Autoantibody discovery across monogenic, acquired, and COVID19-associated autoimmunity with scalable PhIP-Seq

  1. Sara E Vazquez
  2. Sabrina A Mann
  3. Aaron Bodansky
  4. Andrew F Kung
  5. Zoe Quandt
  6. Elise M N Ferré
  7. Nils Landegren
  8. Daniel Eriksson
  9. Paul Bastard
  10. Shen-Ying Zhang
  11. Jamin Liu
  12. Anthea Mitchell
  13. Irina Proekt
  14. David Yu
  15. Caleigh Mandel-Brehm
  16. Chung-Yu Wang
  17. Brenda Miao
  18. Gavin Sowa
  19. Kelsey Zorn
  20. Alice Y Chan
  21. Veronica M Tagi
  22. Chisato Shimizu
  23. Adriana Tremoulet
  24. Kara Lynch
  25. Michael R Wilson
  26. Olle Kämpe
  27. Kerry Dobbs
  28. Ottavia M Delmonte
  29. Rosa Bacchetta
  30. Luigi D Notarangelo
  31. Jane C Burns
  32. Jean-Laurent Casanova
  33. Michail S Lionakis
  34. Troy R Torgerson
  35. Mark S Anderson  Is a corresponding author
  36. Joseph L DeRisi  Is a corresponding author
  1. University of California, San Francisco, United States
  2. National Institute of Allergy and Infectious Diseases, United States
  3. Karolinska Institute, Sweden
  4. Rockefeller University, United States
  5. Stanford University, United States
  6. University of California, San Diego, United States
  7. Seattle Children's Research Institute, United States

Abstract

Phage Immunoprecipitation-Sequencing (PhIP-Seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-Seq for autoantigen discovery, including our previous work (Vazquez et al. 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki Disease (KD), Multisystem Inflammatory Syndrome in Children (MIS-C), and finally, mild and severe forms of COVID19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as PDYN in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in 2 patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-Seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID19, including the endosomal protein EEA1. Together, scaled PhIP-Seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.

Data availability

Full PhIP-Seq data for all cohorts presented is available for download at Dryad at https://doi.org/10.5061/dryad.qfttdz0k4. All available deidentified clinical data for this study is available in Supplemental Table 1.

The following data sets were generated

Article and author information

Author details

  1. Sara E Vazquez

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0601-7001
  2. Sabrina A Mann

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4970-1073
  3. Aaron Bodansky

    Department of Pediatric Critical Care Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Andrew F Kung

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Zoe Quandt

    Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Elise M N Ferré

    Fungal Pathogenesis Unit, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Nils Landegren

    Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6163-9540
  8. Daniel Eriksson

    Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5473-3312
  9. Paul Bastard

    St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Shen-Ying Zhang

    St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jamin Liu

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Anthea Mitchell

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Irina Proekt

    Diabetes Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. David Yu

    Diabetes Center, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Caleigh Mandel-Brehm

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Chung-Yu Wang

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. Brenda Miao

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3393-9837
  18. Gavin Sowa

    School of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2089-8116
  19. Kelsey Zorn

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Alice Y Chan

    Department of Pediatrics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Veronica M Tagi

    Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Chisato Shimizu

    Kawasaki Disease Research Center, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  23. Adriana Tremoulet

    Kawasaki Disease Research Center, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  24. Kara Lynch

    Department of Laboratory Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  25. Michael R Wilson

    Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8705-5084
  26. Olle Kämpe

    Department of Medicine, Karolinska Institute, Stockholm, Sweden
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6091-9914
  27. Kerry Dobbs

    Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3432-3137
  28. Ottavia M Delmonte

    Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  29. Rosa Bacchetta

    Division of Stem Cell Transplantation and Regenerative Medicine, Stanford University, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  30. Luigi D Notarangelo

    Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  31. Jane C Burns

    Kawasaki Disease Research Center, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  32. Jean-Laurent Casanova

    St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  33. Michail S Lionakis

    Fungal Pathogenesis Section, National Institute of Allergy and Infectious Diseases, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  34. Troy R Torgerson

    Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3489-5036
  35. Mark S Anderson

    Diabetes Center, University of California, San Francisco, San Francisco, United States
    For correspondence
    Mark.Anderson@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3093-4758
  36. Joseph L DeRisi

    Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
    For correspondence
    joe@derisilab.ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4611-9205

Funding

National Institute of Allergy and Infectious Diseases (5P01AI118688)

  • Mark S Anderson

UCSF-CTSI TL1 (TR001871)

  • Zoe Quandt

Division of Intramural Research, National Institute of Allergy and Infectious Diseases (1 ZIA AI001222)

  • Luigi D Notarangelo

National Institute of Child Health and Development (1R61HD105590)

  • Adriana Tremoulet
  • Jane C Burns

Multiple sources**

  • Jean-Laurent Casanova

FRM (EA20170638020)

  • Paul Bastard

MD-PhD program of the Imagine Institute

  • Paul Bastard

National Institute of Allergy and Infectious Diseases (1ZIAAI001175)

  • Michail S Lionakis

National Institute of Diabetes and Digestive and Kidney Diseases (1F30DK123915)

  • Sara E Vazquez

Chan Zuckerberg Biohub

  • Joseph L DeRisi

Parker Institute for Cancer Immunotherapy

  • Mark S Anderson

Juvenile Diabetes Research Foundation United States of America

  • Mark S Anderson

Helmsley Charitable Trust

  • Mark S Anderson

National Institute of General Medical Sciences (5T32GM007618)

  • Mark S Anderson

American Diabetes Association (1-19-PDF-131)

  • Zoe Quandt

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.**multiple sources includes: The Laboratory of Human Genetics of Infectious Diseases is supported by the Howard Hughes Medical Institute, the Rockefeller University, the St. Giles Foundation, the National Institutes of Health (NIH) (R01AI088364 and R01AI163029), the National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), the Fisher Center for Alzheimer's Research Foundation, the Meyer Foundation, the JPB Foundation, the French National Research Agency (ANR) under the Investments for the Future" program (ANR-10-IAHU-01)

Reviewing Editor

  1. Antony Rosen, Johns Hopkins University School of Medicine, United States

Ethics

Human subjects: Detailed information on consent, where applicable, is available in the methods section of the manuscript.

Version history

  1. Received: March 23, 2022
  2. Preprint posted: March 25, 2022 (view preprint)
  3. Accepted: October 10, 2022
  4. Accepted Manuscript published: October 27, 2022 (version 1)
  5. Version of Record published: November 30, 2022 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Sara E Vazquez
  2. Sabrina A Mann
  3. Aaron Bodansky
  4. Andrew F Kung
  5. Zoe Quandt
  6. Elise M N Ferré
  7. Nils Landegren
  8. Daniel Eriksson
  9. Paul Bastard
  10. Shen-Ying Zhang
  11. Jamin Liu
  12. Anthea Mitchell
  13. Irina Proekt
  14. David Yu
  15. Caleigh Mandel-Brehm
  16. Chung-Yu Wang
  17. Brenda Miao
  18. Gavin Sowa
  19. Kelsey Zorn
  20. Alice Y Chan
  21. Veronica M Tagi
  22. Chisato Shimizu
  23. Adriana Tremoulet
  24. Kara Lynch
  25. Michael R Wilson
  26. Olle Kämpe
  27. Kerry Dobbs
  28. Ottavia M Delmonte
  29. Rosa Bacchetta
  30. Luigi D Notarangelo
  31. Jane C Burns
  32. Jean-Laurent Casanova
  33. Michail S Lionakis
  34. Troy R Torgerson
  35. Mark S Anderson
  36. Joseph L DeRisi
(2022)
Autoantibody discovery across monogenic, acquired, and COVID19-associated autoimmunity with scalable PhIP-Seq
eLife 11:e78550.
https://doi.org/10.7554/eLife.78550

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https://doi.org/10.7554/eLife.78550

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