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Identifying the immune interactions underlying HLA class I disease associations

Published version
Peer-reviewed

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Authors

Debebe, Bisrat J 
Boelen, Lies 
Lee, James C 
IAVI Protocol C Investigators 
Thio, Chloe L 

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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Keywords

Research Article, Computational and Systems Biology, Immunology and Inflammation, HLA, GWAS, CD8 T cell, natural killer cell, disease association, immunogenetics, Human

Journal Title

eLife

Conference Name

Journal ISSN

2050-084X

Volume Title

9

Publisher

eLife Sciences Publications, Ltd
Sponsorship
Wellcome (103865Z/14/Z)
Medical Research Council (J007439)
Medical Research Council (G1001052)
European Union Seventh Framework Programme (317040)
Bloodwise (15012)
Wellcome (105920/Z/14/Z)
National Institutes of Health (DA13324)
National Institutes of Health (R01-HD-41224)
National Institutes of Health (U01-DA-036297)
National Institutes of Health (R01-DA-12568)
National Institutes of Health (K24-AI118591)