Promiscuity and Polyreactivity of Antibodies and their Binding Modes during B-Cell Differentiation
Promiscuity and Polyreactivity of Antibodies and their Binding Modes during B-Cell Differentiation
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B 细胞分化过程中抗体的混杂性和多反应性及其结合模式
DOI：
10.1016/j.bpj.2015.11.1153
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发表时间：
2016
影响因子：
3.4
通讯作者：
Fraternali F
中科院分区：
文献类型：
--
作者：
Fraternali F
在中心耐受性过程中，多种多样的机制发生，从而产生一系列具有结合特异性的抗体（Abs），其中一些导致多反应性。通过重链和轻链Ig基因的高通量测序，研究了外周血中预B细胞（中心耐受前）、未成熟B细胞（中心耐受期间）和naïve B细胞（中心耐受后）的库。研究表明，老年人产生抗体的细胞种类较少，而这种多样性的丧失与健康状况不佳有关。在应答细胞群中，存在Ab基因CDRH3环的有利特征，这对结合外来抗原至关重要。我们假设有利的物理化学特性使CDRH3的结构能够结合多种外源抗原（多特异性）。在结合特异性方面预测这种混杂行为的能力将大大提高治疗性抗体发现过程的效率。从这些数据中，我们希望通过利用结构和动力学信息提取在多反应性中起作用的分子决定因素。我们使用统计分析对CDRH3的物理化学性质和分子动力学（MD）在原子和/或粗粒度水平上的模拟进行分类，以表征结合多样性的灵活性要求。
Many diversification mechanisms occurr during central tolerance leading to a wide array of antibodies (Abs) with a range of binding specificities, some of which lead to polyreactivity. The repertoire of preB cells (before central tolerance), immature B cells (during central tolerance) and naïve B cells in the peripheral blood (after central tolerance) has been interrogated by high throughput sequencing of heavy and light chain Ig genes. It has been shown that older people display a less diverse repertoire of antibody-producing cells, and that this loss of diversity is associated with poor health. Within a population of responding cells there are favoured characteristics of a the Ab gene CDRH3 loop that is crucial in binding the foreign antigen. We hypothesise that favoured physico-chemical CDRH3 characteristics make a structure capable of binding to multiple foreign antigens (polyspecific).The ability to predict this promiscuous behaviour with respect to binding specificity would greatly improve the efficiency of the therapeutic antibody discovery process. From these data we want to extract the molecular determinants playing a role in polyreactivity by exploiting structural and dynamical information. We use statistical analyses to classify CDRH3 physico-chemical properties and Molecular Dynamics (MD) simulations at the atomistic and/or coarse grained levels to characterise flexibility requirements for binding multiplicity.