Oded Breuer1, Hagit Daum2, Malena Cohen-Cymberknoh3, Susanne Unger4, David Shoseyov3, Polina Stepensky5, Baerbel Keller6, Klaus Warnatz6, Eitan Kerem3. 1. Department of Pediatrics and Pediatric Pulmonary Unit, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. Electronic address: odedbr@hadassah.org.il. 2. Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. 3. Department of Pediatrics and Pediatric Pulmonary Unit, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. 4. Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; University of Freiburg, Faculty of Biology, Schaenzlestrasse 1, 79104 Freiburg, Germany. 5. Department of Pediatric Hematology-Oncology and Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. 6. Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Abstract
BACKGROUND: In a substantial number of patients with non-cystic fibrosis (CF) bronchiectasis an etiology cannot be found. Various complex immunodeficiency syndromes account for a significant portion of these patients but the mechanism elucidating the predisposition for suppurative lung disease often remains unknown. OBJECTIVE: To investigate the cause and mechanism predisposing a patient to severe bronchiectasis. METHODS: A patient presenting with severe non-CF bronchiectasis was investigated. Whole exome analysis (WES) was performed and complemented by extensive immunophenotyping. RESULTS: The genetic analysis revealed an autosomal dominant gain-of-function mutation (AD- GOF) in the signal transducer and activator of transcription 1 (STAT1) in the patient. STAT1 phosphorylation studies showed increased phosphorylation of STAT1 after stimulation with interferon γ (IFN-γ). Immunophenotyping showed normal counts of CD4 and CD8 T cells, B and NK cells, but a reduction of all memory B cells especially class switched memory B cells. Minor changes in the CD8 T cell subpopulations were seen. CONCLUSIONS: Early use of WES in the investigation of non-CF bronchiectasis was highly advantageous. The degree of impairment in class-switched memory B cells may predispose patients with AD- GOF mutations in STAT1 to suppurative sinopulmonary disease.
BACKGROUND: In a substantial number of patients with non-cystic fibrosis (CF) bronchiectasis an etiology cannot be found. Various complex immunodeficiency syndromes account for a significant portion of these patients but the mechanism elucidating the predisposition for suppurative lung disease often remains unknown. OBJECTIVE: To investigate the cause and mechanism predisposing a patient to severe bronchiectasis. METHODS: A patient presenting with severe non-CF bronchiectasis was investigated. Whole exome analysis (WES) was performed and complemented by extensive immunophenotyping. RESULTS: The genetic analysis revealed an autosomal dominant gain-of-function mutation (AD- GOF) in the signal transducer and activator of transcription 1 (STAT1) in the patient. STAT1 phosphorylation studies showed increased phosphorylation of STAT1 after stimulation with interferon γ (IFN-γ). Immunophenotyping showed normal counts of CD4 and CD8 T cells, B and NK cells, but a reduction of all memory B cells especially class switched memory B cells. Minor changes in the CD8 T cell subpopulations were seen. CONCLUSIONS: Early use of WES in the investigation of non-CF bronchiectasis was highly advantageous. The degree of impairment in class-switched memory B cells may predispose patients with AD- GOF mutations in STAT1 to suppurative sinopulmonary disease.
Authors: James E D Thaventhiran; Hana Lango Allen; Oliver S Burren; William Rae; Daniel Greene; Emily Staples; Zinan Zhang; James H R Farmery; Ilenia Simeoni; Elizabeth Rivers; Jesmeen Maimaris; Christopher J Penkett; Jonathan Stephens; Sri V V Deevi; Alba Sanchis-Juan; Nicholas S Gleadall; Moira J Thomas; Ravishankar B Sargur; Pavels Gordins; Helen E Baxendale; Matthew Brown; Paul Tuijnenburg; Austen Worth; Steven Hanson; Rachel J Linger; Matthew S Buckland; Paula J Rayner-Matthews; Kimberly C Gilmour; Crina Samarghitean; Suranjith L Seneviratne; David M Sansom; Andy G Lynch; Karyn Megy; Eva Ellinghaus; David Ellinghaus; Silje F Jorgensen; Tom H Karlsen; Kathleen E Stirrups; Antony J Cutler; Dinakantha S Kumararatne; Anita Chandra; J David M Edgar; Archana Herwadkar; Nichola Cooper; Sofia Grigoriadou; Aarnoud P Huissoon; Sarah Goddard; Stephen Jolles; Catharina Schuetz; Felix Boschann; Paul A Lyons; Matthew E Hurles; Sinisa Savic; Siobhan O Burns; Taco W Kuijpers; Ernest Turro; Willem H Ouwehand; Adrian J Thrasher; Kenneth G C Smith Journal: Nature Date: 2020-05-06 Impact factor: 49.962
Authors: Menno C van Zelm; Julian J Bosco; Pei M Aui; Samuel De Jong; Fiona Hore-Lacy; Robyn E O'Hehir; Robert G Stirling; Paul U Cameron Journal: Front Immunol Date: 2019-04-24 Impact factor: 7.561
Authors: Paula Teixeira Lyra; Ana Carla Augusto Moura Falcão; Rafael Amora Cruz; Antonio Victor Campos Coelho; Edvaldo da Silva Souza; Luiz Claudio Arraes de Alencar; João Bosco Oliveira Journal: Einstein (Sao Paulo) Date: 2022-09-12