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Edited by Peter Cresswell, Yale University School of Medicine, New Haven, CT, and approved November 5, 2014 (received for review May 15, 2014)
Significance
The immune system performs surveillance to identify infected or cancerous cells through recognition of small protein fragments called antigenic peptides on their surface. To do this, the peptides must be cut to a specific length by an enzyme called endoplasmic reticulum aminopeptidase 1 (ERAP1). Variation in this enzyme has recently been linked to the inflammatory rheumatic disease Ankylosing Spondylitis (AS). We have found that ERAP1 is highly polymorphic in humans and that specific combinations of ERAP1 are found in people with AS. These disease-associated combinations have a reduced ability to generate peptides for presentation at the cell surface by MHC class I molecules, including HLA-B27. Understanding this finding may allow easier identification of individuals with AS and allow stratification into prognostic groups.
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-2Kb and -Db 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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: eddjames{at}soton.ac.uk or cedwards{at}soton.ac.uk.
Author contributions: E.R., T.E., C.J.E., and E.J. designed research; E.R., A.C.-B., and E.J. performed research; E.R., A.C.-B., T.E., C.J.E., and E.J. analyzed data; and E.R., T.E., C.J.E., and E.J. wrote the paper.
Conflict of interest statement: A patent relating to the work has been filed.
This article is a PNAS Direct Submission.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. KM357870–KM357891).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1408882111/-/DCSupplemental.
Freely available online through the PNAS open access option.
ERAP1 allotype pairs distinguish AS individuals
Article Classifications
- Biological Sciences
- Immunology and Inflammation
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