A Novel Antibody-Dependent Cellular Cytotoxicity Mechanism Involved in Defense against Malaria Requires Costimulation of Monocytes FcγRII and FcγRIII

Abstract

Clinical experiments have shown that the Ab-dependent cell-mediated inhibition of Plasmodium falciparum is a major mechanism controlling malaria parasitemia and thereby symptoms. In this study, we demonstrate that a single merozoite per monocyte (MN) is sufficient to trigger optimal antiparasitic activity. Using particulate Ag as pseudomerozoites, we show that only Ags, and no other parasite-derived factor, are required to trigger MN activation and that a single Ag is as potent as the complex combination of Ags constituting the merozoite surface. Moreover, we found that soluble Ags binding at least two Abs are as effective as the parasite at stimulating MN and that nonmalarial Ags are as efficient provided they are targeted by cytophilic Abs. Indeed, only cytophilic IgGs are potent and, in agreement with immunoepidemiological findings, IgG3 is superior to IgG1. Very low Ab concentrations (>700 pM), i.e., in the range of molecules having a hormonal effect, are effective, in contrast to Abs having a direct, neutralizing effect. Finally, Ab-dependent cell-mediated inhibition proved to require the synergistic activation of both FcγRIIa and FcγRIIIa which both distinguish it from other Ab-dependent cellular cytotoxicity and implies that all MN are not equally effective. These findings have both fundamental and practical implications, particularly for vaccine discovery.

Toward the Rational Design of a Malaria Vaccine Construct Using the MSP3 Family as an Example: Contribution of Antigenicity Studies in Humans

“…The IgG3 type of response was more prevalent than the IgG1 response, whereas the levels of both were equivalent. The importance of this finding is related to previous studies showing that IgG antibodies either mediating parasite killing in vitro or associated with protection in vivo are restricted to the IgG1 and IgG3 subclasses (4,16,20,30). In agreement with this, all 24 peptides were indeed found to define antigenic determinants able to trigger the antiparasitic ADCI mechanism.…”

“…The negative control was IgG from a pool of French donors with no malaria history (N-IgG). Peripheral blood mononuclear cells (PBMC) from healthy French donors were prepared and cryopreserved as previously described (20). For the ADCI assay, PBMC were rapidly thawed at 37°C and assessed for viability by trypan blue exclusion.…”

Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated Plasmodium falciparum Protein PFF0165c

“…This was as high as 74% SGI at 1:100 dilutions and still significant at 46% at 1:1,000 dilutions. The degree of inhibition obtained with affinity-purified human antibodies was also very high and comparable to that of pooled Igs of adults living in areas of Africa where malaria is endemic (7,12,20). These results, obtained with two different adjuvants in animal models and with naturally induced antibodies from humans, suggest that the primary mechanism of protection employed by P27A antibodies is likely to be in cooperation with MN.…”

“…One of the principal mechanisms that mediates clinical malaria in humans has been shown to be the cooperation between cytophilic antibodies and MN (7,20). The in vitro ADCI assay, based on this mechanism, has been used to assess the capacity of purified human and murine antibodies to inhibit malaria parasite growth (Fig.…”

The Impact of Immune Responses on the Asexual Erythrocytic Stages of Plasmodium and the Implication for Vaccine Development

“…These antibodies were tested in mice transgenic for human Fc-receptors challenged with transgenic rodent malaria parasites (expressing PfMSP-1p19) in an effort to evaluate the role of antibodies in protection. Another study demonstrated that the activation of monocytic cells requires two distinct Fcγ receptors (FcγRII and FcγRIII) simultaneously engaged by a least two cytophilic IgG molecules, which are part of the same immune complexes (Jafarshad et al, 2007). Finally, the concept of the contribution of Fc receptors in natural immunity is supported by epidemiological studies (Shi et al, 2001;Israelsson et al, 2008;Leoratti et al, 2008).…”