Identifying the immune interactions underlying HLA class I disease associations.
Debebe BJ., Boelen L., Lee JC., IAVI Protocol C Investigators None., Sanders EJ., Anzala O., Kamali A., Kaleebu P., Karita E., Kilembe W., Inambao M., Lakhi S., Allen S., Hunter E., Edward VA., Fast PE., Price MA., Gilmour J., Tang J., Thio CL., Astemborski J., Kirk G., Khakoo SI., Donfield SM., Goedert JJ., Asquith B.
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.