title: Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis.
abstract: For more than 40 y, expression of HLA-B27 has been strongly associated with the chronic inflammatory disease Ankylosing Spondylitis (AS); however, the mechanisms underlying this association are still unknown. Single nucleotide polymorphisms within the aminopeptidase endoplasmic reticulum aminopeptidase 1 (ERAP1), which is essential for trimming peptides before they are presented to T cells by major histocompatibility complex (MHC) class I molecules, have been linked with disease. We show that ERAP1 is a highly polymorphic molecule comprising allotypes of single nucleotide polymorphisms. The prevalence of specific ERAP1 allotypes is different between AS cases and controls. Both chromosomal copies of ERAP1 are codominantly expressed, and analysis of allotype pairs provided clear stratification of individuals with AS versus controls. Functional analyses demonstrated that ERAP1 allotype pairs seen in AS cases were poor at generating optimal peptide ligands for binding to murine H-2K(b) and -D(b) and the AS-associated HLA-B*2705. We therefore provide strong evidence that polymorphic ERAP1 alters protein function predisposing an individual to AS via its influence on the antigen processing pathway.
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine and.
authors.forename: Emma
authors.initials: E
authors.lastname: Reeves
authors.affiliation: National Institute for Health Research Wellcome Trust Clinical Research Facility, University Hospital Southampton National Health Service Foundation Trust, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; and.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Colebatch-Bourn
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom.
authors.forename: Tim
authors.initials: T
authors.lastname: Elliott
authors.affiliation: National Institute for Health Research Wellcome Trust Clinical Research Facility, University Hospital Southampton National Health Service Foundation Trust, Southampton General Hospital, Southampton SO16 6YD, United Kingdom; and Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom eddjames@soton.ac.uk cedwards@soton.ac.uk.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Edwards
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton SO17 1BJ, United Kingdom eddjames@soton.ac.uk cedwards@soton.ac.uk.
authors.forename: Edward
authors.initials: E
authors.lastname: James
mesh_terms: D000328:Adult; D000368:Aged; D000626:Aminopeptidases / Q000235:genetics*; D017951:Antigen Presentation; D015415:Biomarkers / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D015331:Cohort Studies; D000939:Epitopes / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D015796:HLA-B27 Antigen / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D013167:Spondylitis, Ankylosing / Q000235:genetics* / Q000276:immunology
chemical_list: D015415:Biomarkers; D000939:Epitopes; C464936:HLA-B*27:05 antigen; D015796:HLA-B27 Antigen; D015778:Minor Histocompatibility Antigens; D000626:Aminopeptidases; C464841:ERAP1 protein, human
keywords: Ankylosing Spondylitis; ERAP1; HLA-B27; antigen presentation; antigen processing