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SDHA gain-of-function engages inflammatory mitochondrial retrograde signaling via KEAP1-Nrf2.

Nature immunology (2019-09-19)
Anne-Valérie Burgener, Glenn R Bantug, Benedikt J Meyer, Rebecca Higgins, Adhideb Ghosh, Olivier Bignucolo, Eric H Ma, Jordan Loeliger, Gunhild Unterstab, Marco Geigges, Rebekah Steiner, Michel Enamorado, Robert Ivanek, Danielle Hunziker, Alexander Schmidt, Bojana Müller-Durovic, Jasmin Grählert, Raja Epple, Sarah Dimeloe, Jonas Lötscher, Ursula Sauder, Monika Ebnöther, Bettina Burger, Ingmar Heijnen, Sarai Martínez-Cano, Nathan Cantoni, Rolf Brücker, Christian R Kahlert, David Sancho, Russell G Jones, Alexander Navarini, Mike Recher, Christoph Hess

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.

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Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone, ≥98% (TLC), powder
2-Deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose, ≥97% (HPLC)
Allyl methyl sulfone, 96%
MISSION® esiRNA, targeting human SDHA

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