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

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-spe...

Malaria in pregnancy shapes the development of foetal and infant immunity

“…Finally, a recent study from Benin found that PM was associated with decreased cord‐to‐maternal ratios of most blood stage‐specific antibodies. In the same study, a specific maternal IgG3 polymorphism (histidine at position 453) was associated with enhanced transplacental transfer of malaria‐specific IgG3, and offspring of women with this mutation had a reduced risk of malaria in infancy . Together, these studies suggest that PM, along with additional maternal factors, may affect the transfer of malaria‐specific antibodies, but the consequences of this in the offspring remain unclear.…”

“…IgG1 is preferentially transferred, followed by IgG4, IgG3 and finally IgG2, the cord level of which is often lower than the maternal level . Factors that are known to affect the transport of IgG include maternal hypergammaglobulinaemia, (which is hypothesized to result from FcRn saturation), maternal HIV and alterations in the binding domain of IgG to FcRn . Maternal malaria, in particular PM, is associated with elevated total maternal IgG as well as placental pathology, both of which might affect the transfer of maternal antibodies .…”

Hinge length contributes to the phagocytic activity of HIV-specific IgG1 and IgG3 antibodies

“…There are likely several reasons for this notable absence, including concerns about half-life, proteolytic susceptibility of the hinge and allotypic polymorphisms [46][47][48][49]. Chief among these perhaps, the majority of IgG3 allotypes bear an Fc sequence in which a histidine residue key to pH-dependent binding to the neonatal Fc receptor (FcRn) responsible for antibody recycling and the long half-life of IgGs [50,51] is substituted with an arginine. Thus, in early studies, rapid plasma clearance was presumed to be a global attribute of IgG3.…”

Genetic Diversity of the Plasmodium falciparum Glutamate-Rich Protein R2 Region Before and Twelve Years after Introduction of Artemisinin Combination Therapies among Febrile Children in Nigeria

“…The geometric mean of parasitemia was 8,702 parasites/μL (confidence interval [CI] = 7,163-10,570) in Group A, whereas in Group B it was 8,955 parasites/μL (CI = 6,973-11,501). The median weight of study participants was 11 kg (IQR = 8-16) and 23 kg (IQR = [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] in Group A and B, respectively ( Table 2). All differences were not statistically significant.…”

“…14 Several studies have associated its allelic variability with geographical location and the intensity of malaria transmission. [15][16][17] Genetic variation has been shown to contribute to reduced acquired immunity in P. falciparum as immunity is essentially strain-specific (Gandhi et al, 2014;Ocholla et al, 2014;Dechavanne et al, 2017). [18][19][20] Information on the allelic heterogeneity of the R2 region of the GLURP gene over a period of time will be valuable for research and development of antimalarial vaccines.…”