Distorted antibody repertoire developed in the absence of pre-B cell receptor formation
Distorted antibody repertoire developed in the absence of pre-B cell receptor formation
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在没有前 B 细胞受体形成的情况下开发出扭曲的抗体库
DOI：
10.1016/j.bbrc.2017.11.171
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Kazuo Ohnishi
中科院分区：
文献类型：
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作者：
Lin Sun;Naoko Kono;Takeyuki Shimizu;Hiroyuki Toh;Hanbing Xue;Osamu Numata;Manabu Ato;Shigeyuki Itamura;Kazuo Ohnishi
前B细胞受体（pre-BCR）由μ重链（μHC）和替代轻链（SLC、Vpre-B和λ5）组成，在B细胞发育过程中起重要作用。前BCR的形成使新生免疫球蛋白HC与SLC结合，被认为是B细胞发育的先决条件。然而，在SLC缺陷小鼠中存在大量的外周成熟（渗漏）B细胞。这些渗漏的B细胞在没有前BCR的情况下发育，并且不经历前BCR检查点。因此，渗漏B细胞的抗体库反映了前BCR功能的缺失。为了研究前BCR的缺失是如何被这些漏B细胞规避的，并检查前BCR检查点对抗体系统的影响，我们使用下一代测序分析了λ5缺陷（λ5−/−）小鼠的抗体库。在λ5−/−小鼠中，脾B细胞显示出与野生型（WT）小鼠不同的VDJ使用模式。此外，渗漏B细胞既不是来源于不寻常的B2细胞，其特征在于在不存在前BCR信号传导的情况下的特定LC基因重排，也不是来源于B1细胞，其来源于不同的B细胞祖细胞。对μ链库的CDR-H3氨基酸序列的分析显示，某些具有特定CDR-H3谱的骨髓B细胞在λ5−/−小鼠中进行克隆扩增。在λ5−/−小鼠中，这些CDR-H3的一部分在CDR-H3环的中间含有精氨酸，而在没有克隆扩增的情况下，WT CDR-H3的中间环中几乎不存在精氨酸。λ5−/−小鼠中的CDR-H3特征可能反映了前BCR在自身抗体调节中的作用，因为精氨酸通常存在于自身抗体的抗原结合位点。在这里，我们提出了一个独特的观点前BCR的作用，通过评估整个抗体库形成SLC缺陷小鼠。
The pre-B cell receptor (pre-BCR), consisting of the μ heavy chain (μHC) and the surrogate light chain (SLC, Vpre-B and λ5), plays important roles during B cell development. The formation of the pre-BCR, which enables the nascent immunoglobulin HC to associate with the SLC, is considered a prerequisite for B cell development. However, a significant number of peripheral mature (leaky) B cells exist in SLC-deficient mice. These leaky B cells develop in the absence of pre-BCR and do not undergo the pre-BCR checkpoint. The antibody repertoires of leaky B cells thus reflect the absence of pre-BCR function. To investigate how the absence of the pre-BCR is circumvented by these leaky-B cells and examine the effect of the pre-BCR checkpoint on the antibody system, we analyzed the antibody repertoires of λ5-deficient (λ5−/−) mice using next-generation sequencing. In λ5−/−mice, spleen B cells displayed different patterns of VDJ-usage, relative to those in wild-type (WT) mice. Moreover, leaky B cells were neither derived from unusual B2 cells, characterized by particular LC gene rearrangements in the absence of pre-BCR signaling, nor from B1 cells, originating from different B cell progenitors. Analysis of the CDR-H3 amino acid sequences of μ-chain repertoires revealed that certain bone marrow B cells with particular CDR-H3 profiles undergo clonal expansion in λ5−/−mice. Part of these CDR-H3s contain arginine(s) in the middle of the CDR-H3 loop in λ5−/−mice, whereas few arginine(s) exist in this middle loop in WT CDR-H3s in the absence of clonal expansion. This CDR-H3 feature in λ5−/−mice presumably reflects the role of the pre-BCR in autoantibody regulation, since arginine(s) are often found in the antigen-binding site of autoantibodies. Here, we present a unique viewpoint on the role of pre-BCR, by assessing the whole antibody repertoire formed in SLC-deficient mice.