Germinal center antibody mutation trajectories are determined by rapid self/foreign discrimination.
Germinal center antibody mutation trajectories are determined by rapid self/foreign discrimination.
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DOI：
10.1126/science.aao3859
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发表时间：
2018-04-13
期刊：
影响因子：
--
通讯作者：
Goodnow CC
中科院分区：
文献类型：
--
作者：
Burnett DL;Langley DB;Schofield P;Hermes JR;Chan TD;Jackson J;Bourne K;Reed JH;Patterson K;Porebski BT;Brink R;Christ D;Goodnow CC
抗体具有精确的特异性来区分模仿“自身”的外来抗原，但仍不清楚这种特异性是如何获得的。我们产生了B细胞，其展示与自身细胞和外来细胞上表达的两种相关蛋白抗原交叉反应的抗体。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逆转，导致生发中心募集和抗体基因超突变。单细胞分析揭示了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性突变的较慢选择。晶体结构显示，这些突变利用了微妙的拓扑差异，实现了对自身表位的5,000倍优先结合。引人注目的是，抗原模拟的解析驱动了最佳亲和力成熟轨迹，突出了保留自身反应性克隆作为保护性抗体应答底物的价值。
Antibodies have exquisite specificity to differentiate foreign antigens that mimic “self”, but it remains unclear how such specificity is acquired. 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 revealed rapid selection for mutations that decrease self affinity and slower selection for epistatic mutations that specifically increase foreign affinity. Crystal structures revealed the mutations exploited subtle topological differences to achieve 5,000-fold preferential binding to foreign targets over self epitopes. Strikingly, resolution of antigenic mimicry drove the optimal affinity maturation trajectory, highlighting the value of retaining self-reactive clones as substrates for protective antibody responses.
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DOI：
10.1084/jem.179.2.425
发表时间：
1994-02-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cooke MP;Heath AW;Shokat KM;Zeng Y;Finkelman FD;Linsley PS;Howard M;Goodnow CC
通讯作者：
Goodnow CC
影响因子：
3.6
作者：
Acchione M;Lipschultz CA;DeSantis ME;Shanmuganathan A;Li M;Wlodawer A;Tarasov S;Smith-Gill SJ
通讯作者：
Smith-Gill SJ
影响因子：
56.9
作者：
Haynes, BF;Fleming, J;Alam, SM
通讯作者：
Alam, SM
DOI：
10.1073/pnas.86.15.5938
发表时间：
1989-08-01
影响因子：
11.1
作者：
PADLAN, EA;SILVERTON, EW;DAVIES, DR
通讯作者：
DAVIES, DR
影响因子：
64.8
作者：
Wyatt, R;Kwong, PD;Sodroski, JG
通讯作者：
Sodroski, JG