Functionally Distinct ERAP1 Haplotype Combinations Distinguish Individuals With Ankylosing Spondylitis

Edward James¹, Emma Reeves¹, Alexandra Colebatch², Tim Elliott¹ and Christopher J. Edwards³, ¹Cancer Sciences Unit, University of Southampton, Southampton, United Kingdom, ²Rheumatology, University Hospital Southampton, Southampton, United Kingdom, ³NIHR Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: Ankylosing spondylitis (AS) and major histocompatibility complex (MHC)

Session Information

Title: Spondyloarthropathies and Psoriatic Arthritis: Pathogenesis, Etiology, Animal Models II

Session Type: Abstract Submissions (ACR)

Background/Purpose:

The association of Ankylosing Spondylitis (AS) with HLA-B27 has been known for many years. Recent genetic linkage studies have identified polymorphisms within the aminopeptidase, ERAP1, associated with the disease. ERAP1 lies on the antigen processing pathway, generating peptide antigens for immune presentation by HLA. We examined the extent of polymorphism of ERAP1 and the haplotype combinations present in affected and control individuals. In addition, we assessed the ability of the identified ERAP1 genotypes to trim peptides for presentation on MHC class I molecules.

Methods:

Individual ERAP1 haplotypes were cloned from patients with AS and control individuals recruited with informed consent and sequenced. ERAP1 trimming function was assessed by observing the ability of Erap1 deficient cells, expressing the identified haplotype molecules, to trim and present peptide for stimulation of an antigen-specific T cell and also to reconstitute surface HLA-B27.

Results:

We found that ERAP1 from both AS cases (n=17) and controls (n=19) are highly polymorphic and comprise nine haplotypes that are predominantly made up of multiple SNPs. ERAP1 haplotype combinations from AS cases were distinct from those found in controls. AS case ERAP1 haplotype combinations trimming capacity was significantly decreased as less than a third of the final epitope was generated from peptide precursors for presentation to T cells compared to controls. In addition, AS case ERAP1 combinations were unable to reconstitute HLA-B27 to normal levels recovering only 50% of that observed with control haplotype combinations.

Conclusion:

These results demonstrate for the first time that ERAP1 from patients with AS is dysfunctional and provides strong evidence that ERAP1 variation predisposes to chronic inflammatory disease via its influence on the antigen processing pathway.

Disclosure:

E. James,
None;

E. Reeves,
None;

A. Colebatch,
None;

T. Elliott,
None;

C. J. Edwards,
None.

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