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REAP: A platform to identify autoantibodies that target the human exoproteome

View ORCID ProfileEric Y. Wang, Yile Dai, View ORCID ProfileConnor E. Rosen, Monica M. Schmitt, Mei X. Dong, Elise M. N. Ferré, View ORCID ProfileFeimei Liu, Yi Yang, Jaime A. Gonzalez-Hernandez, Eric Meffre, Monique Hinchcliffe, Fotios Koumpouras, View ORCID ProfileMichail S. Lionakis, View ORCID ProfileAaron M. Ring
doi: https://doi.org/10.1101/2021.02.11.430703
Eric Y. Wang
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Yile Dai
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Connor E. Rosen
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Monica M. Schmitt
4Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Mei X. Dong
3Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
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Elise M. N. Ferré
4Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Feimei Liu
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Yi Yang
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Jaime A. Gonzalez-Hernandez
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Eric Meffre
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
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Monique Hinchcliffe
3Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
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Fotios Koumpouras
3Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
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Michail S. Lionakis
4Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Aaron M. Ring
1Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA
2Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
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  • For correspondence: aaron.ring@yale.edu
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Abstract

Autoantibodies that recognize extracellular proteins (the “exoproteome”) exert potent biological effects but have proven challenging to detect with existing screening technologies. Here, we developed Rapid Extracellular Antigen Profiling (REAP) as a technique for comprehensive, high-throughput discovery of exoproteome-targeting autoantibodies. With REAP, patient samples are applied to a genetically-barcoded library containing 2,688 human extracellular proteins displayed on the surface of yeast. Antibody-coated cells are isolated by magnetic selection and deep sequencing of their barcodes is used to identify the displayed antigens. To benchmark the performance of REAP, we screened 77 patients with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED). REAP sensitively and specifically detected known autoantibody reactivities in APECED in addition to numerous previously unidentified reactivities. We further screened 106 patients with systemic lupus erythematosus (SLE) and identified novel autoantibody reactivities against a diverse set of antigens including growth factors, extracellular matrix components, cytokines, and immunomodulatory proteins. Several of these responses were associated with disease severity and specific clinical manifestations of SLE and exerted potent functional effects on cell signaling ex vivo. These findings demonstrate the utility of REAP to atlas the expansive landscape of exoproteome-targeting autoantibodies and their impacts on patient health outcomes.

Competing Interest Statement

E.Y.W., Y.D., C.E.R., and A.M.R. are inventors of a patent describing the REAP technology and A.M.R. is the founder of Seranova Bio.

Footnotes

  • corrected mislabelled y-axis in Figure 3e

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 21, 2021.
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REAP: A platform to identify autoantibodies that target the human exoproteome
Eric Y. Wang, Yile Dai, Connor E. Rosen, Monica M. Schmitt, Mei X. Dong, Elise M. N. Ferré, Feimei Liu, Yi Yang, Jaime A. Gonzalez-Hernandez, Eric Meffre, Monique Hinchcliffe, Fotios Koumpouras, Michail S. Lionakis, Aaron M. Ring
bioRxiv 2021.02.11.430703; doi: https://doi.org/10.1101/2021.02.11.430703
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REAP: A platform to identify autoantibodies that target the human exoproteome
Eric Y. Wang, Yile Dai, Connor E. Rosen, Monica M. Schmitt, Mei X. Dong, Elise M. N. Ferré, Feimei Liu, Yi Yang, Jaime A. Gonzalez-Hernandez, Eric Meffre, Monique Hinchcliffe, Fotios Koumpouras, Michail S. Lionakis, Aaron M. Ring
bioRxiv 2021.02.11.430703; doi: https://doi.org/10.1101/2021.02.11.430703

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