Novel IgG3 Allotype Identified in Women From Malaria Endemic Regions That Modulates Fc Effector Functions

Abstract

Allelic variants are found amongst all human IgG subclasses and can influence a range of Fc functions. IgG allotypes have been associated with reduced risk of clinical malaria, an ancient disease that has co-evolved with humanity. However, how they contribute to malaria control is not fully understood. Here, we identified a novel IgG3 allotype in pregnant women from Papua New Guinea who were highly exposed to malaria. The new G3m29 (IGHG3*30) allotype was prominent in women of Sepik ethnicity. Plasma from women with G3m29 induced enhanced antibody-dependent phagocytosis of Plasmodium falciparum CS2-infected erythrocytes. A human monoclonal antibody to P. falciparum VAR2CSA, recombinantly generated as IGHG3*30, showed enhanced affinity to FcγRIIa and induced increased antibody-dependent phagocytosis in comparison to other IgG3 allotypes. This study provides clues to the role of allotypic variants of IgG3 in the control of malaria.

Note:

Funding Information: This work was supported by a Project Grant from the National Health and Medical Research Council of Australia (NHMRC) to SJR, EHA and AWC (APP1143946) and a Program Grant (APP1092789) also from the NHMRC. AKW, SJK and AWC are supported by NHMRC Fellowships (GNT2008092). Sample collection was primarily supported by the Malaria in Pregnancy Consortium, through a Grant from the Bill & Melinda Gates Foundation (46099)

Declaration of Interests: The authors have declared that no conflict of interest exists.

Ethics Approval Statement: Ethical approval was obtained from the PNG Institute of Medical Research Institutional Review Board, the PNG Medical Research Advisory Council, and the Melbourne Health Human Research Ethics Committee.

Keywords: IgG3, allotype, Malaria, Fc Functions