June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Hypoactive endoplasmic reticulum aminopeptidase (ERAP)-1 and ERAP2 are strong risk factors for HLA-A29-associated Birdshot Uveitis.
Author Affiliations & Notes
  • Jonas Kuiper
    Ophthalmology, University Medical Center Utrecht, Utrecht, Netherlands
  • Footnotes
    Commercial Relationships   Jonas Kuiper, None
  • Footnotes
    Support  F.P Fischer stichting
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 2159. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Jonas Kuiper; Hypoactive endoplasmic reticulum aminopeptidase (ERAP)-1 and ERAP2 are strong risk factors for HLA-A29-associated Birdshot Uveitis. . Invest. Ophthalmol. Vis. Sci. 2017;58(8):2159.

      Download citation file:


      © ARVO (1962-2015); The Authors (2016-present)

      ×
  • Supplements
Abstract

Purpose : Adaptive immunity builds on the specialized enzymes ERAP1 and ERAP2 that jointly orchestrate the final check-point for processing thousands of peptides that are presented on the cell surface by HLA molecules. Emerging studies revealed that polymorphisms in ERAP1 and ERAP2 genes affect their enzymatic activities and predispose to autoimmune diseases that commonly manifest with - or as - uveitis. We hypothesize that combinations of functionally distinct ERAP1 and previously reported ERAP2 allotypes confer risk for the development of the prototypic HLA-disease Birdshot Uveitis (BU), which exclusively manifests in HLA-A*29-positive individuals.

Methods : Genotypes of all reported missense ERAP1 and ERAP2 variants were determined in 89 Dutch BU cases and 890 controls from the Netherlands to map the protein allotypes of ERAP1 and ERAP2 and their contributions to BU disease risk. Protein expression of ERAP allotypes was evaluated by Western blot. Fluorogenic and cell-based assays were used to measure enzymatic activities.

Results : Almost all BU cases (>96%) had at least one copy of the ERAP2-coding protein allotype compared to 71% of controls. Considering 10 amino acid positions in ERAP1 together, we identified 8 common (>1%) protein allotypes in cases and controls. After accounting for ERAP2, we observed an independent strong association for a single ERAP1 allotype with BU (OR = 2.3, P = 8.3 × 10−6). Increase in this ERAP1 allotype count was significantly associated with a progressive increased risk for BU (odds ratio for heterozygotes and homozygotes were 2.5 [95% CI 1.6-4.1] and 5.6 [95% CI 2.4–12.8], respectively). 61.4 % of BU cases had at least one copy of this ERAP1 allotype compared to 35.8% of controls. The associated ERAP1 allotype revealed significant reduction in protein expression and aminopeptidase activity.

Conclusions : A functionally distinct combination of ERAP2 and hypoactive ERAP1 are key pathogenic factors for developing BU. These results suggest that risk ERAP allotypes may affect adaptive immunity by changing the available peptides presented by HLA-A*29 and provide rational for targeting ERAPs for treatment of BU and genetically related autoimmune diseases.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×