Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope.
Antihomotypic affinity maturation improves human B cell responses against a repetitive epitope.
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DOI：
10.1126/science.aar5304
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发表时间：
2018-06-22
期刊：
影响因子：
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通讯作者：
Wardemann H
中科院分区：
文献类型：
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作者：
Imkeller K;Scally SW;Bosch A;Martí GP;Costa G;Triller G;Murugan R;Renna V;Jumaa H;Kremsner PG;Sim BKL;Hoffman SL;Mordmüller B;Levashina EA;Julien JP;Wardemann H
亲和力成熟选择表达体细胞突变抗体变体的B细胞，这些抗体变体具有改善的抗原结合特性以保护免受入侵病原体的侵害。我们确定了表达针对恶性疟原虫环子孢子蛋白（PfCSP）的保护性抗体的人B细胞的克隆选择和亲和力成熟的分子机制。我们在分子细节上显示PfCSP的重复性质促进两个PfCSP重复结合的单克隆抗体之间的直接同型相互作用，从而改善抗原亲和力和B细胞活化。这些数据提供了一个机械的解释，强烈的选择介导同型抗体相互作用的体细胞突变后，在人体内重复寄生虫暴露。我们的研究结果证明了不同的抗原介导的亲和力成熟模式，以提高抗体对PfCSP和可能的其他重复抗原的反应。
Affinity maturation selects B cells expressing somatically mutated antibody variants with improved antigen-binding properties to protect from invading pathogens.We determined the molecular mechanism underlying the clonal selection and affinity maturation of human B cells expressing protective antibodies against the circumsporozoite protein of the malaria parasite Plasmodium falciparum (PfCSP).We show in molecular detail that the repetitive nature of PfCSP facilitates direct homotypic interactions between two PfCSP repeat-bound monoclonal antibodies, thereby improving antigen affinity and B cell activation. These data provide a mechanistic explanation for the strong selection of somatic mutations that mediate homotypic antibody interactions after repeated parasite exposure in humans. Our findings demonstrate a different mode of antigen-mediated affinity maturation to improve antibody responses to PfCSP and presumably other repetitive antigens.