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

Abstract

IgG antibodies are known to play a central role in naturally acquired immunity to blood-stage malaria in humans, but little is known about the IgM response to blood-stage malaria, the mechanisms by which IgM may protect, or the underlying biology of Plasmodium falciparum (Pf)-specific IgM B cells. In a Mali cohort spanning infants to adults we conducted a longitudinal analysis of B cells specific for the Pf blood-stage antigens AMA1 and MSP1, as well as the comparator antigen influenza hemagglutinin (HA). At the uninfected baseline, before the malaria season, Pf-specific memory B cells (MBCs) in children are disproportionally IgM + and only gradually shift to IgG + with age, in contrast to HA-specific MBCs that are predominantly IgG + from infancy to adulthood. In response to acute febrile malaria, Pf-specific IgM B cells increase in frequency and upregulate activation and co-stimulatory markers. B cell receptor (BCR) analysis showed that Pf-specific IgM B cells are somatically hypermutated at levels comparable to HA-specific IgG B cells. Finally, IgM antibodies from the plasma of malaria-exposed individuals were comparable to IgG in inhibiting Pf blood-stage growth in vitro, and significantly better at enhancing phagocytosis of Pf merozoites, suggesting that IgM may protect through both direct neutralization and opsonization. Thus, somatically hypermutated Pf-specific IgM MBCs dominate in early life, are activated and expand during acute malaria and are associated with plasma IgM that inhibits parasite growth in vitro.

Microscopic and submicroscopic infection by Plasmodium falciparum: Immunoglobulin M and A profiles as markers of intensity and exposure

“…Indeed, Pf-specific IgM levels should be considered confident serological markers of malaria exposure. Although IgM has been associated by other authors with some protection against malaria given its effector role in complement fixation (Kurtovic et al, 2021), opsonic phagocytosis (Hopp et al, 2021), and clonal selection (Murugan et al, 2018), our data do not directly associate population levels of IgM with protection against the disease. However, it cannot be excluded that progressive exposure to the parasite with age and the associated increase in IgM levels in adults may have some degree of immunological functionality, as the lowest levels of parasitemia were the most frequent in the adult population, and precisely those uninfected adults showed the highest Pf-IgM levels of all age groups.…”

“…Regarding IgM, it has been described as a marker of malaria exposure in travelers (Orlandi-Pradines et al, 2006), and Plasmodium-specific IgM memory B cells are recognized as early responders to malaria re-infection providing a strategical protection barrier until IgG is generated (Krishnamurty et al, 2016). Moreover, IgM has been suggested to contribute to human parasite clearance (Boudin et al, 1993;Bolad et al, 2005;Arama et al, 2015;Boyle et al, 2019;Hopp et al, 2021;Kurtovic et al, 2021), which may highlight an underestimated role of IgM in protecting against the frequent malaria reinfections in endemic regions (Krishnamurty et al, 2016). On the other hand, IgA has been shown as an exposure marker in children (Duah et al, 2010) and induced by vaccination with human vaccine RTS,S/AS 01E (Suau et al, 2021).…”

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

“…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, 37,40,62 and they can produce IgM Abs capable of neutralizing and promoting opsonization. 62 These Ag-specific IgM + MBCs were more abundant than their swIg + counterparts, even after years of repeated Plasmodium infections, 62 Lastly, as markers used to identify MBC populations continue to be defined and their function and biological role on MBCs is deduced, the challenge will be to determine if human MBCs similarly express these markers and if they display a similar functional role.…”

“…In particular, Ag-specific IgM + MBCs are identifiable in the blood of individuals from malaria-endemic regions, 37,40,62 and they can produce IgM Abs capable of neutralizing and promoting opsonization. 62 These Ag-specific IgM + MBCs were more abundant than their swIg + counterparts, even after years of repeated Plasmodium infections, 62 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.…”

Plasmodium falciparum Malaria Vaccines and Vaccine Adjuvants

“…Although the role of IgG and its subclasses is significant in host to symptomatic malaria infection, the role of IgM must not be ignored. Particularly, the protective role of IgM against the blood-stage parasite of P. falciparum has been established [120][121][122].…”