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Kurzfassung
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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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Zitation
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Burgener A V, Bantug G R, Meyer B J, Higgins R, Ghosh A, Bignucolo
O, Ma E H, Loeliger J, Unterstab G, Geigges M, Steiner R, Enamorado
M, Ivanek R, Hunziker D, Schmidt A, Müller-Durovic B, Grählert J,
Epple R, Dimeloe S, Lötscher J, Sauder U, Ebnöther M, Burger B,
Heijnen I, Martínez-Cano S, Cantoni N, Brücker R, Kahlert C R,
Sancho D, Jones R G, Navarini A, Recher M, Hess C. SDHA
gain-of-function engages inflammatory mitochondrial retrograde
signaling via KEAP1-Nrf2. Nat Immunol 2019; 20:1311-1321.
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