The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants.
The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants.
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Vivax Duffy结合蛋白II抗体的存在，持久性和功能特性受HLA II类等位基因变体的影响。
DOI：
10.1371/journal.pntd.0005177
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发表时间：
2016-12
影响因子：
3.8
通讯作者：
Carvalho LH
中科院分区：
文献类型：
--
作者：
Kano FS;Souza-Silva FA;Torres LM;Lima BA;Sousa TN;Alves JR;Rocha RS;Fontes CJ;Sanchez BA;Adams JH;Brito CF;Pires DE;Ascher DB;Sell AM;Carvalho LH
人类疟疾寄生虫间日疟原虫通过一条关键途径感染红细胞，该途径需要达菲结合蛋白 II (DBPII) 与其网织红细胞上的受体（达菲抗原/趋化因子受体 (DARC)）之间的相互作用。很大比例的间日疟原虫暴露个体未能产生抑制 DBPII-DARC 相互作用的抗体，并且调节这种体液免疫反应的遗传因素的特征还很不清楚。在这里，我们研究 DBPII 反应是否可能与 HLA II 类相关。在巴西亚马逊的一个农业定居点进行了一项基于社区的开放队列研究，其中对 336 名无关志愿者进行了 HLA II 类（DRB1、DQA1 和 DQB1 基因座）基因分型，并通过传统血清学（DBPII IgG ELISA 检测）和功能测定（DBPII-红细胞结合抑制）随时间（基线、6 和 12 个月）监测他们的 DBPII 免疫反应。结果表明，DRB1*13:01 携带者发展和维持抗 DBPII IgG 反应的敏感性增加，而具有单倍型 DRB1*14:02-DQA1*05:03-DQB1*03:01 的个体是持续的无反应者。 HLA II 类基因多态性也影响 DBPII 抗体（BIAb，结合抑制抗体）的功能特性，其中三个等位基因（DRB1*07:01、DQA1*02:01 和 DQB1*02:02）包含与 BIAbs 反应的存在和持续性相关的单个单元型。对 HLA-DRB1 变体的结构效应进行建模揭示了肽结合沟的许多差异，这可能导致抗原结合和呈递谱的改变，因此可以解释受试者反应的差异。目前的研究证实了 DBPII 抗体反应的遗传性，HLA II 类基因的遗传变异影响 IgG 抗体反应的发展和持续。通过细胞研究来增加对 DBPII 肽与与良好或不良抗体反应相关的 II 类分子的结合亲和力的了解，可能会导致开发控制响应 DBPII 而激活的辅助 T 细胞类型的策略。疫苗是当前消除疟疾工作的重要组成部分，许多与间日疟原虫疫苗相关的研究都集中在达菲结合蛋白 II (DBPII)，这是人类血液阶段感染的配体。自然暴露于间日疟原虫的很大一部分个体未能产生中和抗体，但调节这种免疫反应的宿主遗传因素却知之甚少。我们研究了 DBPII 反应性是否依赖于参与免疫反应调节的人类白细胞抗原 (HLA) II 类细胞表面蛋白的变异性。为了获得 DBPII 抗体的可靠估计，我们进行了一项纵向研究，在 12 个月的时间内收集了同一个体的血清。结果证实了 DBPII 免疫反应的遗传性，HLA II 类基因的遗传变异影响抗体反应的发展和持续。 HLA II 类基因型也影响 DBPII 抗体在体外阻断配体-受体相互作用的能力。计算方法确定了 HLA 变体之间的结构特异性，我们建议将其作为抗体反应良好或不良之间差异的解释。这些结果可能对疫苗开发产生影响，并可能导致控制 DBPII 激活的免疫反应类型的策略。
The human malaria parasite Plasmodium vivax infects red blood cells through a key pathway that requires interaction between Duffy binding protein II (DBPII) and its receptor on reticulocytes, the Duffy antigen/receptor for chemokines (DARC). A high proportion of P. vivax-exposed individuals fail to develop antibodies that inhibit DBPII-DARC interaction, and genetic factors that modulate this humoral immune response are poorly characterized. Here, we investigate if DBPII responsiveness could be HLA class II-linked. A community-based open cohort study was carried out in an agricultural settlement of the Brazilian Amazon, in which 336 unrelated volunteers were genotyped for HLA class II (DRB1, DQA1 and DQB1 loci), and their DBPII immune responses were monitored over time (baseline, 6 and 12 months) by conventional serology (DBPII IgG ELISA-detected) and functional assays (inhibition of DBPII–erythrocyte binding). The results demonstrated an increased susceptibility of the DRB1*13:01 carriers to develop and sustain an anti-DBPII IgG response, while individuals with the haplotype DRB1*14:02-DQA1*05:03-DQB1*03:01 were persistent non-responders. HLA class II gene polymorphisms also influenced the functional properties of DBPII antibodies (BIAbs, binding inhibitory antibodies), with three alleles (DRB1*07:01, DQA1*02:01 and DQB1*02:02) comprising a single haplotype linked with the presence and persistence of the BIAbs response. Modelling the structural effects of the HLA-DRB1 variants revealed a number of differences in the peptide-binding groove, which is likely to lead to altered antigen binding and presentation profiles, and hence may explain the differences in subject responses. The current study confirms the heritability of the DBPII antibody response, with genetic variation in HLA class II genes influencing both the development and persistence of IgG antibody responses. Cellular studies to increase knowledge of the binding affinities of DBPII peptides for class II molecules linked with good or poor antibody responses might lead to the development of strategies for controlling the type of helper T cells activated in response to DBPII. Vaccines are a crucial component of the current efforts to eliminate malaria, and much of the vaccine-related research on P. vivax has been focused on the Duffy binding protein II (DBPII), a ligand for human blood stage infection. A high proportion of individuals who are naturally exposed to P. vivax fail to develop neutralizing antibodies, but the host genetic factors modulating this immune response are poorly characterized. We investigated whether DBPII responsiveness was dependent on the variability of human leucocyte antigen (HLA) class II cell surface proteins involved in the regulation of immune responses. To obtain a reliable estimate of DBPII antibodies, we carried out a longitudinal study, collecting serum from the same individuals over a period of 12-months. The results confirmed the heritability of the DBPII immune response, with genetic variation in HLA class II genes influencing both the development and persistence of the antibody response. HLA class II genotype also influenced the ability of DBPII antibodies to block the ligand-receptor interaction in vitro. Computational approaches identified structural specificity between HLA variants, which we propose as an explanation for differences between a good or poor antibody responder. These results may have implications for vaccine development, and might lead to strategies for controlling the type of immune response activated in response to DBPII.
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影响因子：
3.1
作者：
Chootong, Patchanee;Ntumngia, Francis B.;Adams, John H.
通讯作者：
Adams, John H.
DOI：
10.1073/pnas.1001772107
发表时间：
2010-04-20
影响因子：
11.1
作者：
Dai, Shaodong;Murphy, Guinevere A.;Fontenot, Andrew P.
通讯作者：
Fontenot, Andrew P.
DOI：
10.1007/978-1-4939-6406-2_17
发表时间：
2017-01-01
期刊：
PREDICTION OF PROTEIN SECONDARY STRUCTURE
影响因子：
--
作者：
EL-Manzalawy, Yasser;Dobbs, Drena;Honavar, Vasant G.
通讯作者：
Honavar, Vasant G.
影响因子：
3.7
作者：
Ceravolo, I. P.;Souza-Silva, F. A.;Carvalho, L. H.
通讯作者：
Carvalho, L. H.
DOI：
10.4269/ajtmh.2005.72.675
发表时间：
2005-06-01
影响因子：
3.3
作者：
Ceravolo, IP;Bruña-Romero, O;Carvalho, LH
通讯作者：
Carvalho, LH