Abstract
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 pathogenesis. 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 spontaneous murine models of lupus and their responses to treatment with the glycolysis inhibitor 2- deoxyglucose (2DG) in drinking water. Therapeutic efficacy in terms of primary autoimmune-cell population sensitivity and survival after 2DG administration was assessed on BXSB.Yaa and NZBWF1 lupus-prone mice. Furthermore, a chimeric antigen receptor (CAR)-T cell approach 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 rates in spontaneous activated autoreactive B cells (AABC) closely resembling germinal center B (GCB) cells compared to those in follicular helper T (Tfh) cells. The differential dependency on glucose oxidation between GCB and Tfh cells was determined, rendering GCB cells highly susceptible to oxidative stress-induced apoptosis triggered by short-term glycolysis inhibition via 2DG. The treatment selectively targeted AABC/GCB cells with high glycolytic dependence, sparing other autoreactive populations, including Tfh cells with greater metabolic flexibility. This reduction of AABC/GCB cells is, in turn, linked with significantly reducing proteinuria and improving lifespan of treated mice. Moreover, we identified a subset of AABC/GCB cells, which express TNFSF17 and exhibit a higher reliance on glucose metabolism than TNFSF17- B cells. Their depletion through its ligand TNFSF13-based CAR-T treatment significantly decreased mortality in lupus-prone mice.
Conclusions Differential metabolic requirement for glucose between autoreactive AABC/GCB cells and Tfh cells dictates different sensitivity to apoptosis via glycolytic inhibition, and our data provide a metabolic niche for novel targeted lupus treatment. Combining therapies that selectively dampen AABC/GCB-cell metabolism 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.
Lay summary The primary metabolic adaptation of activating T and B cells is an increase in glucose metabolism. We found that autoreactive B cells have elevated consumption of glucose over other T or B cell types. Using murine models of lupus, we uncovered that treatment of lupus-prone mice with 2-deoxy- glucose, an inhibitor of glucose utilization, resulted in the preferential reduction of these pathogenic B cells. This reduction resulted in improving kidney function, and extending lifespan. We also used a T cell- based immunotherapy approach targeting a subset of these B cells and successfully reduce the mortality of lupus-prone mice. Overall, these results indicate the promise of two new and highly effective treatments for lupus via targeted removal of autoreactive B cells.
