Hemolysis-associated phosphatidylserine exposure promotes polyclonal plasmablast differentiation

Antimalarial antibody responses are essential for mediating the clearance of Plasmodium parasite-infected RBCs from infected hosts. However, the rapid appearance of large numbers of plasmablasts in Plasmodium-infected hosts can suppress the development and function of durable humoral immunity. Here, we identify that the formation of plasmablast populations in Plasmodium-infected mice is mechanistically linked to both hemolysis-induced exposure of phosphatidylserine on damaged RBCs and inflammatory cues. We also show that virus and Trypanosoma infections known to trigger hemolytic anemia and high-grade inflammation also induce exuberant plasmablast responses. The induction of hemolysis or administration of RBC membrane ghosts increases plasmablast differentiation. The phosphatidylserine receptor Axl is critical for optimal plasmablast formation, and blocking phosphatidylserine limits plasmablast expansions and reduces Plasmodium parasite burden in vivo. Our findings support that strategies aimed at modulating polyclonal B cell activation and phosphatidylserine exposure may improve immune responses against Plasmodium parasites and potentially other infectious diseases that are associated with anemia.

Automated summary

This study uncovers the mechanistic link between hemolysis-induced exposure of phosphatidylserine on damaged RBCs and the formation of plasmablast populations in Plasmodium-infected hosts. Additionally, it shows that virus and Trypanosoma infections triggering hemolytic anemia and inflammation also induce exuberant plasmablast responses. Furthermore, targeting polyclonal B cell activation and phosphatidylserine exposure may enhance immune responses against Plasmodium parasites and other infectious diseases associated with anemia.