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Zuliani E, Canepari E, Pastore S, Neri F, Tesser A, Valencic E, Gortani G, Maschio M, Tommasini A, Taddio A. Significant Reduction of Lung Disease on Baricitinib Therapy in a Patient With COPA Syndrome. Pediatr Pulmonol 2025; 60:e27423. [PMID: 39601531 PMCID: PMC11758762 DOI: 10.1002/ppul.27423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/16/2024] [Accepted: 11/15/2024] [Indexed: 11/29/2024]
Affiliation(s)
- Elettra Zuliani
- Department of Medicine, Surgery and Health SciencesUniversity of TriesteTriesteItaly
| | - Elisa Canepari
- Department of Medicine, Surgery and Health SciencesUniversity of TriesteTriesteItaly
| | - Serena Pastore
- Department of PediatricsInstitute for Maternal and Child Health IRCCS “Burlo Garofolo”TriesteItaly
| | - Francesca Neri
- Department of PediatricsInstitute for Maternal and Child Health IRCCS “Burlo Garofolo”TriesteItaly
| | - Alessandra Tesser
- Department of PediatricsInstitute for Maternal and Child Health IRCCS “Burlo Garofolo”TriesteItaly
| | - Erica Valencic
- Department of PediatricsInstitute for Maternal and Child Health IRCCS “Burlo Garofolo”TriesteItaly
| | - Giulia Gortani
- Department of PediatricsInstitute for Maternal and Child Health IRCCS “Burlo Garofolo”TriesteItaly
| | - Massimo Maschio
- Department of PediatricsInstitute for Maternal and Child Health IRCCS “Burlo Garofolo”TriesteItaly
| | - Alberto Tommasini
- Department of Medicine, Surgery and Health SciencesUniversity of TriesteTriesteItaly
- Department of PediatricsInstitute for Maternal and Child Health IRCCS “Burlo Garofolo”TriesteItaly
| | - Andrea Taddio
- Department of Medicine, Surgery and Health SciencesUniversity of TriesteTriesteItaly
- Department of PediatricsInstitute for Maternal and Child Health IRCCS “Burlo Garofolo”TriesteItaly
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Tumlin J, Rovin B, Anders HJ, Mysler EF, Jayne DR, Takeuchi T, Lindholm C, Weiss G, Sorrentino A, Woollard K, Ferrari N. Targeting the Type I Interferon Pathway in Glomerular Kidney Disease: Rationale and Therapeutic Opportunities. Kidney Int Rep 2025; 10:29-39. [PMID: 39810777 PMCID: PMC11725820 DOI: 10.1016/j.ekir.2024.10.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 01/16/2025] Open
Abstract
Type I interferons (IFNs) are immunostimulatory molecules that can activate the innate and adaptive immune systems. In cases of immune dysfunction, prolonged activation of the type I IFN pathway has been correlated with kidney tissue damage in a wide range of kidney disorders, such as lupus nephritis (LN) and focal segmental glomerulosclerosis (FSGS). Genetic mutations, such as APOL1 risk variants in conjunction with elevated type I IFN expression, are also associated with higher rates of chronic kidney disease in patients with LN and collapsing FSGS. Long-term activation of the type I IFN pathway can result in chronic inflammation, leading to kidney tissue damage, cell death, and decline in organ function. Thus, therapeutic strategies targeting type I IFN could provide clinical benefits to patients with immune dysregulation who are at risk of developing impaired kidney function. Here, we present a critical review of type I IFN signaling, the consequences of chronically elevated type I IFN expression, and therapeutic strategies targeting type I IFN signaling in the context of kidney disease.
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Affiliation(s)
- James Tumlin
- NephroNet Clinical Trials Consortium, Buford, Georgia, USA
| | - Brad Rovin
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | | | | | - Tsutomu Takeuchi
- Department of Rheumatology and Applied Immunology, Saitama Medical University and Division of Rheumatology, Department of Internal Medicine, Keio University, Tokyo, Japan
| | | | - Gudrun Weiss
- Global Medical Affairs, Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK
| | - Alessandro Sorrentino
- Global Medical Affairs, Respiratory and Immunology, BioPharmaceuticals Medical, AstraZeneca, Cambridge, UK
| | - Kevin Woollard
- Bioscience Renal, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Nicola Ferrari
- Translational Science and Experimental Medicine, Early R&I, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
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Padureanu V, Forțofoiu MC, Donoiu I, Tieranu EN, Dumitrascu C, Padureanu R, Mușetescu AE, Alexandru C, Iorgus CC, Bobirca F, Dascalu A, Bobirca A. COPA Syndrome-From Pathogenesis to Treatment. Diagnostics (Basel) 2024; 14:2819. [PMID: 39767180 PMCID: PMC11674574 DOI: 10.3390/diagnostics14242819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Coatomer subunit α (COPA) syndrome is a mendelian autosomal dominant immune dysregulation disease characterized by early onset lung disease in the form of diffuse alveolar hemorrhaging or interstitial lung disease, frequently associated with arthritis, glomerulonephritis, and high titer autoantibodies usually mimicking other autoimmune diseases. While immunosuppressive medication has been effective in controlling arthritis, data on long-term lung disease control remains scarce, which poses a real challenge as the progression of lung disease is the main cause of poor life expectancy in COPA patients. Nevertheless, JAK inhibitor therapy seems to be the most promising therapeutic choice now.
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Affiliation(s)
- Vlad Padureanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (V.P.); (M.-C.F.); (R.P.)
| | - Mircea-Cătălin Forțofoiu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (V.P.); (M.-C.F.); (R.P.)
| | - Ionut Donoiu
- Department of Cardiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Eugen-Nicolae Tieranu
- Department of Cardiology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Catalin Dumitrascu
- Department of Internal Medicine and Rheumatology, “Dr. Ion Cantacuzino” Clinical Hospital, 011437 Bucharest, Romania; (C.A.); (C.C.I.); (A.B.)
| | - Rodica Padureanu
- Department of Internal Medicine, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (V.P.); (M.-C.F.); (R.P.)
| | - Anca Emanuela Mușetescu
- Department of Rheumatology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
| | - Cristina Alexandru
- Department of Internal Medicine and Rheumatology, “Dr. Ion Cantacuzino” Clinical Hospital, 011437 Bucharest, Romania; (C.A.); (C.C.I.); (A.B.)
- Department of Internal Medicine and Rheumatology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Carmen Catalina Iorgus
- Department of Internal Medicine and Rheumatology, “Dr. Ion Cantacuzino” Clinical Hospital, 011437 Bucharest, Romania; (C.A.); (C.C.I.); (A.B.)
| | - Florin Bobirca
- Department of General Surgery, “Carol Davila” University of Medicine and Pharmacy, “Dr. Ion Cantacuzino” Clinical Hospital, 030167 Bucharest, Romania;
| | - Ana Dascalu
- Department of Ophthalmology, Emergency University Hospital Bucharest, 050098 Bucharest, Romania;
| | - Anca Bobirca
- Department of Internal Medicine and Rheumatology, “Dr. Ion Cantacuzino” Clinical Hospital, 011437 Bucharest, Romania; (C.A.); (C.C.I.); (A.B.)
- Department of Internal Medicine and Rheumatology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
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Leśniak K, Płoski R, Rydzanicz M, Rymarz A, Lubas A, Syryło T, Niemczyk S. Non-infectious mixed cryoglobulinemia as a new clinical presentation of mutation in the gene encoding coatomer subunit alpha: a case report of two adult sisters. Front Immunol 2024; 15:1450048. [PMID: 39620212 PMCID: PMC11604590 DOI: 10.3389/fimmu.2024.1450048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 10/25/2024] [Indexed: 04/06/2025] Open
Abstract
Cryoglobulinemia is a rare disease characterized by the presence of cryoglobulins in the blood serum. It is usually caused by autoimmune, lymphoproliferative, or infectious factors. The pathogenesis of cryoglobulinemia is not well understood, therefore, genetic testing is very important. We present the case of two adult sisters with different clinical phenotypes of non-infectious cryoglobulinemic vasculitis associated with a rare genetic variant [(Hg38) 1:160323529 C>G, NP_004362.2:p.(Gly203Ala)]. One of the sisters suffered from essential mixed cryoglobulinemia, while the other suffered from cryoglobulinemia associated with systemic connective tissue disease. In both cases, genetic tests revealed a variant in the COPA gene, encoding coatomer subunit alpha. Mutations in the COPA gene are associated with COPA syndrome, an autoimmune interstitial lung, joint, and kidney monogenic disease, found mainly in children. Only 15 pathogenic COPA variants have been reported thus far which suggests that the full spectrum of disease manifestations remains unknown. Ours is the first report of the association of the COPA gene with non-infectious cryoglobulinemic vasculitis in adults. This unexpected finding may direct research into the pathogenesis of cryoglobulinemia and new treatment strategies for this rare disease.
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Affiliation(s)
- Ksymena Leśniak
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine-National Research Institute, Warsaw, Poland
| | - Rafał Płoski
- Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland
| | | | - Aleksandra Rymarz
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine-National Research Institute, Warsaw, Poland
| | - Arkadiusz Lubas
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine-National Research Institute, Warsaw, Poland
| | - Tomasz Syryło
- Department of General, Functional and Oncological Urology, Military Institute of Medicine- National Research Institute, Warsaw, Poland
| | - Stanisław Niemczyk
- Department of Internal Diseases, Nephrology and Dialysis, Military Institute of Medicine-National Research Institute, Warsaw, Poland
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Griese M, Kurland G, Cidon M, Deterding RR, Epaud R, Nathan N, Schwerk N, Warburton D, Weinman JP, Young LR, Deutsch GH. Pulmonary fibrosis may begin in infancy: from childhood to adult interstitial lung disease. Thorax 2024; 79:1162-1172. [PMID: 39153860 PMCID: PMC11671978 DOI: 10.1136/thorax-2024-221772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 06/25/2024] [Indexed: 08/19/2024]
Abstract
BACKGROUND Childhood interstitial lung disease (chILD) encompasses a group of rare heterogeneous respiratory conditions associated with significant morbidity and mortality. Reports suggest that many patients diagnosed with chILD continue to have potentially progressive or fibrosing disease into adulthood. Over the last decade, the spectrum of conditions within chILD has widened substantially, with the discovery of novel entities through advanced genetic testing. However, most evidence is often limited to small case series, with reports disseminated across an array of subspecialty, clinical and molecular journals. In particular, the frequency, management and outcome of paediatric pulmonary fibrosis is not well characterised, unlike in adults, where clear diagnosis and treatment guidelines are available. METHODS AND RESULTS This review assesses the current understanding of pulmonary fibrosis in chILD. Based on registry data, we have provisionally estimated the occurrence of fibrosis in various manifestations of chILD, with 47 different potentially fibrotic chILD entities identified. Published evidence for fibrosis in the spectrum of chILD entities is assessed, and current and future issues in management of pulmonary fibrosis in childhood, continuing into adulthood, are considered. CONCLUSIONS There is a need for improved knowledge of chILD among pulmonologists to optimise the transition of care from paediatric to adult facilities. Updated evidence-based guidelines are needed that incorporate recommendations for the diagnosis and management of immune-mediated disorders, as well as chILD in older children approaching adulthood.
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Affiliation(s)
- Matthias Griese
- German Center for Lung Research (DZL), University of Munich, LMU Hospital Department of Pediatrics at Dr von Hauner Children's Hospital, Munchen, Germany
| | - Geoffrey Kurland
- Division of Pediatric Pulmonology, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania, USA
| | - Michal Cidon
- Children’s Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Robin R Deterding
- Section of Pediatric Pulmonary and Sleep Medicine Department of Pediatrics, University of Colorado Denver, Denver, Colorado, USA
- Children's Hospital Colorado, Aurora, Colorado, USA
| | - Ralph Epaud
- Pediatric Pulmonology Department, Centre Hospitalier Intercommunal de Créteil; Centre des Maladies Respiratoires Rares (RESPIRARE®); University Paris Est Créteil, INSERM, IMRB, Créteil, France
| | - Nadia Nathan
- Paediatric Pulmonology Department and Reference Centre for Rare Lung Diseases RespiRare, Laboratory of Childhood Genetic Diseases, Inserm UMS_S933, Sorbonne Université and AP-HP, Hôpital Trousseau, Paris, France
| | - Nicolaus Schwerk
- Clinic for Paediatric Pneumology, Allergy and Neonatology, Hannover Medical School, German Center for Lung Research (DZL), Hannover, Germany
| | - David Warburton
- Children’s Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Jason P Weinman
- Department of Radiology, Children's Hospital Colorado, Aurora, Colorado, USA
| | - Lisa R Young
- Division of Pulmonary and Sleep Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - Gail H Deutsch
- Department of Pathology, Seattle Children's Hospital and University of Washington Medical Center, Seattle, Washington, USA
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6
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Fiorino EK, Fishman MP. Approach to the patient with Childhood Interstitial and Diffuse Lung Disease. Pediatr Pulmonol 2024; 59:2267-2275. [PMID: 39056528 DOI: 10.1002/ppul.27162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Revised: 06/06/2024] [Accepted: 06/25/2024] [Indexed: 07/28/2024]
Abstract
Childhood Interstitial and Diffuse Lung Disease (chILD) encompasses a group of rare, chronic lung disorders in infants and children with overlapping clinical features but diverse etiologies. The clinical presentation of chILD is of chronic or recurring respiratory signs and symptoms, often including increased work of breathing and hypoxia, with diffuse radiographic abnormalities on chest imaging. Recognition can be challenging since some clinical features overlap with those of more common pediatric respiratory diseases including asthma and recurrent viral infections, among others. chILD should be considered as an underlying diagnosis when a patient's respiratory symptoms seem disproportionate to the clinical scenario and/or persist. The diagnostic process involves multiple steps and is tailored to the individual patient. Nearly all children will undergo imaging and pulmonary function testing, many will undergo bronchoscopy with bronchoalveolar lavage, many will receive genetic testing, and some will require lung biopsy. Treatment includes preventive care, evaluation for comorbidities, pharmacotherapy according to diagnosis, and ongoing disease surveillance, including revisiting genetic and histopathologic results as new clinical information becomes available and as our understanding of these rare disorders improves. The purpose of this review is to provide a broad approach to the diagnosis and management of patients with chILD.
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Affiliation(s)
- Elizabeth K Fiorino
- Northwell, New Hyde Park, New York, USA
- Departments of Science Education and Pediatrics, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, USA
| | - Martha P Fishman
- Harvard Medical School, Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
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7
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Casey A, Fiorino EK, Wambach J. Innovations in Childhood Interstitial and Diffuse Lung Disease. Clin Chest Med 2024; 45:695-715. [PMID: 39069332 PMCID: PMC11366208 DOI: 10.1016/j.ccm.2024.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Children's interstitial and diffuse lung diseases (chILDs) are a heterogenous and diverse group of lung disorders presenting during childhood. Infants and children with chILD disorders present with respiratory signs and symptoms as well as diffuse lung imaging abnormalities. ChILD disorders are associated with significant health care resource utilization and high morbidity and mortality. The care of patients with chILD has been improved through multidisciplinary care, multicenter collaboration, and the establishment of patient research networks in the United Stated and abroad. This review details past and current innovations in the diagnosis and clinical care of children with chILD.
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Affiliation(s)
- Alicia Casey
- Department of Pediatrics, Division of Pulmonary Medicine, Harvard Medical School, Boston Children's Hospital, Boston, MA 02115, USA.
| | - Elizabeth K Fiorino
- Department of Science Education and Pediatrics, Donald and Barabara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Jennifer Wambach
- Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA
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8
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Wambach JA, Vece TJ. Clinical and research innovations in childhood interstitial lung disease (chILD). Pediatr Pulmonol 2024; 59:2233-2235. [PMID: 38651871 PMCID: PMC11324416 DOI: 10.1002/ppul.27025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 04/12/2024] [Indexed: 04/25/2024]
Affiliation(s)
- Jennifer A Wambach
- Edward Mallinckrodt Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, Saint Louis, Missouri, USA
| | - Timothy J Vece
- Department of Pediatrics, University of North Carolina-Chapel Hill, Chapel Hill, USA
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9
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Delafontaine S, Iannuzzo A, Bigley TM, Mylemans B, Rana R, Baatsen P, Poli MC, Rymen D, Jansen K, Mekahli D, Casteels I, Cassiman C, Demaerel P, Lepelley A, Frémond ML, Schrijvers R, Bossuyt X, Vints K, Huybrechts W, Tacine R, Willekens K, Corveleyn A, Boeckx B, Baggio M, Ehlers L, Munck S, Lambrechts D, Voet A, Moens L, Bucciol G, Cooper MA, Davis CM, Delon J, Meyts I. Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome. J Clin Invest 2024; 134:e163604. [PMID: 38175705 PMCID: PMC10866661 DOI: 10.1172/jci163604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 12/20/2023] [Indexed: 01/05/2024] Open
Abstract
Mutations in the N-terminal WD40 domain of coatomer protein complex subunit α (COPA) cause a type I interferonopathy, typically characterized by alveolar hemorrhage, arthritis, and nephritis. We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity. We showed that these CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI). In COPAR1142X and COPAR1058C fibroblasts, we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect. The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines, albeit through a distinct molecular mechanism in comparison with mutations in the WD40 domain of COPA. We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines. These results demonstrate the importance of the integrity of the CTD of COPA for COPI function and homeostatic intracellular trafficking, essential to ER homeostasis. CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinflammatory signaling.
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Affiliation(s)
- Selket Delafontaine
- Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Alberto Iannuzzo
- Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France
| | - Tarin M. Bigley
- Department of Pediatrics, Division of Rheumatology/Immunology, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Bram Mylemans
- Laboratory of Biomolecular Modelling and Design, Department of Chemistry, KU Leuven, Leuven, Belgium
| | - Ruchit Rana
- Division of Immunology, Allergy and Retrovirology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, USA
| | - Pieter Baatsen
- Electron Microscopy Platform of VIB Bio Imaging Core, KU Leuven, Leuven, Belgium
| | - Maria Cecilia Poli
- Department of Pediatrics, Clínica Alemana de Santiago, Universidad del Desarollo, Santiago, Chile
- Immunology and Rheumatology Unit, Hospital de Niños Dr. Roberto del Rio, Santiago, Chile
| | - Daisy Rymen
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Katrien Jansen
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Djalila Mekahli
- PKD Research Group, Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
- Department of Pediatric Nephrology
| | | | | | - Philippe Demaerel
- Department of Radiology, University Hospitals Leuven, Leuven, Belgium
| | - Alice Lepelley
- Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, Paris, France
| | - Marie-Louise Frémond
- Université Paris Cité, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, INSERM UMR 1163, Paris, France
- Paediatric Haematology-Immunology and Rheumatology Unit, Necker Hospital, AP-HP.Centre - Université Paris Cité, Paris, France
| | - Rik Schrijvers
- Allergy and Clinical Immunology Research Group, Department of Microbiology, Immunology and Transplantation, and
| | - Xavier Bossuyt
- Clinical and Diagnostic Immunology, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Katlijn Vints
- Electron Microscopy Platform of VIB Bio Imaging Core, KU Leuven, Leuven, Belgium
| | - Wim Huybrechts
- Center for Human Genetics, Leuven University Hospitals, Leuven, Belgium
| | - Rachida Tacine
- Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France
| | - Karen Willekens
- Center for Human Genetics, Leuven University Hospitals, Leuven, Belgium
| | - Anniek Corveleyn
- Center for Human Genetics, Leuven University Hospitals, Leuven, Belgium
| | - Bram Boeckx
- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Marco Baggio
- Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Lisa Ehlers
- Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Sebastian Munck
- VIB Bio Imaging Core and VIB–KU Leuven Center for Brain & Disease Research, KU Leuven Department of Neurosciences, Leuven, Belgium
| | - Diether Lambrechts
- Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Arnout Voet
- Laboratory of Biomolecular Modelling and Design, Department of Chemistry, KU Leuven, Leuven, Belgium
| | - Leen Moens
- Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Giorgia Bucciol
- Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
| | - Megan A. Cooper
- Department of Pediatrics, Division of Rheumatology/Immunology, Washington University in St. Louis, St. Louis, Missouri, USA
| | - Carla M. Davis
- Division of Immunology, Allergy and Retrovirology, Baylor College of Medicine, Texas Children’s Hospital, Houston, Texas, USA
| | - Jérôme Delon
- Université Paris Cité, CNRS, INSERM, Institut Cochin, Paris, France
| | - Isabelle Meyts
- Laboratory for Inborn Errors of Immunity, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
- Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium
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10
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Bernardinello N, Griese M, Borie R, Spagnolo P. Emerging Treatments for Childhood Interstitial Lung Disease. Paediatr Drugs 2024; 26:19-30. [PMID: 37948041 PMCID: PMC10770003 DOI: 10.1007/s40272-023-00603-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/17/2023] [Indexed: 11/12/2023]
Abstract
Childhood interstitial lung disease (chILD) is a large and heterogeneous group of disorders characterized by diffuse lung parenchymal markings on chest imaging and clinical signs such as dyspnea and hypoxemia from functional impairment. While some children already present in the neonatal period with interstitial lung disease (ILD), others develop ILD during their childhood and adolescence. A timely and accurate diagnosis is essential to gauge treatment and improve prognosis. Supportive care can reduce symptoms and positively influence patients' quality of life; however, there is no cure for many of the chILDs. Current therapeutic options include anti-inflammatory or immunosuppressive drugs. Due to the rarity of the conditions and paucity of research in this field, most treatments are empirical and based on case series, and less than a handful of small, randomized trials have been conducted thus far. A trial on hydroxychloroquine yielded good safety but a much smaller effect size than anticipated. A trial in fibrotic disease with the multitargeted tyrosine kinase inhibitor nintedanib showed similar pharmacokinetics and safety as in adults. The unmet need for the treatment of chILDs remains high. This article summarizes current treatments and explores potential therapeutic options for patients suffering from chILD.
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Affiliation(s)
- Nicol Bernardinello
- Respiratory Disease Unit, Department of Cardiac Thoracic, Vascular Sciences and Public Health, University of Padova, Via N. Giustiniani n°2, 35128, Padua, Italy
| | - Matthias Griese
- Department of Pediatric Pneumology, Dr. von Hauner Children's Hospital, German Center for Lung Research (DZL), Ludwig-Maximilians University, Munich, Germany
| | - Raphaël Borie
- Université de Paris, INSERM UMR 1152, Service de Pneumologie A, Centre de compétences maladies pulmonaires rares, Hôpital Bichat-Claude Bernard, AP-HP, 75018, Paris, France
| | - Paolo Spagnolo
- Respiratory Disease Unit, Department of Cardiac Thoracic, Vascular Sciences and Public Health, University of Padova, Via N. Giustiniani n°2, 35128, Padua, Italy.
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11
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Zheng Y, Du Y, Wu Y, Li F, Gu W, Zhao C. COPA syndrome caused by a novel p.Arg227Cys COPA gene variant. Mol Genet Genomic Med 2024; 12:e2309. [PMID: 37877458 PMCID: PMC10767596 DOI: 10.1002/mgg3.2309] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 09/13/2023] [Accepted: 10/13/2023] [Indexed: 10/26/2023] Open
Abstract
BACKGROUND COPA syndrome is a recently described and rare monogenic autosomal dominant disease caused by heterozygous missense mutations in the Coatomer Protein Subunit alpha (COPA) gene that encodes the alpha subunit of coat protein complex I (COPI). Its main clinical manifestations are inflammatory lung disease, arthritis, and renal disease. The development of inflammation in COPA syndrome maybe due to abnormal autophagic response and abnormal activation of type I interferon pathway. To date, 59 cases of COPA have been reported worldwide. METHODS In this case, Trio-whole exome sequencing was employed in the proband and her parents to identify the underlying genetic cause. COPA variant were detected and the clinical presentation of the patient was described. RESULTS Herein, we report a case of a 5-year-old girl with COPA syndrome who presented with symptoms of arthritis combined with Anti-neutrophil Cytoplasmic Antibody (ANCA) associated vasculitis (AAV), and progressive renal decline with minimal pulmonary involvement. Trio-whole exome sequencing was performed which revealed a novel heterozygous likely pathogenic variation in the COPA gene (c.679C>T,p.Arg227Cys), which was maternally inherited. Her mother was a heterozygote, but she had no phenotypic manifestations. No other mutations associated with the clinical phenotype were identified. CONCLUSION The present identification and characterization of a novel mutation expands the genotypic spectra of the COPA syndrome and provide reference data to guide future clinical diagnosis and treatment of COPA syndrome.
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Affiliation(s)
- Yue Zheng
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yue Du
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yubin Wu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
| | - Fuwei Li
- Beijing Chigene Translational Medical Research Center Co, Beijing, China
| | - Weiyue Gu
- Beijing Chigene Translational Medical Research Center Co, Beijing, China
| | - Chengguang Zhao
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, China
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12
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Mohan S. Targeted Treatment of Diseases of Immune Dysregulation. Rheum Dis Clin North Am 2023; 49:913-929. [PMID: 37821203 DOI: 10.1016/j.rdc.2023.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
Increasing molecular knowledge of autoinflammatory and autoimmune disorders has enabled more targeted treatment of these conditions. Treatment of inflammasomopathies is often aimed at interleukin-1 (IL-1) blockade, with potential use of other inhibitors targeting cytokines such as IL-18 and IL-6. Interferonopathies and some disorders with overlap features of autoimmunity and autoinflammation may improve with Janus kinase inhibition. Autoimmune conditions may also respond to inhibition of different cytokines, as well as to inhibition of T and B lymphocytes. Effective treatment is increasingly possible through targeted/precision medicine approaches.
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Affiliation(s)
- Smriti Mohan
- Division of Rheumatology, Department of Pediatrics, University of Michigan CS Mott Children's Hospital, 1500 East Medical Ctr Dr SPC 5718, Ann Arbor, MI 48109-5718, USA.
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13
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Gagne S, Sivaraman V, Akoghlanian S. Interferonopathies masquerading as non-Mendelian autoimmune diseases: pattern recognition for early diagnosis. Front Pediatr 2023; 11:1169638. [PMID: 37622085 PMCID: PMC10445166 DOI: 10.3389/fped.2023.1169638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/05/2023] [Indexed: 08/26/2023] Open
Abstract
Type I interferonopathies are a broad category of conditions associated with increased type I interferon gene expression and include monogenic autoinflammatory diseases and non-Mendelian autoimmune diseases such as dermatomyositis and systemic lupus erythematosus. While a wide range of clinical presentations among type I interferonopathies exists, these conditions often share several clinical manifestations and implications for treatment. Presenting symptoms may mimic non-Mendelian autoimmune diseases, including vasculitis and systemic lupus erythematosus, leading to delayed or missed diagnosis. This review aims to raise awareness about the varied presentations of monogenic interferonopathies to provide early recognition and appropriate treatment to prevent irreversible damage and improve quality of life and outcomes in this unique patient population.
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Affiliation(s)
- Samuel Gagne
- Division of Pediatric Rheumatology, Nationwide Children’s Hospital, Columbus, OH, United States
| | - Vidya Sivaraman
- Division of Pediatric Rheumatology, Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
| | - Shoghik Akoghlanian
- Division of Pediatric Rheumatology, Nationwide Children’s Hospital, Columbus, OH, United States
- Department of Pediatrics, The Ohio State University, Columbus, OH, United States
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14
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Melki I, Frémond ML. JAK Inhibition in Juvenile Idiopathic Arthritis (JIA): Better Understanding of a Promising Therapy for Refractory Cases. J Clin Med 2023; 12:4695. [PMID: 37510809 PMCID: PMC10381267 DOI: 10.3390/jcm12144695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 07/03/2023] [Accepted: 07/08/2023] [Indexed: 07/30/2023] Open
Abstract
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases with probably differential underlying physiopathology. Despite the revolutionary era of biologics, some patients remain difficult to treat because of disease severity, drug adverse events, drug allergy or association with severe comorbidities, i.e., uveitis, interstitial lung disease and macrophagic activation syndrome. Janus Kinase (JAK) inhibitors are small molecules that target JAK/Signal Transducers and Activators of Transcription (STAT) pathways, which could then prevent the activity of several proinflammatory cytokines. They may provide a useful alternative in these cases of JIA or in patients actually affected by Mendelian disorders mimicking JIA, such as type I interferonopathies with joint involvement, and might be the bridge for haematopoietic stem cell transplantation in these disabling conditions. As these treatments may have side effects that should not be ignored, ongoing and further controlled studies are still needed to provide data underlying long-term safety considerations in children and delineate subsets of JIA patients that will benefit from these promising treatments.
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Affiliation(s)
- Isabelle Melki
- General Paediatrics, Department of Infectious Disease and Internal Medicine, Robert Debré University Hospital, APHP, Nord-Université Paris Cité, F-75020 Paris, France
- Paediatrics, Rheumatology and Paediatric Internal Medicine, Children's Hospital, F-33000 Bordeaux, France
- Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Université Paris Cité, Inserm UMR 1163, F-75015 Paris, France
| | - Marie-Louise Frémond
- Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Université Paris Cité, Inserm UMR 1163, F-75015 Paris, France
- Paediatric Haematology-Immunology and Rheumatology Unit, Necker Hospital, APHP, Centre-Université Paris Cité, F-75015 Paris, France
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15
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Gao FQ, Zhang JM, Li CF. Clinical Presentation and Treatment of Juvenile Idiopathic Arthritis Combined with Lung Disease: A Narrative Review. Rheumatol Ther 2023; 10:507-522. [PMID: 36906693 PMCID: PMC10008073 DOI: 10.1007/s40744-023-00542-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 02/13/2023] [Indexed: 03/13/2023] Open
Abstract
Juvenile idiopathic Arthritis (JIA) is a common rheumatic disorder in children that can cause multiple systems to be affected simultaneously, leading to severe clinical symptoms and a high mortality rate in those with pulmonary involvement. Pleurisy is the most common manifestation of pulmonary involvement. At the same time, other conditions, such as pneumonia, interstitial lung disease, occlusive bronchiectasis, and alveolar protein deposition, have been increasingly reported in recent years. This review aims to provide an overview of the clinical manifestations of JIA lung damage and the current treatment options to assist in identifying and treating JIA lung involvement.
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Affiliation(s)
- Feng-Qiao Gao
- Department of Rheumatology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Nan Li Shi Road No. 56, Beijing, 100045 China
| | - Jun-Mei Zhang
- Department of Rheumatology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Nan Li Shi Road No. 56, Beijing, 100045 China
| | - Cai-Feng Li
- Department of Rheumatology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Nan Li Shi Road No. 56, Beijing, 100045 China
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16
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Hosahalli Vasanna S, Dalal J. Traffic jam within lymphocytes: A clinician's perspective. Front Immunol 2023; 13:1034317. [PMID: 36726976 PMCID: PMC9885010 DOI: 10.3389/fimmu.2022.1034317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/28/2022] [Indexed: 01/18/2023] Open
Abstract
With the discovery of novel diseases and pathways, as well as a new outlook on certain existing diseases, cellular trafficking disorders attract a great deal of interest and focus. Understanding the function of genes and their products in protein and lipid synthesis, cargo sorting, packaging, and delivery has allowed us to appreciate the intricate pathophysiology of these biological processes at the molecular level and the multi-system disease manifestations of these disorders. This article focuses primarily on lymphocyte intracellular trafficking diseases from a clinician's perspective. Familial hemophagocytic lymphohistiocytosis is the prototypical disease of abnormal vesicular transport in the lymphocytes. In this review, we highlight other mechanisms involved in cellular trafficking, including membrane contact sites, autophagy, and abnormalities of cytoskeletal structures affecting the immune cell function, based on a newer classification system, along with management aspects of these conditions.
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Affiliation(s)
- Smitha Hosahalli Vasanna
- Department of Pediatrics, Division of Pediatric Hematology Oncology, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, United States,School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Jignesh Dalal
- Department of Pediatrics, Division of Pediatric Hematology Oncology, University Hospitals Rainbow Babies & Children's Hospital, Cleveland, OH, United States,School of Medicine, Case Western Reserve University, Cleveland, OH, United States,*Correspondence: Jignesh Dalal,
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17
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Li X, Tang Y, Zhang L, Wang Y, Zhang W, Wang Y, Shen Y, Tang X. Case report: COPA syndrome with interstitial lung disease, skin involvement, and neuromyelitis spectrum disorder. Front Pediatr 2023; 11:1118097. [PMID: 36969269 PMCID: PMC10034176 DOI: 10.3389/fped.2023.1118097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 02/20/2023] [Indexed: 03/29/2023] Open
Abstract
This report describes a case of a 22 months Chinese boy with COPA syndrome bearing the c.715G > C (p.A239P) genotype. In addition to interstitial lung diseae, he also suffered from recurrent chilblain-like rashes, which has not been previously reported, and neuromyelitis optica spectrum disorder (NMOSD), which is a very rare phenotype. Clinical manifestations expanded the phenotype of COPA syndrome. Notably, there is no definitive treatment for COPA syndrome. In this report, the patient has achieved short-term clinical improvement with sirolimus.
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Affiliation(s)
- Xiao Li
- Department of Respiratory Medicine, Children’s Hospital Affiliated to Zhengzhou University/Henan Children’s Hospital/Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Yu Tang
- Department of Respiratory Medicine, Children’s Hospital Affiliated to Zhengzhou University/Henan Children’s Hospital/Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Lei Zhang
- Department of Respiratory Medicine, Children’s Hospital Affiliated to Zhengzhou University/Henan Children’s Hospital/Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Yuan Wang
- Department of Neurology, Children’s Hospital Affiliated to Zhengzhou University/Henan Children’s Hospital/Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Weihua Zhang
- Department of Neurology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Ying Wang
- Department of Neurology, Children’s Hospital Affiliated to Zhengzhou University/Henan Children’s Hospital/Zhengzhou Children’s Hospital, Zhengzhou, China
| | - Yuelin Shen
- Department of Respiratory Medicine, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Xiaolei Tang
- Department of Respiratory Medicine, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
- Correspondence: Xiaolei Tang
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18
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de Moura Rodrigues D, Lacerda-Queiroz N, Couillin I, Riteau N. STING Targeting in Lung Diseases. Cells 2022; 11:3483. [PMID: 36359882 PMCID: PMC9657237 DOI: 10.3390/cells11213483] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/18/2022] [Accepted: 10/27/2022] [Indexed: 01/30/2024] Open
Abstract
The cGAS-STING pathway displays important functions in the regulation of innate and adaptive immunity following the detection of microbial and host-derived DNA. Here, we briefly summarize biological functions of STING and review recent literature highlighting its important contribution in the context of respiratory diseases. Over the last years, tremendous progress has been made in our understanding of STING activation, which has favored the development of STING agonists or antagonists with potential therapeutic benefits. Antagonists might alleviate STING-associated chronic inflammation and autoimmunity. Furthermore, pharmacological activation of STING displays strong antiviral properties, as recently shown in the context of SARS-CoV-2 infection. STING agonists also elicit potent stimulatory activities when used as an adjuvant promoting antitumor responses and vaccines efficacy.
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Affiliation(s)
- Dorian de Moura Rodrigues
- Experimental and Molecular Immunology and Neurogenetics Laboratory, University of Orleans, Centre National de la Recherche Scientifique (CNRS), UMR7355, 45100 Orleans, France
| | | | - Isabelle Couillin
- Experimental and Molecular Immunology and Neurogenetics Laboratory, University of Orleans, Centre National de la Recherche Scientifique (CNRS), UMR7355, 45100 Orleans, France
| | - Nicolas Riteau
- Experimental and Molecular Immunology and Neurogenetics Laboratory, University of Orleans, Centre National de la Recherche Scientifique (CNRS), UMR7355, 45100 Orleans, France
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19
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Miyamoto T, Honda Y, Izawa K, Kanazawa N, Kadowaki S, Ohnishi H, Fujimoto M, Kambe N, Kase N, Shiba T, Nakagishi Y, Akizuki S, Murakami K, Bamba M, Nishida Y, Inui A, Fujisawa T, Nishida D, Iwata N, Otsubo Y, Ishimori S, Nishikori M, Tanizawa K, Nakamura T, Ueda T, Ohwada Y, Tsuyusaki Y, Shimizu M, Ebato T, Iwao K, Kubo A, Kawai T, Matsubayashi T, Miyazaki T, Kanayama T, Nishitani-Isa M, Nihira H, Abe J, Tanaka T, Hiejima E, Okada S, Ohara O, Saito MK, Takita J, Nishikomori R, Yasumi T. Assessment of type I interferon signatures in undifferentiated inflammatory diseases: A Japanese multicenter experience. Front Immunol 2022; 13:905960. [PMID: 36211342 PMCID: PMC9541620 DOI: 10.3389/fimmu.2022.905960] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 09/01/2022] [Indexed: 11/28/2022] Open
Abstract
Purpose Upregulation of type I interferon (IFN) signaling has been increasingly detected in inflammatory diseases. Recently, upregulation of the IFN signature has been suggested as a potential biomarker of IFN-driven inflammatory diseases. Yet, it remains unclear to what extent type I IFN is involved in the pathogenesis of undifferentiated inflammatory diseases. This study aimed to quantify the type I IFN signature in clinically undiagnosed patients and assess clinical characteristics in those with a high IFN signature. Methods The type I IFN signature was measured in patients' whole blood cells. Clinical and biological data were collected retrospectively, and an intensive genetic analysis was performed in undiagnosed patients with a high IFN signature. Results A total of 117 samples from 94 patients with inflammatory diseases, including 37 undiagnosed cases, were analyzed. Increased IFN signaling was observed in 19 undiagnosed patients, with 10 exhibiting clinical features commonly found in type I interferonopathies. Skin manifestations, observed in eight patients, were macroscopically and histologically similar to those found in proteasome-associated autoinflammatory syndrome. Genetic analysis identified novel mutations in the PSMB8 gene of one patient, and rare variants of unknown significance in genes linked to type I IFN signaling in four patients. A JAK inhibitor effectively treated the patient with the PSMB8 mutations. Patients with clinically quiescent idiopathic pulmonary hemosiderosis and A20 haploinsufficiency showed enhanced IFN signaling. Conclusions Half of the patients examined in this study, with undifferentiated inflammatory diseases, clinically quiescent A20 haploinsufficiency, or idiopathic pulmonary hemosiderosis, had an elevated type I IFN signature.
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Affiliation(s)
- Takayuki Miyamoto
- Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yoshitaka Honda
- Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto, Japan
- Department of Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kazushi Izawa
- Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Nobuo Kanazawa
- Department of Dermatology, Hyogo Medical University, Nishinomiya, Japan
| | - Saori Kadowaki
- Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hidenori Ohnishi
- Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Masakazu Fujimoto
- Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan
| | - Naotomo Kambe
- Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Naoya Kase
- Department of Clinical Application, Center for iPS cell (Induced pluripotent stem cell) Research and Application, Kyoto University, Kyoto, Japan
| | - Takeshi Shiba
- Department of Pediatrics, Tenri Hospital, Tenri, Japan
| | - Yasuo Nakagishi
- Department of Pediatric Rheumatology, Hyogo Prefectural Kobe Children’s Hospital, Kobe, Japan
| | - Shuji Akizuki
- Division of Clinical Immunology and Cancer Immunotherapy, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kosaku Murakami
- Division of Clinical Immunology and Cancer Immunotherapy, Center for Cancer Immunotherapy and Immunobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Masahiro Bamba
- Department of Pediatrics, Kawasaki Municipal Hospital, Kawasaki, Japan
| | - Yutaka Nishida
- Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Tomoo Fujisawa
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
| | - Daisuke Nishida
- Department of Infection and Immunology, Aichi Children’s Health and Medical Center, Aichi, Japan
| | - Naomi Iwata
- Department of Infection and Immunology, Aichi Children’s Health and Medical Center, Aichi, Japan
| | - Yoshikazu Otsubo
- Department of Pediatrics, Sasebo City General Hospital, Sasebo, Japan
| | - Shingo Ishimori
- Department of Pediatrics, Takatsuki General Hospital, Takatsuki, Japan
| | - Momoko Nishikori
- Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kiminobu Tanizawa
- Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Tomoyuki Nakamura
- Department of General Medicine, Osaka City Hospital Organization Osaka City General Hospital, Osaka, Japan
| | - Takeshi Ueda
- Department of Emergency and General Internal Medicine, Rakuwakai Marutamachi Hospital, Kyoto, Japan
| | - Yoko Ohwada
- Department of Pediatrics, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Yu Tsuyusaki
- Department of Neurology, Kanagawa Children’s Medical Center, Yokohama, Japan
| | - Masaki Shimizu
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
| | - Takasuke Ebato
- Department of Pediatrics, Kitasato University, School of Medicine, Kanagawa, Japan
| | - Kousho Iwao
- Department of Internal Medicine, Division of Rheumatology, Infectious Diseases and Laboratory Medicine, University of Miyazaki, Miyazaki, Japan
| | - Akiharu Kubo
- Department of Dermatology, Keio University School of Medicine, Tokyo, Japan
| | - Toshinao Kawai
- Division of Immunology, National Center for Child Health and Development, Tokyo, Japan
| | | | | | | | | | - Hiroshi Nihira
- Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Junya Abe
- Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Department of Pediatrics, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka, Japan
| | - Takayuki Tanaka
- Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Department of Pediatrics, Otsu Red Cross Hospital, Otsu, Japan
| | - Eitaro Hiejima
- Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Satoshi Okada
- Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan
| | - Osamu Ohara
- Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan
| | - Megumu K. Saito
- Department of Clinical Application, Center for iPS cell (Induced pluripotent stem cell) Research and Application, Kyoto University, Kyoto, Japan
| | - Junko Takita
- Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Ryuta Nishikomori
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Takahiro Yasumi
- Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
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20
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Wobma H, Perkins R, Bartnikas L, Dedeoğlu F, Chou J, Vleugels RA, Lo MS, Janssen E, Henderson LA, Whangbo J, Vargas SO, Fishman M, Krone KA, Casey A. Genetic diagnosis of immune dysregulation can lead to targeted therapy for interstitial lung disease: A case series and single center approach. Pediatr Pulmonol 2022; 57:1577-1587. [PMID: 35426264 PMCID: PMC9627679 DOI: 10.1002/ppul.25924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 03/23/2022] [Accepted: 04/04/2022] [Indexed: 11/08/2022]
Abstract
In recent years, a growing number of monogenic disorders have been described that are characterized by immune dysregulation. A subset of these "primary immune regulatory disorders" can cause severe interstitial lung disease, often recognized in late childhood or adolescence. Patients presenting to pulmonary clinic may have long and complex medical histories, but lack a unifying genetic diagnosis. It is crucial for pulmonologists to recognize features suggestive of multisystem immune dysregulation and to initiate genetic workup, since targeted therapies based on underlying genetics may halt or even reverse pulmonary disease progression. Through such an approach, our center has been able to diagnose and treat a cohort of patients with interstitial lung disease from gene defects that affect immune regulation. Here we present representative cases related to pathogenic variants in three distinct pathways and summarize disease manifestations and treatment approaches. We conclude with a discussion of our perspective on the outstanding challenges for diagnosing and managing these complex life-threatening and chronic disorders.
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Affiliation(s)
- Holly Wobma
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Ryan Perkins
- Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Lisa Bartnikas
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Fatma Dedeoğlu
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Janet Chou
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Ruth Ann Vleugels
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.,Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Mindy S Lo
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Erin Janssen
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Lauren A Henderson
- Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Jennifer Whangbo
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts, USA
| | - Sara O Vargas
- Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Martha Fishman
- Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Katie A Krone
- Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Alicia Casey
- Division of Pulmonary Medicine, Boston Children's Hospital, Boston, Massachusetts, USA
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21
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Wobma H, Shin DS, Chou J, Dedeoğlu F. Dysregulation of the cGAS-STING Pathway in Monogenic Autoinflammation and Lupus. Front Immunol 2022; 13:905109. [PMID: 35693769 PMCID: PMC9186411 DOI: 10.3389/fimmu.2022.905109] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 05/02/2022] [Indexed: 01/19/2023] Open
Abstract
One of the oldest mechanisms of immune defense against pathogens is through detection of foreign DNA. Since human DNA is compartmentalized into the nucleus, its presence in the cytosol heralds a potential threat. The cGAS-STING pathway is one of the most important cytosolic DNA sensing pathways and leads to interferon signaling, inflammasome activation, autophagy, and cell death. While STING signaling is protective at physiologic levels, chronic activation of this pathway can instead drive autoinflammation and autoimmunity. Here we discuss several monogenic disorders of the STING pathway that highlight its impact on both innate and adaptive immunity in the progressive loss of tolerance. The potential relevance of STING signaling in systemic lupus erythematosus is then discussed with a focus on future avenues for monitoring and targeting this pathway.
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22
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Boz V, Zanchi C, Levantino L, Riccio G, Tommasini A. Druggable monogenic immune defects hidden in diverse medical specialties: Focus on overlap syndromes. World J Clin Pediatr 2022; 11:136-150. [PMID: 35433297 PMCID: PMC8985491 DOI: 10.5409/wjcp.v11.i2.136] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/03/2021] [Accepted: 01/08/2022] [Indexed: 02/06/2023] Open
Abstract
In the last two decades two new paradigms changed our way of perceiving primary immunodeficiencies: An increasing number of immune defects are more associated with inflammatory or autoimmune features rather than with infections. Some primary immune defects are due to hyperactive pathways that can be targeted by specific inhibitors, providing innovative precision treatments that can change the natural history of diseases. In this article we review some of these “druggable” inborn errors of immunity and describe how they can be suspected and diagnosed in diverse pediatric and adult medicine specialties. Since the availability of precision treatments can dramatically impact the course of these diseases, preventing the development of organ damage, it is crucial to widen the awareness of these conditions and to provide practical hints for a prompt detection and cure.
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Affiliation(s)
- Valentina Boz
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34137, Italy
| | - Chiara Zanchi
- Department of Pediatrics, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste 34137, Italy
| | - Laura Levantino
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34137, Italy
| | - Guglielmo Riccio
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34137, Italy
| | - Alberto Tommasini
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34137, Italy
- Department of Pediatrics, Institute for Maternal and Child Health, IRCCS Burlo Garofolo, Trieste 34137, Italy
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Management of a Novel Autoimmune Disease, COPA Syndrome, in Pregnancy. Case Rep Obstet Gynecol 2022; 2022:4865985. [PMID: 35284147 PMCID: PMC8906991 DOI: 10.1155/2022/4865985] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 01/26/2022] [Accepted: 02/14/2022] [Indexed: 11/17/2022] Open
Abstract
Background COPA syndrome is a rare autoimmune disease, demonstrating an autosomal dominant inheritance pattern with variable penetration that occurs more frequently in females than males. This disease manifests in childhood as pulmonary hemorrhage, arthritis, and renal disease. Case We present a case of obstetric management of a 20-year-old nulligravida patient with a diagnosis of COPA syndrome. Her case was further complicated by multiple antepartum admissions for hypoxemia and a complex psychosocial history of substance use. On her first antepartum admission, rheumatology recommended management with hydroxychloroquine, inhaled corticosteroids (budesonide), and bronchodilators (albuterol inhaler) as needed. On admission for induction of labor, she was again noted to have oxygen desaturations. A chronic thrombus was noted on computed tomography (CT), and a multidisciplinary team was recommended against Valsalva. Thus, she had a primary cesarean delivery. Her postpartum course was only remarkable for improved oxygenation status. Conclusion Management of COPA syndrome should be performed by a multidisciplinary team including maternal-fetal medicine, rheumatology, and pulmonology specialists. Traditionally, COPA syndrome is treated with immunomodulator therapy often used to treat autoimmune syndromes. However, many of these medications are not well studied or contraindicated in pregnancy. Preconception counseling is recommended both to ensure pregnancy safe medications being prescribed and to provide information on the genetic inheritance of this disease. At time of entry to care, patients should have a baseline work-up including a radiographic imaging, complete blood count, complete metabolic panel, lactate dehydrogenase, and a 24-hour urine protein collection for baseline. Although thought to be rare, COPA syndrome has an autosomal dominance pattern of inheritance with variable penetrance that is more common in females. Thus, incidence of COPA syndrome in pregnancy will likely increase in the future. Further case studies are warranted to optimize management of patients with COPA syndrome in pregnancy.
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Bai W, Wang R, Shen M, Li M, Zeng X. A 16-year-old Boy with Arthritis, Rash, and Hemoptysis: Beyond "Undifferentiated Connective Tissue Disease"? RHEUMATOLOGY AND IMMUNOLOGY RESEARCH 2022; 3:46-50. [PMID: 36467020 PMCID: PMC9524812 DOI: 10.2478/rir-2022-0008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Accepted: 02/16/2022] [Indexed: 06/17/2023]
Affiliation(s)
- Wei Bai
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science and Technology, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Beijing, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Rongrong Wang
- McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
| | - Min Shen
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science and Technology, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Beijing, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Mengtao Li
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science and Technology, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Beijing, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
| | - Xiaofeng Zeng
- Department of Rheumatology and Clinical Immunology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Ministry of Science and Technology, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital (PUMCH), Beijing, China
- Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, China
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Hadjadj J, Frémond ML, Neven B. Emerging Place of JAK Inhibitors in the Treatment of Inborn Errors of Immunity. Front Immunol 2021; 12:717388. [PMID: 34603291 PMCID: PMC8484879 DOI: 10.3389/fimmu.2021.717388] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 08/25/2021] [Indexed: 12/27/2022] Open
Abstract
Among inborn errors of immunity (IEIs), some conditions are characterized by inflammation and autoimmunity at the front line and are particularly challenging to treat. Monogenic diseases associated with gain-of-function mutations in genes critical for cytokine signaling through the JAK-STAT pathway belong to this group. These conditions represent good candidates for treatment with JAK inhibitors. Type I interferonopathies, a group of recently identified monogenic auto-inflammatory diseases characterized by excessive secretion of type I IFN, are also good candidates with growing experiences reported in the literature. However, many questions remain regarding the choice of the drug, the dose (in particular in children), the efficacy on the various manifestations, the monitoring of the treatment, and the management of potent side effects in particular in patients with infectious susceptibility. This review will summarize the current experiences reported and will highlight the unmet needs.
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Affiliation(s)
- Jérôme Hadjadj
- Department of Internal Medicine, National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital Cochin, APHP-Centre Université de Paris (CUP), Paris, France
- Université de Paris, Institut Imagine, INSERMU1163, Laboratory of Immunogenetics of Pediatric Autoimmuninity, Paris, France
| | - Marie-Louise Frémond
- Pediatric Hematology-Immunology and Rheumatology Department, APHP-Centre Université de Paris (CUP), Necker Hospital, Paris, France
- Université de Paris, Institut Imagine, Laboratory of Neurogenetics and Neuroinflammation, Paris, France
| | - Bénédicte Neven
- Université de Paris, Institut Imagine, INSERMU1163, Laboratory of Immunogenetics of Pediatric Autoimmuninity, Paris, France
- Pediatric Hematology-Immunology and Rheumatology Department, APHP-Centre Université de Paris (CUP), Necker Hospital, Paris, France
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Nigrovic PA, Lee PY, Hoffman HM. Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach. J Allergy Clin Immunol 2021; 146:925-937. [PMID: 33160483 DOI: 10.1016/j.jaci.2020.08.017] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 08/04/2020] [Accepted: 08/11/2020] [Indexed: 02/06/2023]
Abstract
Autoinflammatory diseases are conditions in which pathogenic inflammation arises primarily through antigen-independent hyperactivation of immune pathways. First recognized just over 2 decades ago, the autoinflammatory disease spectrum has expanded rapidly to include more than 40 distinct monogenic conditions. Related mechanisms contribute to common conditions such as gout and cardiovascular disease. Here, we review the basic concepts underlying the "autoinflammatory revolution" in the understanding of immune-mediated disease and introduce major categories of monogenic autoinflammatory disorders recognized to date, including inflammasomopathies and other IL-1-related conditions, interferonopathies, and disorders of nuclear factor kappa B and/or aberrant TNF activity. We highlight phenotypic presentation as a reflection of pathogenesis and outline a practical approach to the evaluation of patients with suspected autoinflammation.
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Affiliation(s)
- Peter A Nigrovic
- Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Boston, Mass; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Mass.
| | - Pui Y Lee
- Division of Immunology, Boston Children's Hospital, Department of Pediatrics, Boston, Mass; Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Mass
| | - Hal M Hoffman
- Division of Pediatric Allergy, Immunology, and Rheumatology, Rady Children's Hospital and University of California at San Diego, San Diego, Calif
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Frémond ML, Crow YJ. STING-Mediated Lung Inflammation and Beyond. J Clin Immunol 2021; 41:501-514. [PMID: 33532887 DOI: 10.1007/s10875-021-00974-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/18/2021] [Indexed: 02/07/2023]
Abstract
Mendelian autoinflammatory diseases characterized by constitutive activation of the type I interferon pathway, the so-called type I interferonopathies, constitute a rapidly expanding group of inborn errors of immunity. Among the type I interferonopathies, STING-associated vasculopathy with onset in infancy (SAVI) and COPA syndrome were described in the last 6 years, both manifesting a major inflammatory lung component associated with significant morbidity and increased mortality. There is striking clinical and histopathological overlap between SAVI and COPA syndrome, although distinct features are also present. Of note, there is a remarkably high frequency of clinical non-penetrance among individuals harboring pathogenic COPA mutations. SAVI is caused by, principally heterozygous, gain-of-function mutations in STING1 (previously referred to as TMEM173) encoding STING, a key adaptor of the interferon signaling pathway induced by DNA. COPA syndrome results from heterozygous dominant-negative mutations in the coatomer protein subunit alpha, forming part of a complex involved in intracellular cargo protein transport between the Golgi and the endoplasmic reticulum (ER). Of importance, a role for COPA in regulating the trafficking of STING, an ER-resident protein which translocates to the Golgi during the process of its activation, was recently defined, thereby possibly explaining some aspects of the phenotypic overlap between SAVI and COPA syndrome. Here, we review the expanding phenotype of these diseases, highlighting common as well as specific features, and recent advances in our understanding of STING biology that have informed therapeutic decision-making in both conditions. Beyond these rare Mendelian disorders, DNA sensing through STING is likely relevant to the pathology of several diseases associated with lung inflammation, including systemic lupus erythematosus, dermatomyositis, environmental toxin exposure, and viral infection.
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Affiliation(s)
- Marie-Louise Frémond
- Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, 24 boulevard du Montparnasse, F-75015, Paris, France. .,Paediatric Haematology-Immunology and Rheumatology Unit, AP-HP, Necker Hospital, F-75015, Paris, France.
| | - Yanick J Crow
- Université de Paris, Imagine Institute, Laboratory of Neurogenetics and Neuroinflammation, 24 boulevard du Montparnasse, F-75015, Paris, France.,Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, Edinburgh, UK
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Zeng J, Hao J, Zhou W, Zhou Z, Miao H. A Novel Mutation c.841C>T in COPA Syndrome of an 11-Year-Old Boy: A Case Report and Short Literature Review. Front Pediatr 2021; 9:773112. [PMID: 34900872 PMCID: PMC8654191 DOI: 10.3389/fped.2021.773112] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 10/18/2021] [Indexed: 01/22/2023] Open
Abstract
COPA syndrome is a rare autosomal dominant disorder with auto-immune and auto-inflammatory abnormalities. This disease is caused by mutations of COPα, a protein that functions in the retrograde transport from the Golgi to the ER. Here we report the first COPA case of an 11-year-old boy with c.841C>T, p.R281W mutation. The arginine at position 281 was located in a highly evolutionary-conserved region. Immunosuppressive drugs and corticosteroids might not improve the long-term outcome of COPA patients. For patients with pulmonary disease, polyarthritis and/or kidney disorder, and suspected of COPA, genetic analysis should be conducted promptly for early diagnosis.
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Affiliation(s)
- Jingxia Zeng
- Department of Emergency Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Jing Hao
- Department of Emergency Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Zhou
- Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Zhaoqun Zhou
- Department of Emergency Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China
| | - Hongjun Miao
- Department of Emergency Medicine, Children's Hospital of Nanjing Medical University, Nanjing, China
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29
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Deng Z, Chong Z, Law CS, Mukai K, Ho FO, Martinu T, Backes BJ, Eckalbar WL, Taguchi T, Shum AK. A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome. J Exp Med 2020; 217:e20201045. [PMID: 32725126 PMCID: PMC7596814 DOI: 10.1084/jem.20201045] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 07/07/2020] [Accepted: 07/08/2020] [Indexed: 12/21/2022] Open
Abstract
Pathogenic COPA variants cause a Mendelian syndrome of immune dysregulation with elevated type I interferon signaling. COPA is a subunit of coat protein complex I (COPI) that mediates Golgi to ER transport. Missense mutations of the COPA WD40 domain impair binding and sorting of proteins targeted for ER retrieval, but how this causes disease remains unknown. Given the importance of COPA in Golgi-ER transport, we speculated that type I interferon signaling in COPA syndrome involves missorting of STING. We show that a defect in COPI transport causes ligand-independent activation of STING. Furthermore, SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi. Activated STING stimulates type I interferon-driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals. Our results demonstrate that COPA maintains immune homeostasis by regulating STING transport at the Golgi. In addition, activated STING contributes to immune dysregulation in COPA syndrome and may be a new molecular target in treating the disease.
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Affiliation(s)
- Zimu Deng
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Zhenlu Chong
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Christopher S. Law
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Kojiro Mukai
- Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Frances O. Ho
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Tereza Martinu
- Toronto Lung Transplant Program, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Bradley J. Backes
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Walter L. Eckalbar
- Department of Medicine, University of California, San Francisco, San Francisco, CA
| | - Tomohiko Taguchi
- Laboratory of Organelle Pathophysiology, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan
| | - Anthony K. Shum
- Department of Medicine, University of California, San Francisco, San Francisco, CA
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA
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Perrin J, Roux N, Maurier F. Coatomer-associated protein subunit alpha syndrome: abnormal trafficking between the Golgi complex and the endoplasmic reticulum. BMJ Case Rep 2020; 13:13/11/e231553. [PMID: 33139352 DOI: 10.1136/bcr-2019-231553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
A 25-year-old woman with a history of juvenile idiopathic arthritis and rheumatoid factor-positive polyarthritis developed dyspnoea. Progressive cystic lung disease was diagnosed. Biomarkers of autoimmunity, such as antinuclear antibodies, antiextractable nuclear antigen antibodies, anti-SCL-70, rheumatoid factor, cyclic citrullinated peptide antibodies, c-antineutrophil cytoplasmic antibody and MPO, were found. No familial disease was reported. Despite lack of kidney manifestations, coatomer-associated protein subunit alpha syndrome was suggested. Type 1 interferon signature score was 40.8 (range, <2.3). A class 4 heterozygous mutation (c.725T>G, p.Val242Gly) was confirmed. Due to abnormal trafficking between the Golgi complex and the endoplasmic reticulum, a Mendelian monogenic autosomal dominant syndrome associating inflammatory arthritis with interstitial lung disease, with several high-titre autoantibodies, was identified. Treatment with tyrosine kinase inhibitors, Janus kinases-signal transducers and activators of transduction, may be beneficial.
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Affiliation(s)
- Julie Perrin
- Pneumology, Groupe Hospitalier UNEOS, Metz, Grand Est, France
| | - Nicolas Roux
- Rheumatology, Groupe Hospitalier UNEOS, Metz, Grand Est, France
| | - François Maurier
- Médecine Interne, Groupe Hospitalier UNEOS, Metz, Grand Est, France
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31
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Lepelley A, Martin-Niclós MJ, Le Bihan M, Marsh JA, Uggenti C, Rice GI, Bondet V, Duffy D, Hertzog J, Rehwinkel J, Amselem S, Boulisfane-El Khalifi S, Brennan M, Carter E, Chatenoud L, Chhun S, Coulomb l’Hermine A, Depp M, Legendre M, Mackenzie KJ, Marey J, McDougall C, McKenzie KJ, Molina TJ, Neven B, Seabra L, Thumerelle C, Wislez M, Nathan N, Manel N, Crow YJ, Frémond ML. Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling. J Exp Med 2020; 217:e20200600. [PMID: 32725128 PMCID: PMC7596811 DOI: 10.1084/jem.20200600] [Citation(s) in RCA: 139] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/04/2020] [Accepted: 07/06/2020] [Indexed: 01/01/2023] Open
Abstract
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.
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Affiliation(s)
- Alice Lepelley
- Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Paris, France
| | | | - Melvin Le Bihan
- Immunity and Cancer Department, Institut Curie, Paris-Sciences-et-Lettres Research University, Institut National de la Santé et de la Recherche Médicale U932, Paris, France
| | - Joseph A. Marsh
- Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
| | - Carolina Uggenti
- Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
| | - Gillian I. Rice
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK
| | - Vincent Bondet
- Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France
- Institut National de la Santé et de la Recherche Médicale U1223, Paris, France
| | - Darragh Duffy
- Immunobiology of Dendritic Cells, Institut Pasteur, Paris, France
- Institut National de la Santé et de la Recherche Médicale U1223, Paris, France
| | - Jonny Hertzog
- Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Jan Rehwinkel
- Medical Research Council Human Immunology Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Serge Amselem
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale/UMRS_933, Trousseau University Hospital, Paris, France
- Genetics Department, Trousseau University Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Paris, France
| | - Siham Boulisfane-El Khalifi
- Emergency, Infectious Disease and Pediatric Rheumatology Department, Centre Hospitalier Régional Universitaire Lille, University of Lille, Lille, France
| | - Mary Brennan
- Department of Paediatric Rheumatology, Royal Hospital for Sick Children, Edinburgh, UK
| | - Edwin Carter
- Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
| | - Lucienne Chatenoud
- Paris Descartes University, Université de Paris, Sorbonne-Paris-Cité, Paris, France
- Laboratory of Immunology, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, Centre-Université de Paris, Paris, France
- Institut Necker-Enfants Malades, Centre National de la Recherche Scientifique UMR8253, Institut National de la Santé et de la Recherche Médicale UMR1151, Team Immunoregulation and Immunopathology, Paris, France
| | - Stéphanie Chhun
- Paris Descartes University, Université de Paris, Sorbonne-Paris-Cité, Paris, France
- Laboratory of Immunology, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, Centre-Université de Paris, Paris, France
- Institut Necker-Enfants Malades, Centre National de la Recherche Scientifique UMR8253, Institut National de la Santé et de la Recherche Médicale UMR1151, Team Immunoregulation and Immunopathology, Paris, France
| | - Aurore Coulomb l’Hermine
- Pathology Department, Trousseau University Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Paris, France
| | - Marine Depp
- Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
| | - Marie Legendre
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale/UMRS_933, Trousseau University Hospital, Paris, France
- Genetics Department, Trousseau University Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Paris, France
| | - Karen J. Mackenzie
- Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
| | - Jonathan Marey
- Pneumology Department, Cochin Hospital, Assistance Publique–Hôpitaux de Paris, Centre-Université de Paris, Paris, France
| | - Catherine McDougall
- Department of Paediatric Respiratory Medicine, Royal Hospital for Sick Children, Edinburgh, UK
| | - Kathryn J. McKenzie
- Paediatric Pathology Department, Royal Infirmary of Edinburgh, Edinburgh, UK
| | - Thierry Jo Molina
- Paris Descartes University, Université de Paris, Sorbonne-Paris-Cité, Paris, France
- Pathology Department, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, Centre-Université de Paris, Paris, France
| | - Bénédicte Neven
- Paris Descartes University, Université de Paris, Sorbonne-Paris-Cité, Paris, France
- Pediatric Hematology-Immunology and Rheumatology Department, Hôpital Necker-Enfants Malades, Assistance Publique–Hôpitaux de Paris, Centre-Université de Paris, Paris, France
- Institut National de la Santé et de la Recherche Médicale UMR 1163, Laboratory of Immunogenetics of Paediatric Autoimmunity, Imagine Institute, Paris, France
| | - Luis Seabra
- Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Paris, France
| | - Caroline Thumerelle
- Pediatric Pneumology Department, Hôpital Jeanne de Flandre, Centre Hospitalier Régional Universitaire Lille, Lille, France
| | - Marie Wislez
- Pneumology Department, Cochin Hospital, Assistance Publique–Hôpitaux de Paris, Centre-Université de Paris, Paris, France
- Cordeliers Research Center, Université Paris Descartes, Université de Paris, UMRS1138 Inflammation, Complement and Cancer Team, Paris, France
| | - Nadia Nathan
- Sorbonne Université, Institut National de la Santé et de la Recherche Médicale/UMRS_933, Trousseau University Hospital, Paris, France
- Pediatric Pulmonology Department and Reference Center for Rare Lung Disease RespiRare, Trousseau University Hospital, Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Paris, France
| | - Nicolas Manel
- Immunity and Cancer Department, Institut Curie, Paris-Sciences-et-Lettres Research University, Institut National de la Santé et de la Recherche Médicale U932, Paris, France
| | - Yanick J. Crow
- Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Paris, France
- Centre for Genomic and Experimental Medicine, Medical Research Council Institute of Genetics and Molecular Medicine, The University of Edinburgh, Edinburgh, UK
| | - Marie-Louise Frémond
- Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, Paris, France
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32
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Sawalha AH. Pediatric rheumatology: A special issue from the European Journal of Rheumatology. Eur J Rheumatol 2020; 7:S1-S2. [PMID: 35929858 PMCID: PMC7004264 DOI: 10.5152/eurjrheum.2020.090120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2023] Open
Affiliation(s)
- Amr H. Sawalha
- Division of Rheumatology, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
- Lupus Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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