Identifying the immune interactions underlying HLA class I disease associations

  1. Bisrat J Debebe
  2. Lies Boelen
  3. James C Lee
  4. IAVI Protocol C Investigators
  5. Chloe L Thio
  6. Jacquie Astemborski
  7. Gregory Kirk
  8. Salim I Khakoo
  9. Sharyne M Donfield
  10. James J Goedert
  11. Becca Asquith  Is a corresponding author
  1. Imperial College London, United Kingdom
  2. University of Cambridge, United Kingdom
  3. Johns Hopkins University, United States
  4. Johns Hopkins, United States
  5. University of Southampton, United Kingdom
  6. Rho, United States
  7. NCI, United States

Abstract

Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms in the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of 'protective' or 'detrimental' CD8+ T cell responses which are restricted by the host HLA class I allotype. However, given the diverse receptors which are bound by HLA class I molecules, alternative interpretations are possible. As well as binding T cell receptors on CD8+ T cells, HLA class I molecules are important ligands for inhibitory and activating killer immunoglobulin-like receptors (KIRs) which are found on natural killer cells and some T cells; for the CD94:NKG2 family of receptors also expressed mainly by NK cells and for leukocyte immunoglobulin-like receptors (LILRs) on myeloid cells. The aim of this study is to develop an immunogenetic approach for identifying and quantifying the relative contribution of different receptor-ligand interactions to a given HLA class I disease association and then to use this approach to investigate the immune interactions underlying HLA class I disease associations in three viral infections: Human T cell Leukemia Virus type 1, Human Immunodeficiency Virus type 1 and Hepatitis C Virus as well as in the inflammatory condition Crohn's disease.

Data availability

Upon acceptance we will upload, to a public database, all the data analysis ie the data underlying Figure 1, Figure 2, Figure 3, Supplementary Figure S1, Supplementary Figure S2, Supplementary Figure S3 and Supplementary Figure S4. We are unable to provide the raw patient data as this has been released to us under MTAs and uploading of data would violate the terms of these MTAs.The PIs we contacted for the various cohorts are: Pat Fast, IAVI, New York (IAVI); Charles Bangham, Imperial College London, UK (Kagoshima cohort); Greg Kirk, Johns Hopkins, USA (ALIVE cohort); James Goedert, NIH (MHCS cohort); Sharyne Donfield, Rho, USA (HGDS cohort); Salim Khakoo, University of Southampton, UK (UK HCV cohort) and James Lee, University of Cambridge, UK (Crohn's disease cohort). Requests for data access and usage are reviewed by the relevant boards at each institution.

Article and author information

Author details

  1. Bisrat J Debebe

    Infectious Disease, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Lies Boelen

    Infectious Disease, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. James C Lee

    Gastroenterology, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. IAVI Protocol C Investigators

  5. Chloe L Thio

    Epidemiology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jacquie Astemborski

    Epidemiology, Johns Hopkins, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Gregory Kirk

    Epidemiology, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Salim I Khakoo

    Medicine, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Sharyne M Donfield

    Rho, Chapel Hill, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. James J Goedert

    Division of Cancer Epidemiology and Genetics, NCI, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Becca Asquith

    Infectious Disease, Imperial College London, London, United Kingdom
    For correspondence
    b.asquith@imperial.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5911-3160

Funding

Wellcome (103865Z/14/Z)

  • Becca Asquith

National Institutes of Health (R01-DA-12568)

  • Gregory Kirk

National Institutes of Health (K24-AI118591)

  • Gregory Kirk

Medical Research Council (J007439)

  • Becca Asquith

Medical Research Council (G1001052)

  • Becca Asquith

European Commission (317040)

  • Becca Asquith

Bloodwise (15012)

  • Becca Asquith

Wellcome (105920/Z/14/Z)

  • James C Lee

National Institutes of Health (DA13324)

  • Chloe L Thio

National Institutes of Health (R01-HD-41224)

  • Sharyne M Donfield

National Institutes of Health (U01-DA-036297)

  • Gregory Kirk

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

Ethics

Human subjects: This study was approved by the NHS Research Ethics Committee (13/WS/0064) and the Imperial College Research Ethics Committee (ICREC_11_1_2). Informed consent was obtained at the study sites from all individuals. The study was conducted according to the principles of the Declaration of Helsinki.

Reviewing Editor

  1. Miles P Davenport, University of New South Wales, Australia

Publication history

  1. Received: December 18, 2019
  2. Accepted: March 6, 2020
  3. Accepted Manuscript published: April 2, 2020 (version 1)
  4. Version of Record published: May 27, 2020 (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. Bisrat J Debebe
  2. Lies Boelen
  3. James C Lee
  4. IAVI Protocol C Investigators
  5. Chloe L Thio
  6. Jacquie Astemborski
  7. Gregory Kirk
  8. Salim I Khakoo
  9. Sharyne M Donfield
  10. James J Goedert
  11. Becca Asquith
(2020)
Identifying the immune interactions underlying HLA class I disease associations
eLife 9:e54558.
https://doi.org/10.7554/eLife.54558

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