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.
Hemolysis-associated phosphatidylserine exposure promotes polyclonal plasmablast differentiation
Disclosures: R.A. Brekken reported grants from OncXerna Therapeutics outside the submitted work and had a patent to PS-targeting antibodies licensed (OncXerna Therapeutics). No other disclosures were reported.
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Rahul Vijay, Jenna J. Guthmiller, Alexandria J. Sturtz, Sequoia Crooks, Jordan T. Johnson, Lei Li, Linda Yu-Ling Lan, Rosemary L. Pope, Yani Chen, Kai J. Rogers, Nirmal Dutta, Jason E. Toombs, Mary E. Wilson, Patrick C. Wilson, Wendy Maury, Rolf A. Brekken, Noah S. Butler; Hemolysis-associated phosphatidylserine exposure promotes polyclonal plasmablast differentiation. J Exp Med 7 June 2021; 218 (6): e20202359. doi: https://doi.org/10.1084/jem.20202359
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