Human peripheral blood antibodies with long HCDR3s are established primarily at original recombination using a limited subset of germline genes.
Human peripheral blood antibodies with long HCDR3s are established primarily at original recombination using a limited subset of germline genes.
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DOI：
10.1371/journal.pone.0036750
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Crowe JE Jr
中科院分区：
文献类型：
--
作者：
Briney BS;Willis JR;Crowe JE Jr
许多有效中和微生物靶标的抗体含有长重链互补决定区3（HCDR 3）环。对于HIV，几种最广泛和最有效的中和抗体具有特别长的HCDR 3。两种广泛的有效中和HIV特异性抗体，PG 9和PG 16，表现出二级结构。另外两种长HCDR 3抗体2F5和4E10可保护粘膜免受SHIV攻击。这种长HCDR 3抗体的诱导对于设计针对HIV和其他病原体的有效疫苗策略可能是至关重要的，然而目前尚不清楚如何诱导这种抗体。在这里，我们提出的遗传学证据表明，人外周血抗体含有长HCDR3主要不是由体细胞超突变过程中引入的插入产生。相反，它们通常由作为原始重组事件的一部分发生的过程形成。因此，编码具有长HCDR 3的抗体的B细胞的应答是从幼稚库中选择不寻常的克隆而不是通过插入的积累产生的。这些抗体通常使用特别适合于编码长HCDR 3的D和J基因区段的小子集，导致在编码长HCDR 3的大多数抗体序列中掺入高度保守的遗传元件。
A number of antibodies that efficiently neutralize microbial targets contain long heavy chain complementarity determining region 3 (HCDR3) loops. For HIV, several of the most broad and potently neutralizing antibodies have exceptionally long HCDR3s. Two broad potently neutralizing HIV-specific antibodies, PG9 and PG16, exhibit secondary structure. Two other long HCDR3 antibodies, 2F5 and 4E10, protect against mucosal challenge with SHIV. Induction of such long HCDR3 antibodies may be critical to the design of an effective vaccine strategy for HIV and other pathogens, however it is unclear at present how to induce such antibodies. Here, we present genetic evidence that human peripheral blood antibodies containing long HCDR3s are not primarily generated by insertions introduced during the somatic hypermutation process. Instead, they are typically formed by processes occurring as part of the original recombination event. Thus, the response of B cells encoding antibodies with long HCDR3s results from selection of unusual clones from the naïve repertoire rather than through accumulation of insertions. These antibodies typically use a small subset of D and J gene segments that are particularly suited to encoding long HCDR3s, resulting in the incorporation of highly conserved genetic elements in the majority of antibody sequences encoding long HCDR3s.
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