1. Immunology and Inflammation
  2. Structural Biology and Molecular Biophysics
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Biochemical patterns of antibody polyreactivity revealed through a bioinformatics-based analysis of CDR loops

Research Article
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Cite this article as: eLife 2020;9:e61393 doi: 10.7554/eLife.61393

Abstract

Antibodies are critical components of adaptive immunity, binding with high affinity to pathogenic epitopes. Antibodies undergo rigorous selection to achieve this high affinity, yet some maintain an additional basal level of low affinity, broad reactivity to diverse epitopes, a phenomenon termed 'polyreactivity'. While polyreactivity has been observed in antibodies isolated from various immunological niches, the biophysical properties that allow for promiscuity in a protein selected for high affinity binding to a single target remain unclear. Using a database of over 1,000 polyreactive and non-polyreactive antibody sequences, we created a bioinformatic pipeline to isolate key determinants of polyreactivity. These determinants, which include an increase in inter-loop crosstalk and a propensity for a neutral binding surface, are sufficient to generate a classifier able to identify polyreactive antibodies with over 75% accuracy. The framework from which this classifier was built is generalizable, and represents a powerful, automated pipeline for future immune repertoire analysis.

Article and author information

Author details

  1. Christopher T Boughter

    Graduate Program in Biophysical Sciences, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Marta T Borowska

    Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jenna J Guthmiller

    Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Albert Bendelac

    Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Patrick C Wilson

    Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Benoit Roux

    Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5254-2712
  7. Erin J Adams

    Department of Biochemistry and Molecular Biology; Committee on Immunology, University of Chicago, Chicago, United States
    For correspondence
    ejadams@uchicago.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6271-8574

Funding

National Institute of Biomedical Imaging and Bioengineering (EB009412)

  • Christopher T Boughter

National Institute of Allergy and Infectious Diseases (AI147954)

  • Christopher T Boughter
  • Marta T Borowska
  • Erin J Adams

National Institute of Allergy and Infectious Diseases (AI115471)

  • Christopher T Boughter
  • Marta T Borowska
  • Erin J Adams

National Science Foundation (MCB-1517221)

  • Christopher T Boughter
  • Benoit Roux

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Pamela J Bjorkman, California Institute of Technology, United States

Publication history

  1. Received: July 23, 2020
  2. Accepted: November 9, 2020
  3. Accepted Manuscript published: November 10, 2020 (version 1)

Copyright

? 2020, Boughter et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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