Glucose oxidation-dependent survival of activated B cells provides a putative novel therapeutic target for lupus treatment

• DOI: 10.1016/j.isci.2023.107487
• Publication Date: 2023-07-27T17:41:57Z
• Authors: John J. Wilson; Jian Wei; Andrea R. Daamen; John D. Sears; Elaine Bechtel; Colleen L. Mayberry; Grace A. Stafford; Lesley Bechtold; Amrie C. Grammer; Peter E. Lipsky; Derry C. Roopenian; Chih-Hao Chang
• Keywords: Biological sciences; Cell biology; Model organism; Science; Immunology; Q; Transcriptomics; Article; 3. Good health; JMG

Aberrant metabolic demand is observed in immune/inflammatory disorders, yet the role in pathogenesis remains unclear. Here, we discover that in lupus, activated B cells, including germinal center B (GCB) cells, have remarkably high glycolytic requirement for survival over T cell populations, as demonstrated by increased metabolic activity in lupus-activated B cells compared to immunization-induced cells. The augmented reliance on glucose oxidation makes GCB cells vulnerable to mitochondrial ROS-induced oxidative stress and apoptosis. Short-term glycolysis inhibition selectively reduces pathogenic activated B in lupus-prone mice, extending their lifespan, without affecting T follicular helper cells. Particularly, BCMA-expressing GCB cells rely heavily on glucose oxidation. Depleting BCMA-expressing activated B cells with APRIL-based CAR-T cells significantly prolongs the lifespan of mice with severe autoimmune disease. These results reveal that glycolysis-dependent activated B and GCB cells, especially those expressing BCMA, are potentially key lupus mediators, and could be targeted to improve disease outcomes.