Multimeric antibodies from antigen-specific human IgM+ memory B cells restrict Plasmodium parasites

Abstract

Multimeric immunoglobulin-like molecules arose early in vertebrate evolution, yet the unique contributions of multimeric IgM antibodies to infection control are not well understood. This is partially due to the difficulty of distinguishing low-affinity IgM, secreted rapidly by plasmablasts, from high-affinity antibodies derived from later-arising memory cells. We developed a pipeline to express B cell receptors (BCRs) from Plasmodium falciparum–specific IgM+ and IgG+ human memory B cells (MBCs) as both IgM and IgG molecules. BCRs from both subsets were somatically hypermutated and exhibited comparable monomeric affinity. Crystallization of one IgM+ MBC-derived antibody complexed with antigen defined a linear epitope within a conserved Plasmodium protein. In its physiological multimeric state, this antibody displayed exponentially higher antigen binding than a clonally identical IgG monomer, and more effectively inhibited P. falciparum invasion. Forced multimerization of this IgG significantly improved both antigen binding and parasite restriction, underscoring how avidity can alter antibody function. This work demonstrates the potential of high-avidity IgM in both therapeutics and vaccines.

IgM+and IgM-memory B cells represent heterogeneous populations capable of producing class-switched antibodies and germinal center B cells upon re-challenge withP. yoelii

“…Alternatively, the multimeric shape of IgM may improve its avidity for binding Ag and thus enhance its ability to bind and restrict parasite invasion of host cells. 68…”

“…Although we found no evidence of rapid induction of IgM + MBCs into IgM-secreting cells, this does not diminish the potential importance of these cells to the recall response in humans. In particular, Ag-specific IgM + MBCs are identifiable in the blood of individuals from malaria-endemic regions, 38, 41, 67, 68 and they can produce IgM Abs capable of neutralizing and promoting opsonization. 67, 68 These Ag-specific IgM + MBCs were more abundant than their IgM - counterparts, even after years of repeated Plasmodium infections, 67 suggesting their capacity to play a protective role from severe disease and illustrating the inefficient acquisition of protective IgG responses against Plasmodium .…”

“…In particular, Ag-specific IgM + MBCs are identifiable in the blood of individuals from malaria-endemic regions, 38, 41, 67, 68 and they can produce IgM Abs capable of neutralizing and promoting opsonization. 67, 68 These Ag-specific IgM + MBCs were more abundant than their IgM - counterparts, even after years of repeated Plasmodium infections, 67 suggesting their capacity to play a protective role from severe disease and illustrating the inefficient acquisition of protective IgG responses against Plasmodium . Although, the reduced rate of somatically mutated BCRs in IgM + MBCs may make them better suited to recognize a broader range of variant P. falciparum Ags.…”

Cytolytic memory CD4+ T cell clonotypes are expanded during Plasmodium falciparum infection

“…Once merozoites are released from the liver to the blood circulation, which occurs within ~7 days in humans, parasite-specific antibodies (Abs), most notably IgG [33][34][35][36] but also IgM 37,38 , represent essential mediators of naturally acquired immunity. The production of parasite-specific protective Abs is a lengthy and complex process that may take years of endemic exposure to malaria, likely as a result of multiple negative regulatory mechanisms 39 .…”

A comparative analysis of memory B cell and antibody responses against Plasmodium falciparum merozoite surface protein 1 in children and adults from Uganda

“…This naturally acquired humoral immunity against malaria is associated with the presence of circulating immunoglobulin G (IgG) against Plasmodium blood stage antigens (6)(7)(8)(9)(10)(11)(12)(13). Recently, immunoglobulin M (IgM) has received increased attention as IgM responses were also shown to correlate with protection and were able to inhibit parasite growth in vitro (14)(15)(16). A complete understanding of the development of humoral immune responses against P. falciparum blood stage antigens over time will help with the development of a more effective and longer lasting vaccine than RTS,S.…”