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Identifying the immune interactions underlying HLA class I disease associations

Identifying the immune interactions underlying HLA class I disease associations
Identifying the immune interactions underlying HLA class I disease associations

Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms at 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.

2050-084X
Debebe, Bisrat J.
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Boelen, Lies
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Lee, James C.
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Thio, Chloe L.
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Astemborski, Jacquie
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Kirk, Gregory
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Khakoo, Salim I.
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Donfield, Sharyne M.
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Goedert, James J.
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Asquith, Becca
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Sanders, Eduard J.
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Anzala, Omu
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Kamali, Anatoli
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Kaleebu, Pontiano
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Karita, Etienne
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Kilembe, William
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Inambao, Mubiana
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Lakhi, Shabir
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Allen, Susan
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Hunter, Eric
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Edward, Vinodh A.
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Fast, Pat E.
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Price, Matt A.
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Gilmour, Jill
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Tang, Jianming
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IAVI Protocol C Investigators
Debebe, Bisrat J.
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Boelen, Lies
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Lee, James C.
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Thio, Chloe L.
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Astemborski, Jacquie
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Kirk, Gregory
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Khakoo, Salim I.
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Donfield, Sharyne M.
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Goedert, James J.
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Asquith, Becca
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Sanders, Eduard J.
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Anzala, Omu
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Kamali, Anatoli
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Kaleebu, Pontiano
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Karita, Etienne
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Kilembe, William
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Inambao, Mubiana
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Lakhi, Shabir
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Allen, Susan
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Hunter, Eric
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Edward, Vinodh A.
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Fast, Pat E.
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Price, Matt A.
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Gilmour, Jill
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Tang, Jianming
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Debebe, Bisrat J., Boelen, Lies, Lee, James C., Thio, Chloe L., Astemborski, Jacquie, Kirk, Gregory, Khakoo, Salim I., Donfield, Sharyne M., Goedert, James J. and Asquith, Becca , IAVI Protocol C Investigators (2020) Identifying the immune interactions underlying HLA class I disease associations. eLife, 9, [e54558]. (doi:10.7554/eLife.54558).

Record type: Article

Abstract

Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms at 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.

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elife-54558-v2 - Version of Record
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Submitted date: 18 December 2019
Accepted/In Press date: 6 March 2020
Published date: 2 April 2020

Identifiers

Local EPrints ID: 444388
URI: http://eprints.soton.ac.uk/id/eprint/444388
ISSN: 2050-084X
PURE UUID: 8ef07753-fc86-4850-b087-df9bfd2125f6

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Date deposited: 16 Oct 2020 16:30
Last modified: 16 Mar 2021 17:42

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Contributors

Author: Bisrat J. Debebe
Author: Lies Boelen
Author: James C. Lee
Author: Chloe L. Thio
Author: Jacquie Astemborski
Author: Gregory Kirk
Author: Salim I. Khakoo
Author: Sharyne M. Donfield
Author: James J. Goedert
Author: Becca Asquith
Author: Eduard J. Sanders
Author: Omu Anzala
Author: Anatoli Kamali
Author: Pontiano Kaleebu
Author: Etienne Karita
Author: William Kilembe
Author: Mubiana Inambao
Author: Shabir Lakhi
Author: Susan Allen
Author: Eric Hunter
Author: Vinodh A. Edward
Author: Pat E. Fast
Author: Matt A. Price
Author: Jill Gilmour
Author: Jianming Tang
Corporate Author: IAVI Protocol C Investigators

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