Research Article: Associations between an IgG3 polymorphism in the binding domain for FcRn, transplacental transfer of malaria-specific IgG3, and protection against Plasmodium falciparum malaria during infancy: A birth cohort study in Benin

Date Published: October 9, 2017

Publisher: Public Library of Science

Author(s): Celia Dechavanne, Sebastien Dechavanne, Ibrahim Sadissou, Adjimon Gatien Lokossou, Fernanda Alvarado, Magalie Dambrun, Kabirou Moutairou, David Courtin, Gregory Nuel, Andre Garcia, Florence Migot-Nabias, Christopher L. King, Lorenz von Seidlein

Abstract: BackgroundTransplacental transfer of maternal immunoglobulin G (IgG) to the fetus helps to protect against malaria and other infections in infancy. Recent studies have emphasized the important role of malaria-specific IgG3 in malaria immunity, and its transfer may reduce the risk of malaria in infancy. Human IgGs are actively transferred across the placenta by binding the neonatal Fc receptor (FcRn) expressed within the endosomes of the syncytiotrophoblastic membrane. Histidine at position 435 (H435) provides for optimal Fc–IgG binding. In contrast to other IgG subclasses, IgG3 is highly polymorphic and usually contains an arginine at position 435, which reduces its binding affinity to FcRn in vitro. The reduced binding to FcRn is associated with reduced transplacental transfer and reduced half-life of IgG3 in vivo. Some haplotypes of IgG3 have histidine at position 435. This study examines the hypotheses that the IgG3-H435 variant promotes increased transplacental transfer of malaria-specific antibodies and a prolonged IgG3 half-life in infants and that its presence correlates with protection against clinical malaria during infancy.Methods and findingsIn Benin, 497 mother–infant pairs were included in a longitudinal birth cohort. Both maternal and cord serum samples were assayed for levels of IgG1 and IgG3 specific for MSP119, MSP2 (both allelic families, 3D7 and FC27), MSP3, GLURP (both regions, R0 and R2), and AMA1 antigens of Plasmodium falciparum. Cord:maternal ratios were calculated. The maternal IgG3 gene was sequenced to identify the IgG3-H435 polymorphism. A multivariate logistic regression was used to examine the association between maternal IgG3-H435 polymorphism and transplacental transfer of IgG3, adjusting for hypergammaglobulinemia, maternal malaria, and infant malaria exposure. Twenty-four percent of Beninese women living in an area highly endemic for malaria had the IgG3-H435 allele (377 women homozygous for the IgG3-R435 allele, 117 women heterozygous for the IgG3-R/H alleles, and 3 women homozygous for the IgG3-H435 allele). Women with the IgG3-H435 allele had a 78% (95% CI 17%, 170%, p = 0.007) increased transplacental transfer of GLURP-R2 IgG3 compared to those without the IgG3-H435 allele. Furthermore, in infants born to mothers with the IgG3-H435 variant, a 28% longer IgG3 half-life was noted (95% CI 4%, 59%, p = 0.02) compared to infants born to mothers homozygous for the IgG3-R435 allele. Similar findings were observed for AMA1, MSP2-3D7, MSP3, GLURP-R0, and GLURP-R2 but not for MSP119 and MSP2-FC27. Infants born to women with IgG3-H435 had a 32% lower risk of symptomatic malaria during infancy (incidence rate ratio [IRR] = 0.68 [95% CI 0.51, 0.91], p = 0.01) compared to infants born to mothers homozygous for IgG3-R435. We did not find a lower risk of asymptomatic malaria in infants born to women with or without IgG3-H435. Limitations of the study were the inability to determine (i) the actual amount of IgG3-H435 relative to IgG-R435 in serum samples and (ii) the proportion of malaria-specific IgG produced by infants versus acquired from their mothers.ConclusionsAn arginine-to-histidine replacement at residue 435 in the binding domain of IgG3 to FcRn increases the transplacental transfer and half-life of malaria-specific IgG3 in young infants and is associated with reduced risk of clinical malaria during infancy. The IgG3-H435 allele may be under positive selection, given its relatively high frequency in malaria endemic areas.

Partial Text: Plasmodium falciparum malaria remains a major cause of mortality and morbidity in children under 5 years of age in many endemic countries [1]. Death or severe disease typically arises from 1 to 3 overlapping syndromes: severe anemia, respiratory distress, or loss of consciousness [2]. Young infants under 6 months of age experience less clinical malaria compared to older children [3], but the mechanisms conferring immunity are not well understood [4]. One potential mechanism is active transplacental transfer of malaria-specific maternal immunoglobulin G (IgG) during gestation; however, the antigen targets and types of antibodies involved remain poorly defined [4]. Functional assays using cord blood plasma, such as antibody-dependent respiratory burst assays, show that immunoglobulins provide protection against severe malaria during the first 6 months of life [2]. This suggests that cytophilic immunoglobulin subclasses with potent opsonizing and complement fixing functions (e.g., IgG1 and IgG3) are important in protection against malaria. Recent studies have shown that malaria-specific IgG3 relative to other IgG subclasses is more strongly associated with malaria immunity (reviewed in [4]), and its passive transfer to the fetus may contribute to reduced risk of malaria in early infancy. IgG3 is notable compared to other IgG subclasses: it has higher affinity for complement component C1q and Fc gamma receptors (FcγRs), a 4-fold longer flexible hinge region, that are characteristics to enhance opsonization of malaria-infected erythrocytes and promotion of effector functions such as complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and respiratory burst phagocytosis [5,6]. In studies of malaria blood stage vaccine candidate antigens (e.g., GLURP), increased opsonic phagocytosis activity of IgG3 in vitro is strongly associated with reduced risk of febrile malaria, thus confirming the importance of IgG3 function in immunity to malaria [7].

The overall frequency of the IgG3-H435 variant in the population group of Tori-Bossito, south Benin, was 0.12 compared to 0.88 for IgG3-R435. A total of 117 mothers were heterozygous and 3 were homozygous for IgG3-H435, resulting in 24% of study participants (pregnant women) carrying the allele (Table 1). The IgG3-H435 variant was not associated with prespecified confounding factors likely to influence transplacental antibody transfer and/or malaria risk in mothers and infants (Table 1).

Human IgG is the only antibody isotype that is actively transferred across the placenta, providing passive immunity for the newborn. With respect to all IgG subclasses, IgG3 is noteworthy for its shorter half-life and diminished capacity for transplacental transfer. Due to an arginine substitution for histidine at position 435, found exclusively in IgG3, binding to FcRn is reduced [5]. Why IgG3 differs from other IgG subclasses in several respects is unclear. One possibility is that by limiting the transplacental transfer of maternal IgG3 directed to fetal antigens, the risk of fetal alloimmune pathology is reduced [28]. Also, the potent pro-inflammatory properties of IgG3 could be tempered by its shorter half-life [29]. Yet the powerful effector function of IgG3 may be beneficial against some pathogens such as P. falciparum, where malaria-specific cytophilic IgGs have been most strongly associated with protection [7,30]. Since infants are most susceptible to malaria infection, enhanced transplacental transfer of IgG3 with prolonged half-life may be advantageous. In support of this hypothesis, we showed that 24% of Beninese women living in an area highly endemic for malaria possess the IgG3-H435 allele, which enhances IgG3 binding to FcRn [5]. We demonstrated that women with this allele have increased transplacental transfer of malaria-specific IgG3 to their fetus, and this IgG3 persists longer in infant blood than IgG3-R435. We showed that increased transplacental transfer of IgG3 directed to the malarial GLURP antigen is strongly associated with reduced risk of clinical malaria, and offspring of mothers with the IgG3-H435 allele have reduced risk of clinical malaria in infancy compared to offspring of women with homozygous IgG3-R435. Together, these data support the conclusion that malaria-specific IgG3 contributes to protection against clinical malaria during infancy.



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