Background Lupus is an autoimmune disease characterized by antibodies directed against nuclear components that induce immune complex-mediated injury to multiple organs. Underlying lupus is the induction of T-cell-dependent activation and clonal expansion of autoreactive B cells in germinal centers resulting in their differentiation into plasma cells that secrete pathogenic autoantibodies. Heightened glucose metabolism is inherent to immune/inflammatory disorders, but little is known of its role in lupus etiology. Present treatments for lupus rely heavily on broad-spectrum immunosuppressive agents, and there is a need for targeted therapies that effectively counteract this systemic autoimmune disorder.
Methods Here we examined the metabolic and gene expression profiles of key autoimmune populations in mouse models of spontaneous lupus and their responses to treatment with the glycolysis inhibitor 2-deoxyglucose (2DG) in drinking water. Therapeutic efficacy in terms of survival after long- vs. short-term 2DG-exposed times was assessed on BXSB.Yaa and NZBWF1 lupus-prone mice. Furthermore, a chimeric antigen receptor (CAR)-T immunotherapy was used to determine whether a targeted removal of an identified B cell subset can improve disease outcomes.
Results We found greater glucose uptake and glycolysis rate in spontaneous germinal center B cells (GCB) compared to that in follicular helper T cells (Tfh). The differential dependency on glucose oxidation between GCB and Tfh was determined, rendering GCB highly susceptible to oxidative stress-induced apoptosis triggered by glycolysis inhibition via 2DG. Short-term glycolytic inhibition selectively targeted GCB, sparing other autoreactive populations, including Tfh. This reduction of GCB is, in turn, responsible for improving kidney function and lifespan of treated mice. Moreover, we identified a subset of GCB, which express TNFSF17 and exhibit a higher reliance on glucose metabolism than TNFSF17- GCB. Their depletion through its ligand TNFSF13-based CAR-T treatment significantly decreased mortality from lupus.
Conclusions Differential metabolic requirement for glucose between autoreactive GCB and Tfh dictates different sensitivity to apoptosis via glycolytic inhibition, and this provides a metabolic niche for targeted lupus treatment. Combining therapies that selectively dampen GCB metabolism for survival with T cell-based immunotherapy could provide new effective treatments for lupus.
Acknowledgments We thank the funding resources from JAX Director Initiative Fund, the RILITE Foundation, and the John and Marcia Goldman Foundation.
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