IgM in human immunity to Plasmodium falciparum malaria

Abstract

Most studies on human immunity to malaria have focused on the roles of immunoglobulin G (IgG), whereas the roles of IgM remain undefined. Analyzing multiple human cohorts to assess the dynamics of malaria-specific IgM during experimentally induced and naturally acquired malaria, we identified IgM activity against blood-stage parasites. We found that merozoite-specific IgM appears rapidly in Plasmodium falciparum infection and is prominent during malaria in children and adults with lifetime exposure, together with IgG. Unexpectedly, IgM persisted for extended periods of time; we found no difference in decay of merozoite-specific IgM over time compared to that of IgG. IgM blocked merozoite invasion of red blood cells in a complement-dependent manner. IgM was also associated with significantly reduced risk of clinical malaria in a longitudinal cohort of children. These findings suggest that merozoite-specific IgM is an important functional and long-lived antibody response targeting blood-stage malaria parasites that contributes to malaria immunity.

Plasmodium falciparum-specific IgM B cells dominate in children, expand with malaria and produce parasite inhibitory IgM

“…Several studies have reported Pf-specific IgM responses in malaria-exposed populations and in some cases have shown that these responses associate with protection from clinical malaria (9)(10)(11)(12)(13)(14)(15). For example, the malaria-resistant Fulani in West Africa have a higher breadth and magnitude of Pfspecific IgM compared to the more susceptible Dogon, whereas Pf-specific IgG did not distinguish the two groups (16,17).…”

“…For example, the malaria-resistant Fulani in West Africa have a higher breadth and magnitude of Pfspecific IgM compared to the more susceptible Dogon, whereas Pf-specific IgG did not distinguish the two groups (16,17). More recent studies showed that Pf-and P. vivax-specific IgM antibodies can mediate complement fixation (13,15), and that IgM from malaria-experienced individuals can inhibit Pf merozoite invasion in vitro in the presence of complement (15). Furthermore, merozoite-specific IgM antibodies correlated with protection from malaria in a longitudinal cohort of children (15).…”

Immunoglobulin M, more than just an early responder to malaria

“…In 2016, memory B cells producing IgM against malaria were reported in both mice and humans . Now, in a recent publication in Science Advances , Boyle et al . have significantly added to the weight of evidence supporting the role of IgM in both early and long‐lived immunity to malaria by examining the kinetics and function of the antibody response in humans (Figure b).…”

“…(b) In a new emerging paradigm of immunity against malaria, the IgM response is sustained and protects against infection long term. (c) Boyle et al . have recently shown that IgM prevents red blood cell invasion by fixing complement (blue) to the parasite (red), that IgM can persist for at least 1 year in humans after malaria infection and that IgM levels are associated with protection against clinical malaria.…”

“…The field of malaria vaccinology is ripe for approaches integrating systems serology with assays that probe antigen‐specific B cells to understand which components of humoral immunity are necessary and sufficient for achieving long‐lived sterilizing immunity. The work by Boyle et al . adds substantial weight to a new paradigm of a long‐lived functional IgM response against the merozoite blood stage that confers protection against clinical malaria in humans.…”