from the Bank of Montreal Chair of Pediatric Immunology, Foundation of CHU Sainte-Justine, CIHR grants PCC-466901 and MM1-181123, and a Canadian Pediatric Society IMPACT study. Q.P.-H. received funding from the European Union's Horizon 2020 research and innovation program (ATAC, 101003650), the Swedish Research Council, and the Knut and Alice Wallenberg Foundation. Work in the Laboratory of Virology and Infectious Disease was supported by NIH grants P01AI138398-S1, 2U19AI111825, R01AI091707-10S1, and R01AI161444; a George Mason University Fast Grant; the G. Harold and Leila Y. Mathers Charitable Foundation; the Meyer Foundation; and the Bawd Foundation. R.P.L. is on the board of directors of both Roche and the Roche subsidiary Genentech. J.L.P. was supported by a Francois Wallace Monahan Postdoctoral Fellowship at the Rockefeller University and by a European Molecular Biology Organization Long-Term Fellowship (ALTF 380-2018). Publisher Copyright: © 2023 American Association for the Advancement of Science. All rights reserved.Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of OAS1, OAS2, or RNASEL in five unrelated children with MIS-C. The cytosolic double-stranded RNA (dsRNA)-sensing OAS1 and OAS2 generate 2'-5'-linked oligoadenylates (2-5A) that activate the single-stranded RNA-degrading ribonuclease L (RNase L). Monocytic cell lines and primary myeloid cells with OAS1, OAS2, or RNase L deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stimulation. Exogenous 2-5A suppresses cytokine production in OAS1-deficient but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by mitochondrial antiviral-signaling protein (MAVS) deficiency. Recessive OAS-RNase L deficiencies in these patients unleash the production of SARS-CoV-2-triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.publishersversionpublishe

Rôle des variants de PRKCD, IKZF1 et LYN dans l'homéostasie lymphocytaire B et le développement du lupus érythémateux systémique juvénile

Systemic lupus erythematosus (SLE) is a rare autoimmune disease that can affect multiple organs. SLE usually appears in adults and less frequently in children, where the pathology is more severe. Some forms of SLE associated with single gene mutation have been recently identified, primarily in children. A large-scale genetic analysis was performed in a cohort of pediatric SLE patients. Among genes expressed in B cells, a variant of PRKCD was identified in one family as well as mutations of LYN and IKZF1 in another family. Due to difficulties in accessing pediatric samples, functional studies are challenging. For this reason, we have generated several mouse models carrying the mutations found in patients. The goal of my PhD work was, on one hand to determine the effect of new variants on the functionality of IKAROS and LYN proteins, and on the other hand, to determine the role of the G510S homozygous mutation of PRKCD in the development of SLE, to dissect the altered underlying molecular mechanisms.Le lupus systémique érythémateux (LES) est une maladie auto-immune rare pouvant affecter divers organes. Le LES apparaît habituellement chez l’adulte et moins fréquemment chez les enfants, où la pathologie est plus sévère. Certaines formes de LES associées à la mutation d’un seul gène ont été récemment identifiées, essentiellement dans les LES juvéniles. Une large cohorte de patients a été constituée sur laquelle des analyses génétiques à grande échelle ont été réalisées. Au sein des gènes exprimés dans les lymphocytes B, un variant de PRKCD a été identifié dans une famille ainsi que des variants de LYN et de IKZF1 dans une autre famille. Du fait de la rareté des échantillons pédiatriques, il est difficile d’étudier les conséquences fonctionnelles des variants sélectionnés à partir de matériel humain. Pour cette raison, nous avons généré plusieurs modèles murins ayant les mêmes mutations que celles retrouvées chez les patients. L’objectif de mes travaux de thèse était d’une part de déterminer l’effet des nouveaux variants sur la fonctionnalité des protéines IKAROS et LYN, d’étudier le phénotype des modèles murins porteurs de ces mutations et d’autre part de confirmer le rôle de la mutation homozygote de PRKCD G510S dans le développement du LES, de réaliser un immunophénotypage approfondi du modèle murin et de disséquer les mécanismes moléculaires altérées

Rôle des variants de PRKCD, IKZF1 et LYN dans l'homéostasie lymphocytaire B et le développement du lupus érythémateux systémique juvénile

Systemic lupus erythematosus (SLE) is a rare autoimmune disease that can affect multiple organs. SLE usually appears in adults and less frequently in children, where the pathology is more severe. Some forms of SLE associated with single gene mutation have been recently identified, primarily in children. A large-scale genetic analysis was performed in a cohort of pediatric SLE patients. Among genes expressed in B cells, a variant of PRKCD was identified in one family as well as mutations of LYN and IKZF1 in another family. Due to difficulties in accessing pediatric samples, functional studies are challenging. For this reason, we have generated several mouse models carrying the mutations found in patients. The goal of my PhD work was, on one hand to determine the effect of new variants on the functionality of IKAROS and LYN proteins, and on the other hand, to determine the role of the G510S homozygous mutation of PRKCD in the development of SLE, to dissect the altered underlying molecular mechanisms.Le lupus systémique érythémateux (LES) est une maladie auto-immune rare pouvant affecter divers organes. Le LES apparaît habituellement chez l’adulte et moins fréquemment chez les enfants, où la pathologie est plus sévère. Certaines formes de LES associées à la mutation d’un seul gène ont été récemment identifiées, essentiellement dans les LES juvéniles. Une large cohorte de patients a été constituée sur laquelle des analyses génétiques à grande échelle ont été réalisées. Au sein des gènes exprimés dans les lymphocytes B, un variant de PRKCD a été identifié dans une famille ainsi que des variants de LYN et de IKZF1 dans une autre famille. Du fait de la rareté des échantillons pédiatriques, il est difficile d’étudier les conséquences fonctionnelles des variants sélectionnés à partir de matériel humain. Pour cette raison, nous avons généré plusieurs modèles murins ayant les mêmes mutations que celles retrouvées chez les patients. L’objectif de mes travaux de thèse était d’une part de déterminer l’effet des nouveaux variants sur la fonctionnalité des protéines IKAROS et LYN, d’étudier le phénotype des modèles murins porteurs de ces mutations et d’autre part de confirmer le rôle de la mutation homozygote de PRKCD G510S dans le développement du LES, de réaliser un immunophénotypage approfondi du modèle murin et de disséquer les mécanismes moléculaires altérées

Rôle des variants de PRKCD, IKZF1 et LYN dans l'homéostasie lymphocytaire B et le développement du lupus érythémateux systémique juvénile

Systemic lupus erythematosus (SLE) is a rare autoimmune disease that can affect multiple organs. SLE usually appears in adults and less frequently in children, where the pathology is more severe. Some forms of SLE associated with single gene mutation have been recently identified, primarily in children. A large-scale genetic analysis was performed in a cohort of pediatric SLE patients. Among genes expressed in B cells, a variant of PRKCD was identified in one family as well as mutations of LYN and IKZF1 in another family. Due to difficulties in accessing pediatric samples, functional studies are challenging. For this reason, we have generated several mouse models carrying the mutations found in patients. The goal of my PhD work was, on one hand to determine the effect of new variants on the functionality of IKAROS and LYN proteins, and on the other hand, to determine the role of the G510S homozygous mutation of PRKCD in the development of SLE, to dissect the altered underlying molecular mechanisms.Le lupus systémique érythémateux (LES) est une maladie auto-immune rare pouvant affecter divers organes. Le LES apparaît habituellement chez l’adulte et moins fréquemment chez les enfants, où la pathologie est plus sévère. Certaines formes de LES associées à la mutation d’un seul gène ont été récemment identifiées, essentiellement dans les LES juvéniles. Une large cohorte de patients a été constituée sur laquelle des analyses génétiques à grande échelle ont été réalisées. Au sein des gènes exprimés dans les lymphocytes B, un variant de PRKCD a été identifié dans une famille ainsi que des variants de LYN et de IKZF1 dans une autre famille. Du fait de la rareté des échantillons pédiatriques, il est difficile d’étudier les conséquences fonctionnelles des variants sélectionnés à partir de matériel humain. Pour cette raison, nous avons généré plusieurs modèles murins ayant les mêmes mutations que celles retrouvées chez les patients. L’objectif de mes travaux de thèse était d’une part de déterminer l’effet des nouveaux variants sur la fonctionnalité des protéines IKAROS et LYN, d’étudier le phénotype des modèles murins porteurs de ces mutations et d’autre part de confirmer le rôle de la mutation homozygote de PRKCD G510S dans le développement du LES, de réaliser un immunophénotypage approfondi du modèle murin et de disséquer les mécanismes moléculaires altérées

Monogenic lupus: Dissecting heterogeneity

Systemic lupus erythematosus (SLE) is a severe lifelong multisystem autoimmune disease characterized by the presence of autoantibodies targeting nuclear autoantigens, increased production of type I interferon and B cell abnormalities. Clinical presentation of SLE is extremely heterogeneous and different groups of disease are likely to exist. Recently, childhood-onset SLE (cSLE) cases have been linked to single gene mutations, defining the concept of monogenic or Mendelian lupus. Genes associated with Mendelian lupus can be grouped in at least three functional categories. First, complement deficiencies represent the main cause of monogenic lupus and its components are involved in the clearance of dying cells, a mechanism also called efferocytosis. Mutations in extracellular DNASE have been also identified in cSLE patients and represent additional causes leading to defective clearance of nucleic acids and apoptotic bodies. Second, the study of Aicardi-Goutières syndromes has introduced the concept of type-I interferonopathies. Bona fide lupus syndromes have been associated to this genetic condition, driven by defective nucleic acids metabolism or innate sensors overactivity. Interferon signalling anomalies can be detected and monitored during therapies, such as Janus-kinase (JAK) inhibitors. Third, tolerance breakdown can occur following genetic mutations in B and/or T cell expressing key immunoregulatory molecules. Biallelic mutations in PRKCD are associated to lupus and lymphoproliferative diseases as PKC-δ displays proapoptotic activity and is crucial to eliminate self-reactive transitional B cells. Here we review the literature of the emerging field of Mendelian lupus and discuss the physiopathological learning from these inborn errors of immunity. In addition, clinical and biological features are highlighted as well as specific therapies that have been tested in these genetic contexts

Sequential actions of EOMES and T-BET promote stepwise maturation of natural killer cells

International audienceEOMES and T-BET are related T-box transcription factors that control natural killer (NK) cell development. Here we demonstrate that EOMES and T-BET regulate largely distinct gene sets during this process. EOMES is dominantly expressed in immature NK cells and drives early lineage specification by inducing hallmark receptors and functions. By contrast, T-BET is dominant in mature NK cells, where it induces responsiveness to IL-12 and represses the cell cycle, likely through transcriptional repressors. Regardless, many genes with distinct functions are co-regulated by the two transcription factors. By generating two gene-modified mice facilitating chromatin immunoprecipitation of endogenous EOMES and T-BET, we show a strong overlap in their DNA binding targets, as well as extensive epigenetic changes during NK cell differentiation. Our data thus suggest that EOMES and T-BET may distinctly govern, via differential expression and co-factors recruitment, NK cell maturation by inserting partially overlapping epigenetic regulations

LACC1 deficiency links juvenile arthritis with autophagy and metabolism in macrophages

International audienceJuvenile idiopathic arthritis is the most common chronic rheumatic disease in children, and its etiology remains poorly understood. Here, we explored four families with early-onset arthritis carrying homozygous loss-of-expression mutations in LACC1. To understand the link between LACC1 and inflammation, we performed a functional study of LACC1 in human immune cells. We showed that LACC1 was primarily expressed in macrophages upon mTOR signaling. We found that LACC1 deficiency had no obvious impact on inflammasome activation, type I interferon response, or NF-κB regulation. Using bimolecular fluorescence complementation and biochemical assays, we showed that autophagy-inducing proteins, RACK1 and AMPK, interacted with LACC1. Autophagy blockade in macrophages was associated with LACC1 cleavage and degradation. Moreover, LACC1 deficiency reduced autophagy flux in primary macrophages. This was associated with a defect in the accumulation of lipid droplets and mitochondrial respiration, suggesting that LACC1-dependent autophagy fuels macrophage bioenergetics metabolism. Altogether, LACC1 deficiency defines a novel form of genetically inherited juvenile arthritis associated with impaired autophagy in macrophages

Pre-Covid-19, SARS-CoV-2-Negative Multisystem Inflammatory Syndrome in Children.

To The Editor: In early 2020, multisystemic inflammatory syndrome in children (MIS-C) was recognized as an emerging life-threatening disease occurring 2 to 6 weeks after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with symptoms resembling those of Kawasaki’s disease or toxic shock syndrome.1 Unlike typical Kawasaki’s disease, MIS-C has been frequently associated with gastrointestinal symptoms and circulatory failure necessitating treatment with vasoactive drugs

Early-onset autoimmunity associated with SOCS1 haploinsufficiency

International audienc

Expertise collective CRREF « Coupes Rases et Renouvellement des peuplements Forestiers en contexte de changement climatique » : Rapport scientifique de l’expertise: Rapport scientifique de l'expertise

Cette synthèse, ainsi que le rapport d’expertise et les exposés du séminaire de restitution, estdisponible sur le site web du GIP Ecofor (http://www.gip-ecofor.org/)