fumarates and Lymphocytosis

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.

Topics: Anti-Inflammatory Agents; B-Lymphocytes; Cell Respiration; Cells, Cultured; Electron Transport Complex II; Exome Sequencing; 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