Por favor, use este identificador para citar o enlazar este Item:http://hdl.handle.net/20.500.12105/15163
Título
SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2.
Autor(es)
Burgener, Anne-Valérie | Bantug, Glenn R | Meyer, Benedikt J | Higgins, Rebecca | Ghosh, Adhideb | Bignucolo, Olivier | Ma, Eric H | Loeliger, Jordan | Unterstab, Gunhild | Geigges, Marco | Steiner, Rebekah | Enamorado, Michel CNIC | Ivanek, Robert | Hunziker, Danielle | Schmidt, Alexander | Müller-Durovic, Bojana | Grählert, Jasmin | Epple, Raja | Dimeloe, Sarah | Lötscher, Jonas | Sauder, Ursula | Ebnöther, Monika | Burger, Bettina | Heijnen, Ingmar | Martínez-Cano, Sarai | Cantoni, Nathan | Brücker, Rolf | Kahlert, Christian R | Sancho, David CNIC | Jones, Russell G | Navarini, Alexander | Recher, Mike | Hess, Christoph
Fecha de publicación
2019
Cita
Nat Immunol . 2019 Oct;20(10):1311-1321
Idioma
Inglés
Tipo de documento
journal article
Resumen
Whether screening the metabolic activity of immune cells facilitates discovery of molecular pathology remains unknown. Here we prospectively screened the extracellular acidification rate as a measure of glycolysis and the oxygen consumption rate as a measure of mitochondrial respiration in B cells from patients with primary antibody deficiency. The highest oxygen consumption rate values were detected in three study participants with persistent polyclonal B cell lymphocytosis (PPBL). Exome sequencing identified germline mutations in SDHA, which encodes succinate dehydrogenase subunit A, in all three patients with PPBL. SDHA gain-of-function led to an accumulation of fumarate in PPBL B cells, which engaged the KEAP1-Nrf2 system to drive the transcription of genes encoding inflammatory cytokines. In a single patient trial, blocking the activity of the cytokine interleukin-6 in vivo prevented systemic inflammation and ameliorated clinical disease. Overall, our study has identified pathological mitochondrial retrograde signaling as a disease modifier in primary antibody deficiency.
MESH
Anti-Inflammatory Agents | B-Lymphocytes | Cell Respiration | Cells, Cultured | Electron Transport Complex II | Fumarates | Glycolysis | Humans | Inflammation | Interleukin-6 | Kelch-Like ECH-Associated Protein 1 | Lymphocytosis | Mitochondria | Mutation | NF-E2-Related Factor 2 | Oxygen Consumption | Prospective Studies | Signal Transduction | Whole Exome Sequencing
Versión en línea
DOI
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- Burgener et al postprint.pdf
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- Postprint