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bioRxiv · 10.1101/2020.08.21.261917

Integrative proteomics reveals exceptional diversity and versatility of mammalian humoral immunity

Xiang, Y.·Sang, Z.·Bitton, L.·Xu, J.·Liu, Y.·Schneidman-Duhovny, D.·Shi, Y.
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Abstract

The humoral immune response is essential for the survival of mammals. However, we still lack a systematic understanding of the specific serologic antibody repertoire in response to an antigen. We developed a proteomic strategy to survey, at an unprecedented scale, the landscapes of antigen-engaged, serum-circulating repertoires of camelid heavy-chain antibodies (hcAbs). The sensitivity and robustness of this technology were validated using three antigens spanning orders of magnitude in immune response; thousands of divergent, high-affinity hcAb families were confidently identified and quantified. Using high-throughput structural modeling, cross-linking mass spectrometry, mutagenesis, and deep learning, we mapped and analyzed the epitopes of > 100,000 antigen-antibody complexes. Our results revealed a surprising diversity of high-affinity hcAbs for specific antigen binding on a variety of dominant epitopes. hcAbs perfect both shape and charge complementarity to target challenging antigens specifically; they can rapidly evolve to recognize a conserved, promiscuous cellular protein interaction interface, unraveling the convergent force that drives protein-protein interactions.

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Xiang, Y., Sang, Z., Bitton, L., Xu, J., Liu, Y., Schneidman-Duhovny, D., Shi, Y.. 2020-08-23. Integrative proteomics reveals exceptional diversity and versatility of mammalian humoral immunity. https://doi.org/10.1101/2020.08.21.261917

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