eLife (Apr 2020)

Identifying the immune interactions underlying HLA class I disease associations

  • Bisrat J Debebe,
  • Lies Boelen,
  • James C Lee,
  • IAVI Protocol C Investigators,
  • Chloe L Thio,
  • Jacquie Astemborski,
  • Gregory Kirk,
  • Salim I Khakoo,
  • Sharyne M Donfield,
  • James J Goedert,
  • Becca Asquith

DOI
https://doi.org/10.7554/eLife.54558
Journal volume & issue
Vol. 9

Abstract

Read online

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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