G6PD deficiency decreases B cell production of IgM to oxidation specific neoepitopes and increases atherosclerosis 2260194

Abstract

Abstract Introduction Glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDdef) is the most common enzymopathy worldwide, resulting in impaired redox homeostasis and oxidative stress. Until now, no studies have primarily focused on the role of G6PDdef in lymphocytes. Given the importance of redox homeostasis in regulating B cells, this study sought to investigate how G6PDdef induced oxidative stress regulates B cell function in atherosclerosis. Methods To address this, we engineered novel humanized mice harboring the most common variant of G6PDdef in the US, the African variant (hG6PDA-) or the nondeficient human G6PD allele (hG6PDND) and induced oxidative stress through hyperlipidemia. Results To our knowledge, this is the first study to demonstrate that G6PDdef leads to a loss of G6PD enzymatic activity in B cells. Moreover, our study supports that hG6PDA- has functional effects on the humoral immune response as hyperlipidemic hG6PDA- mice had significantly reduced levels of IgM antibodies to oxidation specific neoepitopes (IgMOSE) compared to hG6PDND controls, along with increased atherosclerosis. Importantly, B cell G6PD enzymatic activity levels directly correlated with the number of IgMOSE antibody secreting cells. To determine if differences in IgMOSE in hG6PDA- mice were intrinsic to the B cell, we utilized a G6PD specific inhibitor (G6PDi-1) in-vitro on cultured peritoneal B cells. We found that in-vitro G6PD inhibition of B cells resulted in increased intracellular reactive oxygen species accumulation and reduced LPS-induced production of IgMOSE. In parallel, human B cells were treated with G6PDi-1 and we found that G6PD inhibition resulted in a significant reduction in the CPG-induced production of IgMOSE, indicating a conserved mechanism of G6PDdef impairing B cell function in both murine and human models. Conclusion Together, these data provide evidence that G6PD may act as a metabolic regulator of antibody production by B cells and demonstrate that hG6PDA- may promote atherosclerosis. Funding Source n/a Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)