Glucose oxidation-dependent survival of activated B cells provides a putative novel therapeutic target for lupus treatment.
Document Type
Article
Publication Date
9-15-2023
Original Citation
Wilson J,
Wei J,
Daamen A,
Sears J,
Bechtel E,
Mayberry C,
Stafford G,
Bechtold L,
Grammer A,
Lipsky P,
Roopenian DC,
Chang C.
Glucose oxidation-dependent survival of activated B cells provides a putative novel therapeutic target for lupus treatment. iScience. 2023;26(9):107487
Keywords
JMG
JAX Source
iScience. 2023;26(9):107487
ISSN
2589-0042
PMID
37636066
DOI
https://doi.org/10.1016/j.isci.2023.107487
Grant
This work was funded by The Jackson Laboratory Director’s Innovation Fund (19000-18-19 and 19000-21-07) and the US Department of Defense (HT9425-23-1-0308) to CC, and supported by the RILITE Foundation, and the John and Marcia Goldman Foundation to PEL.
Abstract
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.