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.
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.
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DOI：
10.1371/journal.pmed.1002403
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发表时间：
2017-10
期刊：
影响因子：
15.8
通讯作者：
King CL
中科院分区：
文献类型：
--
作者：
Dechavanne C;Dechavanne S;Sadissou I;Lokossou AG;Alvarado F;Dambrun M;Moutairou K;Courtin D;Nuel G;Garcia A;Migot-Nabias F;King CL
通过胎盘将母体免疫球蛋白G(Ig G)转移到胎儿，有助于预防婴儿时期的疟疾和其他感染。最近的研究强调了疟疾特异性IgG3在疟疾免疫中的重要作用，它的转移可能会降低婴儿患疟疾的风险。人免疫球蛋白通过与合体滋养细胞膜内小体表达的新生儿Fc受体(FcRN)结合，通过胎盘主动转移。第435位组氨酸(H435)提供最佳的Fc-Ig G结合。与其他免疫球蛋白亚类不同的是，IgG3具有高度的多态性，通常在435位含有精氨酸，这降低了它在体外与FcRN的结合亲和力。与FcRN结合的减少与IgG3在体内的胎盘转运和半衰期减少有关。一些单倍型的IgG3在第435位有组氨酸。这项研究检验了以下假设，即IgG3-H435变异促进了疟疾特异性抗体的经胎盘转移增加，延长了婴儿的IgG3半衰期，并且它的存在与预防婴儿期临床疟疾有关。在贝宁，497对母婴被纳入纵向出生队列。检测母血和脐血标本中恶性疟原虫MSP119、MSP2(3D7和FC27)、MSP3、GLUP(R0和R2)和AMA1抗原的特异性IgG1和IgG3水平。脐带：计算母体比例。对母体的IgG3基因进行测序，以确定IgG3-H435基因的多态性。采用多因素Logistic回归分析，在调整高丙种球蛋白血症、母亲疟疾和婴儿疟疾暴露因素后，研究母亲IgG3-H435基因多态与经胎盘转移的IgG3之间的关系。生活在疟疾高度流行地区的贝宁妇女中，有24%的人有IgG3-H435等位基因(377名妇女的IgG3-R435等位基因纯合，117名妇女的IgG3-R/H等位基因杂合，3名妇女的IgG3-H435等位基因纯合)。与不携带Ig G3-H435等位基因的妇女相比，携带Ig G3-H435等位基因的妇女经胎盘转运Glup-R2 Ig G3增加了78%(95%可信区间为17%，170%，p=0.007)。此外，在母亲携带IgG3-H435变异的婴儿中，与母亲携带纯合子的婴儿相比，婴儿的IgG3半衰期延长了28%(95%可信区间为4%，59%，p=0.02)。在AMA1、MSP2-3D7、MSP3、GLULP-R0和GLURP-R2上也观察到了类似的结果，但MSP119和MSP2-FC27没有观察到类似的结果。与携带IgG3-R435纯合子的母亲所生的婴儿相比，携带IgG3-H435纯合子的母亲所生婴儿在婴儿期患有症状疟疾的风险低32%(发病率比[IRR]=0.68[95%可信区间0.51，0.91]，p=0.01)。我们没有发现携带或不携带IgG3-H435的母亲所生婴儿患无症状疟疾的风险较低。这项研究的局限性在于无法确定(I)血清样本中IgG3-H435相对于Ig-R435的实际数量，以及(Ii)婴儿产生的疟疾特异性Ig的比例与从其母亲那里获得的比例。在IgG3与FcRN结合区域的第435位精氨酸到组氨酸的替换增加了疟疾特异性IgG3在婴幼儿中的胎盘转移和半衰期，并与降低婴儿期临床疟疾的风险有关。鉴于IgG3-H435等位基因在疟疾流行地区的频率相对较高，因此可能处于正选择状态。在贝宁的一项出生队列研究中，Celia Dechavanne和他的同事研究了IgG3-H435变异、疟疾特异性IgG3的胎盘转移和婴儿时期对恶性疟原虫疟疾的保护之间的关系。人免疫球蛋白G对包括疟疾在内的许多感染的免疫力至关重要。孕期免疫球蛋白通过胎盘的主动转运有助于在婴儿早期预防疟疾和其他感染。免疫球蛋白分为4个亚类，具有不同的功能。IgG3在人类亚类中是独一无二的，因为它只占总免疫球蛋白的5%，但它是激活补体和细胞免疫反应(调理)最有效的亚类。它在血液中的半衰期为7天，而其他亚类的半衰期为21天。IgG3强大的调理特性可能有助于预防疟疾，特别是在婴儿时期，这是母亲通过胎盘运输免疫球蛋白的结果。最近的研究发现，在IgG3的结合域中存在一个单一突变，它与一种受体结合，该受体调节血液中的免疫球蛋白G的持久性，并介导免疫球蛋白在胎盘中的转运。在这项研究中，我们研究了携带该突变的女性是否增加了疟疾特异性IgG3的胎盘转移，以及她们的后代是否延长了血清IgG3的半衰期，并增强了对疟疾的保护。我们研究了来自西非贝宁的497名孕妇，对她们的后代进行了出生队列研究，并对她们在出生后第一年是否存在疟疾进行了密切评估。我们发现，与缺乏该突变的女性相比，24%的女性具有特定的IgG3突变，这与显著增强经胎盘转移和延长婴儿血液中疟疾特异性IgG3的持续时间有关。携带这种IgG3突变的女性的后代在婴儿期患临床疟疾的风险较低。这项研究提供了经胎盘转移疟疾特异性IgG3抗体有助于预防疟疾的证据。所研究的IgG3结合域的突变可能是为了促进对疟疾的保护。刺激IgG3产生的疟疾疫苗可能显示出更强的效力。
Transplacental 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. In 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. An 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. In a birth cohort study in Benin, Celia Dechavanne and colleagues examines associations between the IgG3-H435 variant, transplacental transfer of malaria-specific IgG3, and protection against Plasmodium falciparum malaria during infancy. Human immunoglobulin G (IgG) is critical for immunity to many infections including malaria. The active transport of IgG across the placenta during pregnancy contributes to protection against malaria and other infections during early infancy. IgG is divided into 4 subclasses with different functions. IgG3 is unique among human subclasses in that it represents only 5% of total IgG, yet it is the most potent subclass for activating complement and cellular immune responses (opsonization). Its half-life in blood is 7 days, compared to 21 days for other subclasses. The potent opsonizing characteristics of IgG3 may contribute to protection against malaria, particularly during infancy as a result of transplacental transport of IgG from the mother. Recent studies have identified a single mutation in the binding domain of IgG3 that engages a receptor that regulates IgG persistence in blood and mediates IgG transport across the placenta. In this study, we examined whether women with this mutation had increased transplacental transfer of malaria-specific IgG3, and whether their offspring had a prolonged half-life of serum IgG3 and increased protection against malaria. We studied 497 pregnant women from Benin, west Africa, in a birth cohort study of their offspring, who were closely evaluated for the presence of malaria during the first year of life. We found that 24% of women had a specific mutation for IgG3 that was associated with significantly enhanced transplacental transfer and extended persistence of malaria-specific IgG3 in infant blood, compared to women who lacked the mutation. Offspring of women with this IgG3 mutation had a reduced risk of clinical malaria during infancy. This study provides evidence that transplacental transfer of malaria-specific IgG3 antibodies contributes to protection against malaria. The studied mutation in the IgG3 binding domain may have arisen to facilitate protection against malaria. Malaria vaccines that stimulate IgG3 production may demonstrate enhanced efficacy.
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影响因子：
4
作者：
Murungi LM;Sondén K;Odera D;Oduor LB;Guleid F;Nkumama IN;Otiende M;Kangoye DT;Fegan G;Färnert A;Marsh K;Osier FH
通讯作者：
Osier FH
影响因子：
--
作者：
Palmeira P;Quinello C;Silveira-Lessa AL;Zago CA;Carneiro-Sampaio M
通讯作者：
Carneiro-Sampaio M
影响因子：
4.4
作者：
Kapur, Rick;Einarsdottir, Helga K.;Vidarsson, Gestur
通讯作者：
Vidarsson, Gestur
影响因子：
--
作者：
Spiegelberg, H L
通讯作者：
Spiegelberg, H L
影响因子：
4.6
作者：
Dechavanne, Celia;Sadissou, Ibrahim;Garcia, Andre
通讯作者：
Garcia, Andre