Antibodies with 'Original Antigenic Sin' Properties Are Valuable Components of Secondary Immune Responses to Influenza Viruses.
Antibodies with 'Original Antigenic Sin' Properties Are Valuable Components of Secondary Immune Responses to Influenza Viruses.
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DOI：
10.1371/journal.ppat.1005806
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发表时间：
2016-08
期刊：
影响因子：
6.7
通讯作者：
Hensley SE
中科院分区：
文献类型：
--
作者：
Linderman SL;Hensley SE
流感病毒引发的人抗体（Abs）通常与过去的流感病毒株具有高亲和力，但矛盾的是，不与实际引起反应的病毒株结合。这种现象被称为“原始抗原原罪”（original antigenic sin， OAS），因为这可能以产生新的新生抗体为代价。在这里，我们描述了在连续暴露于两种抗原性不同的H1N1流感病毒株的小鼠中诱导的抗体的特异性和功能。在这些条件下获得的许多抗体具有OAS表型，因为它们与用于第一次暴露的病毒株结合强烈，而与用于第二次暴露的病毒株结合非常弱。我们发现OAS和非OAS抗体靶向流感血凝素蛋白的相同一般区域，并且表达这两种类型抗体的B细胞可能是克隆相关的。令人惊讶的是，尽管OAS抗体结合的亲和力非常低，但在体内被动转移后，一些抗体能够有效地抵抗抗原漂移的病毒株。综上所述，我们的数据表明，OAS抗体在启动和召回病毒株之间具有一定程度的交叉反应性，产生这些抗体的B细胞在被召回到二次免疫反应中时具有保护作用。人类持续暴露于抗原性不同的流感病毒株。生命早期的流感病毒感染引起免疫反应，随后在接触不同的流感病毒株时被召回。针对旧流感病毒株的抗体可主导针对新流感病毒株的免疫反应。这一过程被称为“原始抗原原罪”，因为召回针对过去流感毒株的抗体可能以产生针对新病毒毒株的抗体为代价。有人提出，“原始抗原罪”是疫苗失败的原因之一。在这里，我们使用小鼠模型来显示具有“原始抗原sin”表型的抗体令人惊讶地靶向流感病毒的相同区域，这些区域被菌株特异性抗体识别。最重要的是，尽管观察到“原始抗原sin”抗体在常规结合试验中结合不良，但这些抗体能够有效地在体内保护。这些数据表明，具有“原始抗原sin”表型的抗体是对流感病毒的二次免疫反应中未被充分认识的有价值的组成部分。
Human antibodies (Abs) elicited by influenza viruses often bind with a high affinity to past influenza virus strains, but paradoxically, do not bind to the viral strain actually eliciting the response. This phenomena is called ‘original antigenic sin’ (OAS) since this can occur at the expense of generating new de novo Abs. Here, we characterized the specificity and functionality of Abs elicited in mice that were sequentially exposed to two antigenically distinct H1N1 influenza virus strains. Many Abs elicited under these conditions had an OAS phenotype, in that they bound strongly to the viral strain used for the first exposure and very weakly to the viral strain used for the second exposure. We found that OAS and non-OAS Abs target the same general region of the influenza hemagglutinin protein and that B cells expressing these two types of Abs can be clonally-related. Surprisingly, although OAS Abs bound with very low affinities, some were able to effectively protect against an antigenically drifted viral strain following passive transfer in vivo. Taken together, our data indicate that OAS Abs share some level of cross-reactivity between priming and recall viral strains and that B cells producing these Abs can be protective when recalled into secondary immune responses. Humans are continuously exposed to antigenically distinct influenza virus strains. Influenza virus infections early in life elicit immune responses that are subsequently recalled upon exposures with different influenza virus strains. Antibodies elicited against older influenza strains can dominate immune responses elicited against new influenza strains. This process is referred to as ‘original antigenic sin’ since the recall of antibodies against past influenza strains can occur at the apparent expense of generating antibodies against new viral strains. It has been proposed that ‘original antigenic sin’ contributes to vaccine failures. Here, we use a mouse model to show that antibodies that have an ‘original antigenic sin’ phenotype surprisingly target the same regions of influenza viruses that are recognized by strain-specific antibodies. Most importantly, despite the observation that ‘original antigenic sin’ antibodies bound poorly in conventional binding assays, these antibodies were able to efficiently protect in vivo. These data indicate that antibodies with an ‘original antigenic sin’ phenotype are an underappreciated valuable component of secondary immune responses to influenza viruses.