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oai:repisalud.isciii.es:20.500.12105/151632024-09-27T09:30:19Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Burgener, Anne-Valérie author Bantug, Glenn R author Meyer, Benedikt J author Higgins, Rebecca author Ghosh, Adhideb author Bignucolo, Olivier author Ma, Eric H author Loeliger, Jordan author Unterstab, Gunhild author Geigges, Marco author Steiner, Rebekah author Enamorado, Michel author Ivanek, Robert author Hunziker, Danielle author Schmidt, Alexander author Müller-Durovic, Bojana author Grählert, Jasmin author Epple, Raja author Dimeloe, Sarah author Lötscher, Jonas author Sauder, Ursula author Ebnöther, Monika author Burger, Bettina author Heijnen, Ingmar author Martínez-Cano, Sarai author Cantoni, Nathan author Brücker, Rolf author Kahlert, Christian R author Sancho, David author Jones, Russell G author Navarini, Alexander author Recher, Mike author Hess, Christoph author 2019 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. Nat Immunol . 2019 Oct;20(10):1311-1321 http://hdl.handle.net/20.500.12105/15163 31527833 10.1038/s41590-019-0482-2 1529-2916 Nature immunology SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2.