IgM, FcμRs, and Malarial Immune Evasion

Abstract

IgM is an ancestral Ab class found in all jawed vertebrates, from sharks to mammals. This ancient ancestry is shared by malaria parasites (genus Plasmodium) that infect all classes of terrestrial vertebrates with whom they coevolved. IgM, the least studied and most enigmatic of the vertebrate Igs, was recently shown to form an intimate relationship with the malaria parasite Plasmodium falciparum. In this article, we discuss how this association might have come about, building on the recently determined structure of the human IgM pentamer, and how this interaction could affect parasite survival, particularly in light of the just-discovered FcμR localized to B and T cell surfaces. Because this parasite may exploit an interaction with IgM to limit immune detection, as well as to manipulate the immune response when detected, a better understanding of this association may prove critical for the development of improved vaccines or vaccination strategies.

Investigating the function of Fc-specific binding of IgM toPlasmodium falciparumerythrocyte membrane protein 1 mediating erythrocyte rosetting

“…Several lines of evidence show that the interaction between non‐specific IgM and VAR2CSA‐type PfEMP1 involves the Cμ4 domain of IgM and the C‐terminal DBL domains in that type of PfEMP1 (Rasti et al ., ; Semblat et al ., ; Czajkowsky et al ., ; Barfod et al ., ). We found that antibodies specific for the IgM Cμ4 domain (and to a lesser extent Cμ3) inhibited binding of IgM to HB3VAR06 + IEs (Fig.…”

Mouse IgM Fc Receptor, FCMR, Promotes B Cell Development and Modulates Antigen-Driven Immune Responses

“…This role is exemplified by the finding that Sμ −/− mice respond poorly to infection with Cryptococcus neoformans (5). Interestingly, natural IgM is reported to bind malarial parasites and FCMR is implicated in innate immunity against malaria infection (47). …”

Evasion of immunity to Plasmodium falciparum malaria by IgM masking of protective IgG epitopes in infected erythrocyte surface-exposed PfEMP1

“…Nonspecific IgM binds to DBL4β in the PfEMP1 protein TM284var1 through residues in Cμ4 located in the armpit between two adjacent IgM monomers within the pentameric structure (17,18). It seems that this binding causes IgM to straddle TM284var1 in a manner that might stabilize the formation of rosettes around TM284var1 + IEs (17,25).…”

“…Furthermore, the detailed topology of the interaction of IgM-Cμ4 and VAR2CSA deserves attention, because it might provide additional clues relevant to vaccine development. Finally, it should be investigated whether the immunoevasive character of the interaction between nonspecific IgM and VAR2CSA also applies to the interaction between nonspecific IgM and rosetting PfEMP1 proteins, which are also mediated through IgM-Cμ4 (17), or whether that interaction serves other purposes (for example, by facilitating or stabilizing rosette formation) (17,18,25). We are currently pursuing all these leads.…”

“…Noticeably, rosette-forming PfEMP1 proteins (12) and CSA-adhering PfEMP1 proteins (13,14) share the ability to bind nonspecific IgM, although CSA-adhering IEs are not prone to rosette formation (15,16). Although the molecular details of the interaction between rosette-forming PfEMP1 proteins and nonspecific IgM are known in considerable detail (17), the biological significance of the nonspecific IgM binding to PfEMP1 in general, and to VAR2CSA in particular, is essentially unknown (18). Here, we present evidence that nonspecific IgM binding to VAR2CSA represents a hitherto unknown immunoevasive mechanism that allows the parasites to shield a functionally important protein from specific IgG-dependent immune attack without compromising its function or rendering IEs susceptible to destruction by complement-mediated lysis.…”