1208 Differential reliance on glucose oxidation by activated autoreactive B cells provides a novel target of therapeutic intervention (2022)

<h3>Background</h3> 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. <h3>Methods</h3> 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.<i>Yaa</i> 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. <h3>Results</h3> 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<sup>-</sup> B cells. Their depletion through its ligand TNFSF13-based CAR-T treatment significantly decreased mortality in lupus-prone mice. <h3>Conclusions</h3> 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. <h3>Acknowledgments</h3> We thank the funding resources from JAX Director Initiative Fund, the RILITE Foundation, and the John and Marcia Goldman Foundation. <h3>Lay summary</h3> 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.