Burgener, Anne-ValérieBantug, Glenn RMeyer, Benedikt JHiggins, RebeccaGhosh, AdhidebBignucolo, OlivierMa, Eric HLoeliger, JordanUnterstab, GunhildGeigges, MarcoSteiner, RebekahEnamorado, MichelIvanek, RobertHunziker, DanielleSchmidt, AlexanderMüller-Durovic, BojanaGrählert, JasminEpple, RajaDimeloe, SarahLötscher, JonasSauder, UrsulaEbnöther, MonikaBurger, BettinaHeijnen, IngmarMartínez-Cano, SaraiCantoni, NathanBrücker, RolfKahlert, Christian RSancho, DavidJones, Russell GNavarini, AlexanderRecher, MikeHess, Christoph2022-11-162022-11-162019Nat Immunol . 2019 Oct;20(10):1311-1321http://hdl.handle.net/20.500.12105/15163Whether 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.engAMhttp://creativecommons.org/licenses/by/4.0/Anti-Inflammatory AgentsB-LymphocytesCell RespirationCells, CulturedElectron Transport Complex IIFumaratesGlycolysisHumansInflammationInterleukin-6Kelch-Like ECH-Associated Protein 1LymphocytosisMitochondriaMutationNF-E2-Related Factor 2Oxygen ConsumptionProspective StudiesSignal TransductionWhole Exome SequencingAtribución 4.0 Internacional3152783320101311-132110.1038/s41590-019-0482-21529-2916Nature immunologyopen access