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Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis

Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis
Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis
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.
ankylosing spondylitis, ERAP1, HLA-B27, antigen presentation, antigen processing
0027-8424
17594-17599
Reeves, Emma
bd61ff0c-6555-47fd-884f-74dc6105e846
Colebatch-Bourn, Alexandra
fe0c7828-fda0-44b5-9f14-2f18fd254c94
Elliott, Tim
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Edwards, Christopher J.
dcb27fec-75ea-4575-a844-3588bcf14106
James, Edward
7dc1afb7-d326-4050-89fc-1f4e2a1a19a4
Reeves, Emma
bd61ff0c-6555-47fd-884f-74dc6105e846
Colebatch-Bourn, Alexandra
fe0c7828-fda0-44b5-9f14-2f18fd254c94
Elliott, Tim
16670fa8-c2f9-477a-91df-7c9e5b453e0e
Edwards, Christopher J.
dcb27fec-75ea-4575-a844-3588bcf14106
James, Edward
7dc1afb7-d326-4050-89fc-1f4e2a1a19a4

Reeves, Emma, Colebatch-Bourn, Alexandra, Elliott, Tim, Edwards, Christopher J. and James, Edward (2014) Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis. Proceedings of the National Academy of Sciences, 111 (49), 17594-17599. (doi:10.1073/pnas.1408882111). (PMID:25422414)

Record type: Article

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.

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More information

Accepted/In Press date: 5 November 2014
e-pub ahead of print date: 24 November 2014
Published date: 9 December 2014
Keywords: ankylosing spondylitis, ERAP1, HLA-B27, antigen presentation, antigen processing
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 380413
URI: http://eprints.soton.ac.uk/id/eprint/380413
ISSN: 0027-8424
PURE UUID: e9af079b-2111-4b0f-a33f-ee87452a624f
ORCID for Tim Elliott: ORCID iD orcid.org/0000-0003-1097-0222
ORCID for Edward James: ORCID iD orcid.org/0000-0001-8638-7928

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Date deposited: 14 Sep 2015 12:54
Last modified: 15 Mar 2024 03:26

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Contributors

Author: Emma Reeves
Author: Alexandra Colebatch-Bourn
Author: Tim Elliott ORCID iD
Author: Edward James ORCID iD

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