Glucose oxidation-dependent survival of activated B cells provides a putative novel therapeutic target for lupus treatment
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
Affiliations
John J. Wilson
The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA
Jian Wei
The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China
Andrea R. Daamen
AMPEL BioSolutions and the RILITE Research Institute, Charlottesville, VA 22902, USA
John D. Sears
The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA
Elaine Bechtel
The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA
Colleen L. Mayberry
The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA
Grace A. Stafford
The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA
Lesley Bechtold
The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA
Amrie C. Grammer
AMPEL BioSolutions and the RILITE Research Institute, Charlottesville, VA 22902, USA
Peter E. Lipsky
AMPEL BioSolutions and the RILITE Research Institute, Charlottesville, VA 22902, USA
Derry C. Roopenian
The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA
Chih-Hao Chang
The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA; Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA; Corresponding author
Summary: 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.
