Autoantibody redemption through rapid mutations Antibodies distinguish foreign epitopes from closely related self-antigens by poorly understood mechanisms. In mice, Burnett et al. found that a proportion of B cells could cross-react with similar foreign and self-antigens (see the Perspective by Kara and Nussenzweig). Challenge with self-antigen resulted in anergy (i.e., a lack of immune response), which was reversed by exposure to high-density foreign antigen. Mutations that decreased self-affinity were rapidly selected for, whereas selection for epistatic mutations that enhanced foreign reactivity took longer. Self-reactivity, rather than being an impediment to immunization, resulted in higher affinities against a foreign immunogen. Science, this issue p. 223; see also p. 152 The rapid mutations of autoantibodies target foreign-antigen look-alikes. Antibodies have the specificity to differentiate foreign antigens that mimic self antigens, but it remains unclear how such specificity is acquired. In a mouse model, we generated B cells displaying an antibody that cross-reacts with two related protein antigens expressed on self versus foreign cells. B cell anergy was imposed by self antigen but reversed upon challenge with high-density foreign antigen, leading to germinal center recruitment and antibody gene hypermutation. Single-cell analysis detected rapid selection for mutations that decrease self affinity and slower selection for epistatic mutations that specifically increase foreign affinity. Crystal structures revealed that these mutations exploited subtle topological differences to achieve 5000-fold preferential binding to foreign over self epitopes. Resolution of antigenic mimicry drove the optimal affinity maturation trajectory, highlighting the value of retaining self-reactive clones as substrates for protective antibody responses.

中文翻译：

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生发中心抗体突变轨迹由快速自体/外体辨别确定


通过快速突变进行自身抗体救赎抗体通过知之甚少的机制区分外来表位和密切相关的自身抗原。在小鼠中，伯内特等人。发现一部分 B 细胞可以与类似的外来抗原和自身抗原发生交叉反应（参见 Kara 和 Nussenzweig 的观点）。自身抗原的攻击导致无反应性（即缺乏免疫反应），通过暴露于高密度外来抗原可以逆转这种情况。降低自亲和力的突变被快速选择，而选择增强外源反应性的上位突变则需要更长的时间。自身反应性并没有成为免疫的障碍，而是导致对外源免疫原具有更高的亲和力。科学，本期第 14 页。 223；另见 p. 152 自身抗体的快速突变针对相似的外来抗原。抗体具有区分模仿自身抗原的外来抗原的特异性，但目前尚不清楚如何获得这种特异性。在小鼠模型中，我们生成了展示抗体的 B 细胞，该抗体与自身细胞和外来细胞上表达的两种相关蛋白抗原发生交叉反应。 B 细胞无反应性是由自身抗原造成的，但在高密度外源抗原的攻击下会逆转，导致生发中心募集和抗体基因超突变。单细胞分析检测到对降低自身亲和力的突变的快速选择和对特异性增加外源亲和力的上位突变的较慢选择。晶体结构表明，这些突变利用微妙的拓扑差异来实现与外源表位的优先结合，比与自身表位的结合高 5000 倍。 抗原拟态的解析推动了最佳亲和力成熟轨迹，突出了保留自身反应克隆作为保护性抗体反应底物的价值。