Autosomal dominant gain of function STAT1 mutation and severe bronchiectasis. (May 2017)

• Record Type: Journal Article
• Authors: Breuer, Oded; Daum, Hagit; Cohen-Cymberknoh, Malena; Unger, Susanne; Shoseyov, David; Stepensky, Polina; Keller, Baerbel; Warnatz, Klaus; Kerem, Eitan
• Is Part Of: Respiratory medicine. Volume 126(2017)
• Page Start: 39
• Page End: 45
• Publication Date: 2017-05
• Subjects: Bronchiectasis -- Chronic mucocutaneous candidiasis -- Autosomal dominant gain-of-function STAT1 mutations (AD-GOF STAT1 mutations) -- Memory B cells; Chest -- Diseases -- Periodicals; Chest -- Diseases -- Great Britain -- Periodicals; Respiratory organs -- Diseases -- Periodicals; Respiratory Tract Diseases -- Periodicals; Appareil respiratoire -- Maladies -- Périodiques; Thorax -- Maladies -- Périodiques; Appareil respiratoire -- Maladies -- Traitement -- Périodiques; Electronic journals; 616.2
• DOI: 10.1016/j.rmed.2017.03.018
• Languages: English
• ISSNs: 0954-6111

Abstract

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. Highlights: AD-GOF mutations in STAT1 may cause sinopulmonary disease in a subset of patients. Impairment in class-switched memory B cells is present in these patients. The mechanism linking the B-cell dysfunction to the STAT1 mutation is unknown. The impairment in memory B cells may correlate to the sinopulmonary disease.