Fig. 7: G6PD-d and B cells in ASCVD.
a B cell subsets can be atheroprotective (B1a, B1b, MZB) or proatherogenic (FoB). Atheroprotective B cells produce IgM to oxidation specific epitopes (IgMOSE). Proatherogenic FoB cells produce IgG (IgGOSE) which can form immune complexes with oxLDL that promote inflammatory macrophage responses or may sequester and clear oxLDL, depending on the IgG subclass and its receptor. In G6PD-d, plasma cell differentiation, IgMOSE and IgGOSE may all be reduced due to b impaired ROS production following BCR/TLR engagement and c impaired redox homeostasis inhibiting proper oxidative protein folding. d ROS may also inhibit BLIMP-1 expression, which is critical in promoting plasma differentiation and IgM production. e B1a and B1b cells require fatty acids (FA) to sustain self-renewal and survival. They acquire a significant proportion of FA through autophagy. However, in G6PD-d, deficient NADPH leads to reduced FA synthesis and accumulation of ROS due to insufficient GSH. ROS accumulation may then impair autophagy. Together, these factors may contribute to reduced self-renewal of important atheroprotective B cells. The increased ROS may also inhibit B1 migration to sites that support IgMOSE production (i.e. spleen). Lastly, ROS may disproportionately promote cell death or ferroptosis in atheroprotective B1 and MZB cells given these subsets are uniquely susceptible to lipid peroxidation compared to proatherogenic FoB cells.
