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A Novel Antibody-Dependent Cellular Cytotoxicity Mechanism Involved in Defense against Malaria Requires Costimulation of Monocytes FcRII and FcRIII¹

Ali Jafarshad^*, Morten H. Dziegiel, Rasmus Lundquist, Leif K. Nielsen, Subhash Singh^2,* and Pierre L. Druilhe^3,*

^* Bio-Medical Parasitology Unit, Pasteur Institute, Paris, France; and H:S Blodbank KI2033, Copenhagen University Hospital, Copenhagen, Denmark

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 FcRIIa and FcRIIIa 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by the PAL+ program. A.J. was supported by a fellowship from the French Ministère de la Recherche.

² Current address: Laboratory of Malaria and Vector Research/National Institute of Allergy and Infectious Diseases/National Institutes of Health, 12735, Twinbrook Parkway, Twinbrook III, Rockville, MD 20852.

³ Address correspondence and reprint requests to Dr. Pierre L. Druilhe, Bio-Medical Parasitology Unit, Institut Pasteur, 28, rue du Dr. Roux, 75015 Paris, France. E-mail address: druilhe{at}pasteur.fr

⁴ Abbreviations used in this paper: MN, monocyte; ADCI, Ab-dependent cellular inhibition; PMN, polymorphonuclear; MSP, merozoite surface protein; GLURP, glutamate-rich protein; SERP, serine repeat protein; PIAG, pool of immune African globulins; N-IgG, negative control IgG; anti-RhD, anti-rhesus D; CM, culture medium; PEMS, parasitophorous vacuole membrane-enclosed merozoite structure; PMz, pseudomerozoite; SGI, specific growth inhibition; ADCC, Ab-dependent cellular cytotoxicity.