IgM, Fc mu Rs, 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 Fc mu R 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.

Fig 1. Contact areas of Fc with pathogen Fc-binding proteins

Ribbon diagrams of the IgM-Fc in complex with the DBL4β domain of the TM284var1 variant of PfEMP1 (left) and the IgG-Fc in complex with domain C2 of Staphylococcal Protein G (right). The structure of the IgM-DBLβ complex is described in Fig. 1. Both proteins bind at analogous positions in the inter-domain region of the immunoglobulin Fc.

Fig. 2. Homology-based model of the lgM-DBL4β complex

(A) The mushroom-shaped structure of IgM (white) is based on the known bent structure of IgE and direct cryo-AFM images (described in ref 30), and was left unaltered in the modelling with DBL4β. The novel homology model of TM284var1 DBL4β (blue) shown here is based on the known structures of members of the DBL family (,,,–64). The DBL4β domain was manually docked onto the IgM structure, taking heed of constraints described in the text. The top and middle panels show views of the lgM-DBL4β complex looking down onto the “protruding”-side of the IgM molecule and from the side, respectively. The residues in IgM identified in mutational analyses to be critical for binding to TMR284var1 DBL4β (Pro³⁹⁴-Pro³⁹⁷ and Pro⁴⁴⁴-Pro⁴⁴⁷ of the Cμ4 domain) are shown in orange (16). (B) Regions within sub-domain 2 of TM284 DBL4β (blue) and FCR3 DBL6ε (green) domains that directly interact with IgM (white). A pocket of charged residues found at the monomer-monomer interface of IgM (boxed inset) is directly adjacent to oppositely charged residues found in the DBL domain loops, suggesting a mechanism of association between members of the DBL protein family and human IgM molecules. Notice that the modeled TM284 DBL4β domain in this region has a much longer loop than in the FCR3 DBL6ε domain, yet this loop is found to be easily accommodated within the DBL-IgM interface, and with this interaction, furthers the apparent charge complementarity at this DBL-IgM interface.

Fig. 3. Possible functional consequences of the PfEMP1-lgM interaction

Shown are several potential IgM-effector associations that could be altered as a result of the known DBL-IgM interaction. As described more fully in the text, these include those with the recently identified FcµR protein found both in T cells, where it could play a role in mediating immunological synapse formation (A), and in B cells, where it is possibly involved in activating these cells through interactions with BCR (and CR1/2 (B)); the Fcα/µR protein predominantly localized to FDCs (D); the endothelial receptor, CD300LG (F); and the potent activator of the classical complement pathway, C1q (G). Also depicted in the figure are the possibilities for direct interactions between PfEMP1 proteins and BCR complexes in B cells, which could promote activation of these complexes through clustering (C), and a blocking of potential antigens on infected RBCs as a result of a “shielding” mechanism of IgM bound to PfEMP1 (E).

Fig. 4. C1q-binding sites in the lgM-DBL4β complex

The image shows the lgM-DBL4β model looking down onto the “flat”-side of the IgM molecule, where the putative C1q binding sites on IgM (green) are located (30). It is clear that C1q would not be expected to sterically interfere with DBL4β binding to IgM, consistent with experimental observations (16).