PT  - JOURNAL ARTICLE
AU  - Yufei Xiang
AU  - Zhe Sang
AU  - Lirane Bitton
AU  - Jianquan Xu
AU  - Yang Liu
AU  - Dina Schneidman-Duhovny
AU  - Yi Shi
TI  - Integrative proteomics reveals exceptional diversity and versatility of mammalian humoral immunity
AID  - 10.1101/2020.08.21.261917
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.08.21.261917
4099  - http://biorxiv.org/content/early/2020/08/23/2020.08.21.261917.short
4100  - http://biorxiv.org/content/early/2020/08/23/2020.08.21.261917.full
AB  - 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.Competing Interest StatementThe University of Pittsburgh has filed a provisional patent in connection to the manuscript.