美国麻省理工学院Daniel Lingwood课题组发现，等位基因多态性控制人类对流感病毒的广义中和抗体的自反应性和疫苗诱导性。相关论文于2022年8月10日在线发表在《免疫》杂志上。

研究人员表示，靶向第一组甲型流感病毒（IAV）血凝素秆结构的人类广谱中和抗体（bnAbs）偏向于IGHV1-69等位基因，这些等位基因在其CDRH2环中使用苯丙氨酸（F54）而不是亮氨酸（L54）。

尽管如此，研究人员证明这两个等位基因编码的人类IAV bnAbs采用结构上趋同的模式接触相同的表位。为了解决谱系扩展性的差异，研究人员比较了F54与L54作为人源化小鼠的底物，其中抗体的发展具有类似人类的CDRH3多样性，但仅限于单个VH基因。虽然两个等位基因都编码了bnAb前体，但只有F54 IGHV1-69支持在用秆结构纳米颗粒疫苗免疫后激发异型血清bnAbs。L54 IGHV1-69是没有生产力的，它共同编码的过敏性B细胞和自反应性秆结构抗体被从B细胞记忆中清除。

此外，人类的秆结构抗体也表现出L54依赖性的自反应性。因此，IGHV1-69的多态性为流感bnAbs的耐受性和疫苗可扩展性把关。

附：英文原文

Title: Allelic polymorphism controls autoreactivity and vaccine elicitation of human broadly neutralizing antibodies against influenza virus

Author: Maya Sangesland, Alba Torrents de la Pea, Seyhan Boyoglu-Barnum, Larance Ronsard, Faez Amokrane Nait Mohamed, Thalia Bracamonte Moreno, Ralston M. Barnes, Daniel Rohrer, Nils Lonberg, Musie Ghebremichael, Masaru Kanekiyo, Andrew Ward, Daniel Lingwood

Issue&Volume: 2022-08-10

Abstract: Human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin stalk ofgroup 1 influenza A viruses (IAVs) are biased for IGHV1-69 alleles that use phenylalanine(F54) but not leucine (L54) within their CDRH2 loops. Despite this, we demonstratedthat both alleles encode for human IAV bnAbs that employ structurally convergent modesof contact to the same epitope. To resolve differences in lineage expandability, wecompared F54 versus L54 as substrate within humanized mice, where antibodies developwith human-like CDRH3 diversity but are restricted to single VH genes. While both alleles encoded for bnAb precursors, only F54 IGHV1-69 supportedelicitation of heterosubtypic serum bnAbs following immunization with a stalk-onlynanoparticle vaccine. L54 IGHV1-69 was unproductive, co-encoding for anergic B cellsand autoreactive stalk antibodies that were cleared from B cell memory. Moreover,human stalk antibodies also demonstrated L54-dependent autoreactivity. Therefore,IGHV1-69 polymorphism, which is skewed ethnically, gates tolerance and vaccine expandabilityof influenza bnAbs.

DOI: 10.1016/j.immuni.2022.07.006

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00339-9