@article{fdi:010071317,
  title = {{A}ssociations between an {I}g{G}3 polymorphism in the binding domain for {F}c{R}n, transplacental transfer of malaria-specific {I}g{G}3, and protection against {P}lasmodium falciparum malaria during infancy : a birth cohort study in {B}enin},
  author = {{D}echavanne, {C}. and {D}echavanne, {S}. and {S}adissou, {I}. and {L}okossou, {A}. {G}. and {A}lvarado, {F}. and {D}ambrun, {M}. and {M}outairou, {K}. and {C}ourtin, {D}avid and {N}uel, {G}. and {G}arcia, {A}ndr{\'e} and {M}igot {N}abias, {F}lorence and {K}ing, {C}. {L}.},
  editor = {},
  language = {{ENG}},
  abstract = {{B}ackground {T}ransplacental transfer of maternal immunoglobulin {G} ({I}g{G}) to the fetus helps to protect against malaria and other infections in infancy. {R}ecent studies have emphasized the important role of malaria-specific {I}g{G}3 in malaria immunity, and its transfer may reduce the risk of malaria in infancy. {H}uman {I}g{G}s are actively transferred across the placenta by binding the neonatal {F}c receptor ({F}c{R}n) expressed within the endosomes of the syncytiotrophoblastic membrane. {H}istidine at position 435 ({H}435) provides for optimal {F}c-{I}g{G} binding. {I}n contrast to other {I}g{G} subclasses, {I}g{G}3 is highly polymorphic and usually contains an arginine at position 435, which reduces its binding affinity to {F}c{R}n in vitro. {T}he reduced binding to {F}c{R}n is associated with reduced transplacental transfer and reduced half-life of {I}g{G}3 in vivo. {S}ome haplotypes of {I}g{G}3 have histidine at position 435. {T}his study examines the hypotheses that the {I}g{G}3-{H}435 variant promotes increased transplacental transfer of malaria-specific antibodies and a prolonged {I}g{G}3 half-life in infants and that its presence correlates with protection against clinical malaria during infancy. {M}ethods and findings {I}n {B}enin, 497 mother-infant pairs were included in a longitudinal birth cohort. {B}oth maternal and cord serum samples were assayed for levels of {I}g{G}1 and {I}g{G}3 specific for {MSP}1(19), {MSP}2 (both allelic families, 3{D}7 and {FC}27), {MSP}3, {GLURP} (both regions, {R}0 and {R}2), and {AMA}1 antigens of {P}lasmodium falciparum. {C}ord: maternal ratios were calculated. {T}he maternal {I}g{G}3 gene was sequenced to identify the {I}g{G}3-{H}435 polymorphism. {A} multivariate logistic regression was used to examine the association between maternal {I}g{G}3-{H}435 polymorphism and transplacental transfer of {I}g{G}3, adjusting for hypergammaglobulinemia, maternal malaria, and infant malaria exposure. {T}wenty-four percent of {B}eninese women living in an area highly endemic for malaria had the {I}g{G}3-{H}435 allele (377 women homozygous for the {I}g{G}3-{R}435 allele, 117 women heterozygous for the {I}g{G}3-{R}/{H} alleles, and 3 women homozygous for the {I}g{G}3-{H}435 allele). {W}omen with the {I}g{G}3-{H}435 allele had a 78% (95% {CI} 17%, 170%, p = 0.007) increased transplacental transfer of {GLURP}-{R}2 {I}g{G}3 compared to those without the {I}g{G}3-{H}435 allele. {F}urthermore, in infants born to mothers with the {I}g{G}3-{H}435 variant, a 28% longer {I}g{G}3 half-life was noted (95% {CI} 4%, 59%, p = 0.02) compared to infants born to mothers homozygous for the {I}g{G}3-{R}435 allele. {S}imilar findings were observed for {AMA}1, {MSP}2-3{D}7, {MSP}3, {GLURP}-{R}0, and {GLURP}-{R}2 but not for {MSP}119 and {MSP}2-{FC}27. {I}nfants born to women with {I}g{G}3-{H}435 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 {I}g{G}3-{R}435. {W}e did not find a lower risk of asymptomatic malaria in infants born to women with or without {I}g{G}3-{H}435. {L}imitations of the study were the inability to determine (i) the actual amount of {I}g{G}3-{H}435 relative to {I}g{G}-{R}435 in serum samples and (ii) the proportion of malaria-specific {I}g{G} produced by infants versus acquired from their mothers. {C}onclusions {A}n arginine-to-histidine replacement at residue 435 in the binding domain of {I}g{G}3 to {F}c{R}n increases the transplacental transfer and half-life of malaria-specific {I}g{G}3 in young infants and is associated with reduced risk of clinical malaria during infancy. {T}he {I}g{G}3-{H}435 allele may be under positive selection, given its relatively high frequency in malaria endemic areas.},
  keywords = {{BENIN}},
  booktitle = {},
  journal = {{PLOS} {M}edicine},
  volume = {14},
  numero = {10},
  pages = {e1002403 [19 p.]},
  ISSN = {1549-1676},
  year = {2017},
  DOI = {10.1371/journal.pmed.1002403},
  URL = {https://www.documentation.ird.fr/hor/fdi:010071317},
}