Differences in phenotype between long-lived memory B cells against Plasmodium falciparum merozoite antigens and variant surface antigens

by Raphael A. Reyes, Louise Turner, Isaac Ssewanyana, Prasanna Jagannathan, Margaret E. Feeney, Thomas Lavstsen, Bryan Greenhouse, Sebastiaan Bol, Evelien M. Bunnik

Plasmodium falciparum infections elicit strong humoral immune responses to two main groups of antigens expressed by blood-stage parasites: merozoite antigens that are involved in the erythrocyte invasion process and variant surface antigens that mediate endothelial sequestration of infected erythrocytes. Long-lived B cells against both antigen classes can be detected in the circulation for years after exposure, but have not been directly compared. Here, we studied the phenotype of long-lived memory and atypical B cells to merozoite antigens (MSP1 and AMA1) and variant surface antigens (the CIDRα1 domain of PfEMP1) in ten Ugandan adults before and after local reduction of P. falciparum transmission. After a median of 1.7 years without P. falciparum infections, the percentage of antigen-specific activated B cells declined, but long-lived antigen-specific B cells were still detectable in all individuals. The majority of MSP1/AMA1-specific B cells were CD95⁺CD11c⁺ memory B cells, which are primed for rapid differentiation into antibody-secreting cells, and FcRL5^-T-bet^- atypical B cells. On the other hand, most CIDRα1-specific B cells were CD95^-CD11c^- memory B cells. CIDRα1-specific B cells were also enriched among a subset of atypical B cells that seem poised for antigen presentation. These results point to differences in how these antigens are recognized or processed by the immune system and how P. falciparum-specific B cells will respond upon re-infection.