Selective Recognition of Carbohydrate Antigens by Germline Antibodies Isolated from AID Knockout Mice,Journal of the American Chemical Society

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Selective Recognition of Carbohydrate Antigens by Germline Antibodies Isolated from AID Knockout Mice
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2022-03-12 , DOI: 10.1021/jacs.1c12745
Andrew T DeLaitsch ₁ , Jacey R Pridgen ₁ , Avery Tytla ₁ , Megan L Peach ₂ , Rayleen Hu ₁ , David W Farnsworth ₁ , Aislinn K McMillan ₁ , Natalie Flanagan ₁ , J Sebastian Temme ₁ , Marc C Nicklaus ₁ , Jeffrey C Gildersleeve ₁

Affiliation

Germline antibodies, the initial set of antibodies produced by the immune system, are critical for host defense, and information about their binding properties can be useful for designing vaccines, understanding the origins of autoantibodies, and developing monoclonal antibodies. Numerous studies have found that germline antibodies are polyreactive with malleable, flexible binding pockets. While insightful, it remains unclear how broadly this model applies, as there are many families of antibodies that have not yet been studied. In addition, the methods used to obtain germline antibodies typically rely on assumptions and do not work well for many antibodies. Herein, we present a distinct approach for isolating germline antibodies that involves immunizing activation-induced cytidine deaminase (AID) knockout mice. This strategy amplifies antigen-specific B cells, but somatic hypermutation does not occur because AID is absent. Using synthetic haptens, glycoproteins, and whole cells, we obtained germline antibodies to an assortment of clinically important tumor-associated carbohydrate antigens, including Lewis Y, the Tn antigen, sialyl Lewis C, and Lewis X (CD15/SSEA-1). Through glycan microarray profiling and cell binding, we demonstrate that all but one of these germline antibodies had high selectivity for their glycan targets. Using molecular dynamics simulations, we provide insights into the structural basis of glycan recognition. The results have important implications for designing carbohydrate-based vaccines, developing anti-glycan monoclonal antibodies, and understanding antibody evolution within the immune system.

中文翻译：

从 AID 基因敲除小鼠中分离的种系抗体选择性识别碳水化合物抗原

种系抗体是免疫系统产生的最初一组抗体，对于宿主防御至关重要，有关其结合特性的信息可用于设计疫苗、了解自身抗体的起源和开发单克隆抗体。大量研究发现种系抗体具有多反应性，具有可延展、灵活的结合袋。虽然富有洞察力，但目前尚不清楚该模型的应用范围有多广，因为还有许多抗体家族尚未被研究。此外，用于获得种系抗体的方法通常依赖于假设，并且对于许多抗体来说效果不佳。在此，我们提出了一种分离种系抗体的独特方法，该方法涉及免疫激活诱导的胞苷脱氨酶（AID）敲除小鼠。这种策略扩增了抗原特异性 B 细胞，但由于不存在 AID，因此不会发生体细胞超突变。使用合成的半抗原、糖蛋白和全细胞，我们获得了针对各种临床上重要的肿瘤相关碳水化合物抗原的种系抗体，包括 Lewis Y、Tn 抗原、唾液酸 Lewis C 和 Lewis X (CD15/SSEA-1)。通过聚糖微阵列分析和细胞结合，我们证明除了一种之外，所有这些种系抗体都对其聚糖靶标具有高选择性。通过分子动力学模拟，我们深入了解聚糖识别的结构基础。这些结果对于设计基于碳水化合物的疫苗、开发抗聚糖单克隆抗体以及了解免疫系统内的抗体进化具有重要意义。

更新日期：2022-03-12

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