Epitope-specific human influenza antibody repertoires diversify by B cell intraclonal sequence divergence and interclonal convergence.
Epitope-specific human influenza antibody repertoires diversify by B cell intraclonal sequence divergence and interclonal convergence.
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DOI：
10.4049/jimmunol.1101823
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发表时间：
2011-10-01
期刊：
影响因子：
--
通讯作者：
Crowe JE Jr
中科院分区：
文献类型：
--
作者：
Krause JC;Tsibane T;Tumpey TM;Huffman CJ;Briney BS;Smith SA;Basler CF;Crowe JE Jr
我们从一份单一血液样本中产生了五种独立的人单克隆抗体，这些抗体能够识别流感血凝素（HA）头部的Sa抗原位点，并对多种H1N1毒株表现出抑制活性。所有五种抗体都使用了VH3 - 7和JH6基因片段，但通过连接区分析确定了至少四个独立的克隆。对循环B细胞的高通量序列分析显示，每个独立的克隆都是复杂系统发育谱系的成员，这些谱系通过体细胞突变以渐进多样化的模式广泛分化。出乎意料的是，编码这些克隆的多个不同谱系的B细胞，包括许多抗体基因中突变极少的B细胞，在循环中持续存在。相反，我们注意到独立克隆成员所呈现的抗原结合位点中氨基酸序列频繁趋同，这表明对最佳结合位点存在强烈的选择。我们认为，主要克隆的多种体细胞变体在循环中的维持可能有助于识别在快速突变的病毒抗原（如流感血凝素）中出现的漂移变异病毒表位。事实上，这些抗体克隆识别的一个表位获得了三个糖基化位点，从而介导了对先前分离的人源抗体的逃逸。
We generated from a single blood sample five independent human monoclonal antibodies that recognized the Sa antigenic site on the head of influenza HA and exhibited inhibitory activity against a broad panel of H1N1 strains. All five Abs used the VH3-7 and JH6 gene segments, but at least four independent clones were identified by junctional analysis. High throughput sequence analysis of circulating B cells revealed that each of the independent clones were members of complex phylogenetic lineages that had diversified widely using a pattern of progressive diversification through somatic mutation. Unexpectedly, B cells encoding multiple diverging lineages of these clones, including many containing very few mutations in the antibody genes, persisted in the circulation. Conversely, we noted frequent instances of amino acid sequence convergence in the antigen combining sites exhibited by members of independent clones, suggesting a strong selection for optimal binding sites. We suggest that maintenance in circulation of a wide diversity of somatic variants of dominant clones may facilitate recognition of drift variant virus epitopes that occur in rapidly mutating virus antigens, such as influenza HA. In fact, these Ab clones recognize an epitope that acquired three glycosylation sites mediating escape from previously isolated human antibodies.
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影响因子：
5.4
作者：
Krause, Jens C.;Tumpey, Terrence M.;Crowe, James E., Jr.
通讯作者：
Crowe, James E., Jr.
影响因子：
6.7
作者：
Gustchina E;Li M;Louis JM;Anderson DE;Lloyd J;Frisch C;Bewley CA;Gustchina A;Wlodawer A;Clore GM
通讯作者：
Clore GM
影响因子：
64.5
作者：
CATON, AJ;BROWNLEE, GG;GERHARD, W
通讯作者：
GERHARD, W
影响因子：
3.6
作者：
Abhinandan, K. R.;Martin, Andrew C. R.
通讯作者：
Martin, Andrew C. R.
DOI：
10.1084/jem.183.5.2053
发表时间：
1996-05-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Liu AH;Jena PK;Wysocki LJ
通讯作者：
Wysocki LJ