Hinge influences in murine IgG binding to Cryptococcus neoformans capsule,Immunology

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Hinge influences in murine IgG binding to Cryptococcus neoformans capsule
Immunology ( IF 4.9 ) Pub Date : 2021-08-30 , DOI: 10.1111/imm.13411
Diane Sthefany Lima de Oliveira ₁ , Verenice Paredes ₂ , Adrielle Veloso Caixeta ₂ , Nicole Moreira Henriques ₃ , Maggie P Wear ₄ , Patrícia Albuquerque ₅ , Maria Sueli Soares Felipe ₆ , Arturo Casadevall ₄ , André Moraes Nicola _{2,

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Affiliation

Decades of studies on antibody structure led to the tenet that the V region binds antigens while the C region interacts with immune effectors. In some antibodies, however, the C region affects affinity and/or specificity for the antigen. One example is the 3E5 monoclonal murine IgG family, in which the mIgG3 isotype has different fine specificity to the Cryptococcus neoformans capsule polysaccharide than the other mIgG isotypes despite their identical variable sequences. Our group serendipitously found another pair of mIgG1/mIgG3 antibodies based on the 2H1 hybridoma to the C. neoformans capsule that recapitulated the differences observed with 3E5. In this work, we report the molecular basis of the constant domain effects on antigen binding using recombinant antibodies. As with 3E5, immunofluorescence experiments show a punctate pattern for 2H1-mIgG3 and an annular pattern for 2H1-mIgG1; these binding patterns have been associated with protective efficacy in murine cryptococcosis. Also as observed with 3E5, 2H1-mIgG3 bound on ELISA to both acetylated and non-acetylated capsular polysaccharide, whereas 2H1-mIgG1 only bound well to the acetylated form, consistent with differences in fine specificity. In engineering hybrid mIgG1/mIgG3 antibodies, we found that switching the 2H1-mIgG3 hinge for its mIgG1 counterpart changed the immunofluorescence pattern to annular, but a 2H1-mIgG1 antibody with an mIgG3 hinge still had an annular pattern. The hinge is thus necessary but not sufficient for these changes in binding to the antigen. This important role for the constant region in antigen binding could affect antibody biology and engineering.

中文翻译：

铰链对鼠 IgG 与新型隐球菌胶囊结合的影响

数十年对抗体结构的研究得出了这样一个原则，即 V 区与抗原结合，而 C 区与免疫效应物相互作用。然而，在一些抗体中，C 区影响对抗原的亲和力和/或特异性。一个例子是 3E5 单克隆鼠 IgG 家族，其中 mIgG3 同种型对新型隐球菌荚膜多糖的精细特异性不同于其他 mIgG 同种型，尽管它们具有相同的可变序列。我们小组偶然发现了另一对基于C的 2H1 杂交瘤的 mIgG1/mIgG3 抗体。 新生代胶囊概括了用 3E5 观察到的差异。在这项工作中，我们报告了使用重组抗体的恒定结构域对抗原结合的影响的分子基础。与 3E5 一样，免疫荧光实验显示 2H1-mIgG3 呈点状图案，2H1-mIgG1 呈环状图案；这些结合模式与鼠隐球菌病的保护功效有关。同样如用 3E5 观察到的，2H1-mIgG3 在 ELISA 上与乙酰化和非乙酰化荚膜多糖结合，而 2H1-mIgG1 仅与乙酰化形式很好地结合，这与精细特异性的差异一致。在工程混合 mIgG1/mIgG3 抗体中，我们发现将 2H1-mIgG3 铰链转换为其 mIgG1 对应物将免疫荧光模式变为环状，但是带有 mIgG3 铰链的 2H1-mIgG1 抗体仍然具有环形图案。因此，铰链对于与抗原结合的这些变化是必要的，但还不够。恒定区在抗原结合中的这一重要作用可能会影响抗体生物学和工程。

更新日期：2021-08-30

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