Mechanisms of glycolysis dependence of lupus antigen-specific B cells 4091

Description Differing metabolic requirements of autoreactive and non-autoreactive B cells could potentially be targeted by therapeutics to selectively inhibit autoantibody (autoAb) production in systemic lupus erythematosus. While glycolysis is not necessary for immunization-induced Ab production, it is required for autoAb production in mouse models of lupus. We used rheumatoid factor-specific AM14 BCR Tg B cells to dissect how glycolysis contributes to lupus autoreactive B cell activation. Pharmacologic inhibition of glycolysis with 2DG selectively decreased the differentiation of AM14 B cells into antibody-forming cells when transferred into mice treated with PL2-3 (the cognate Ag of AM14 B cells), but not R848 (a non-Ag-specific TLR7/8 agonist). 2DG induced transcriptional changes unique to the AM14 B cells of PL2-3-treated mice at both the gene and pathway levels, revealing downregulation of several pathways related to immune responses, including IFNα and IFNγ signaling, complement activation, and regulation of pathogen recognition receptor signaling. Pathways related to metabolism and signal transduction were also specifically downregulated in AM14 B cells of PL2-3-treated mice, including hypoxia, IL-2/STAT5, IL-6/JAK/STAT3, ERK, PI3K, and RAS protein signaling cascades. Ongoing work supports the existence of distinctive pathways regulated by glycolysis in autoAg-specific B cells, which in turn, regulate autoAb production. Funding Sources NIH R37AI128901 Topic Categories Basic Autoimmunity (BA)