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Structural Requirements of the Major Protective Antibody to Haemophilus influenzae Type b

机译：b型流感嗜血杆菌主要保护抗体的结构要求

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Protective antibodies to the important childhood pathogenHaemophilus influenzae type b (Hib) are directed against the capsular polysaccharide (HibCP). Most of the antibody is encoded by a well-defined set of (“canonical”) immunoglobulin genes, including the Vκ A2 gene, and expresses an idiotypic marker (HibId-1). In comparison to noncanonical antibodies, the canonical antibody is generally of higher avidity, shows higher levels of in vitro bactericidal activity, and is more protective in infant rats. Using site-directed mutagenesis, we here characterize canonical HibCP antibodies expressed as antigen-binding fragments (Fabs) in Escherichia coli, define amino acids involved in antigen binding and idiotype expression, and propose a three-dimensional structure for the variable domains. We found that canonical Fabs, unlike a noncanonical Fab, bound effectively to HibCP in the absence of somatic mutations. Nevertheless, pronounced mutation-based affinity maturation was demonstrated in vivo. An almost perfect correlation was found between unmutated gene segments that mediated binding in vitro and those encoding canonical HibCP antibodies in vivo. Thus, the Vκ A2a gene could be replaced by the A2c gene but not by the highly homologous sister gene, A18b, corresponding to the demonstrated usage of A2c but not of A18b in vivo. Similarly, only Jκ1 and Jκ3, which predominate in the response in vivo, were able to facilitate binding in vitro. These findings suggest that the restricted immunoglobulin gene usage in HibCP antibodies reflects strict structural demands ensuring relatively high affinity prior to somatic mutations—requirements met by only a limited spectrum of immunoglobulin gene combinations.
机译：针对重要的儿童期病原体乙型流感嗜血杆菌（Hib）的保护性抗体针对荚膜多糖（HibCP）。大多数抗体由一组明确定义的（“规范”）免疫球蛋白基因编码，包括V κ A2基因，并表达独特型标记（HibId-1）。与非经典抗体相比，经典抗体通常具有更高的亲和力，表现出更高水平的体外杀菌活性，并且在婴儿大鼠中更具保护性。使用定点诱变，我们在这里表征了在大肠杆菌中表达为抗原结合片段（Fabs）的典型HibCP抗体，定义了参与抗原结合和独特型表达的氨基酸，并提出了三维结构对于可变域。我们发现，与非经典Fab不同，经典Fab在没有体细胞突变的情况下可有效结合HibCP。然而，在体内证明了基于突变的亲和力成熟。发现在体外介导结合的未突变基因区段与在体内编码经典HibCP抗体的区段之间存在几乎完美的相关性。因此，V κ A2a基因可以被A2c基因取代，而不能被高度同源的姊妹基因A18b取代，这与已证明的A2c在体内的用法而不是A18c在体内的用途相符。同样，只有J κ 1和J κ 3（它们在体内的响应中占主导）能够促进体外结合。这些发现表明，HibCP抗体中有限的免疫球蛋白基因使用反映了严格的结构要求，确保在体细胞突变之前具有相对较高的亲和力-仅有限范围的免疫球蛋白基因组合可以满足要求。

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