Factors associated with immunoglobulin G subclass polarization in naturally acquired antibodies to Plasmodium falciparum merozoite surface proteins: a cross-sectional survey in Brazilian Amazonia

Abstract

We investigated immunoglobulin G (IgG) subclass antibody responses to Plasmodium falciparum merozoite surface protein 1 (MSP-1) and MSP-2 in 112 malaria-exposed subjects in Brazil. IgG3 polarization was primarily epitope driven, being little affected by cumulative or current exposure to malaria and not affected by a subject's age and Fcgamma receptor IIA genotype.

FIG. 1.

(A) Schematic representation of the recombinant antigens used for serological analysis. Variable, semiconserved, and conserved domains of P. falciparum MSP-1 and MSP-2 (10) are shown as white, gray, and black boxes; repetitive domains are indicated by the striped patterns. MSP-1 block 2 antigens represent the three major variants (MAD20, K1, and RO33) of this domain found in local parasites (proportions, 38, 42, and 23%, respectively [25]). MSP-2 antigens represent the central region (blocks 2 and 3) of two major allelic families: four IC1-type variants and two FC27-type variants. Three MSP-2 antigens (25, AM89, and S20) represent “local” variants commonly found in Amazonian isolates of P. falciparum (24, 32), while three “foreign” variants (FUP/CP, 3D7, and FC27) are commonly found on other continents but less frequently in Brazil. (B) Proportions (%) of malaria-exposed adult subjects living in northwestern Brazil with naturally acquired antibodies of each IgG subclass, detected by ELISA, to recombinant antigens derived from P. falciparum MSP-1 and MSP-2. IgG1, IgG2, IgG3, and IgG4 subclass antibodies are represented by white, hatched, gray, and black boxes, respectively. Error bars indicate the upper limit of exact 95% confidence intervals of proportions. For all antigens but MSP-1₁₉, the proportion of subjects with detectable IgG3 antibodies significantly exceeds that of subjects with IgG1 antibodies (by the MacNemar test, P was 0.24 for MSP-1₁₉ and P was <0.01 for all other antigens). (C) Mean levels of naturally acquired antibodies of each IgG subclass, measured as ELISA reactivity indices, to recombinant antigens derived from P. falciparum MSP-1 and MSP-2 among malaria-exposed adult subjects living in northwestern Brazil. Error bars indicate the upper limit of 95% confidence intervals of means. Note that levels of antibodies to RO33 (a highly conserved MSP-1 block 2 variant) are substantially higher than those to any other antigen tested. The IgG1/IgG3 ratio for each antigen is given in parentheses. For all antigens except MSP-1₁₉, levels of IgG3 antibodies significantly exceed those of IgG1 antibodies (by the Wilcoxon test, P was 0.30 for MSP-1₁₉ and P was <0.005 for all other antigens).