Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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.

Original publication

DOI

10.1073/pnas.1408882111

Type

Journal article

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Date

12/2014

Volume

111

Pages

17594 - 17599

Addresses

Cancer Sciences Unit, Faculty of Medicine and.

Keywords

Cell Membrane, Humans, Spondylitis, Ankylosing, Inflammation, Aminopeptidases, HLA-B27 Antigen, Minor Histocompatibility Antigens, Epitopes, Cohort Studies, Antigen Presentation, Polymorphism, Genetic, Polymorphism, Single Nucleotide, Molecular Sequence Data, Adult, Aged, Middle Aged, Female, Male, HEK293 Cells, Biomarkers