Cargando…
ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29
Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent pe...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950316/ https://www.ncbi.nlm.nih.gov/pubmed/33717175 http://dx.doi.org/10.3389/fimmu.2021.634441 |
_version_ | 1783663563915657216 |
---|---|
author | Venema, Wouter J. Hiddingh, Sanne de Boer, Joke H. Claas, Frans H. J. Mulder, Arend den Hollander, Anneke I. Stratikos, Efstratios Sarkizova, Siranush van der Veken, Lars T. Janssen, George M. C. van Veelen, Peter A. Kuiper, Jonas J. W. |
author_facet | Venema, Wouter J. Hiddingh, Sanne de Boer, Joke H. Claas, Frans H. J. Mulder, Arend den Hollander, Anneke I. Stratikos, Efstratios Sarkizova, Siranush van der Veken, Lars T. Janssen, George M. C. van Veelen, Peter A. Kuiper, Jonas J. W. |
author_sort | Venema, Wouter J. |
collection | PubMed |
description | Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent peptide presentation by HLA-A29 drives the pathogenesis of BU. However, it remains poorly understood whether the effects of ERAP2 on the HLA-A29 peptidome are distinct from its effect on other HLA allotypes. To address this, we focused on the effects of ERAP2 on the immunopeptidome in patient-derived antigen presenting cells. Using complementary HLA-A29-based and pan-class I immunopurifications, isotope-labeled naturally processed and presented HLA-bound peptides were sequenced by mass spectrometry. We show that the effects of ERAP2 on the N-terminus of ligands of HLA-A29 are shared across endogenous HLA allotypes, but discover and replicate that one peptide motif generated in the presence of ERAP2 is specifically bound by HLA-A29. This motif can be found in the amino acid sequence of putative autoantigens. We further show evidence for internal sequence specificity for ERAP2 imprinted in the immunopeptidome. These results reveal that ERAP2 can generate an HLA-A29-specific antigen repertoire, which supports that antigen presentation is a key disease pathway in BU. |
format | Online Article Text |
id | pubmed-7950316 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-79503162021-03-12 ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29 Venema, Wouter J. Hiddingh, Sanne de Boer, Joke H. Claas, Frans H. J. Mulder, Arend den Hollander, Anneke I. Stratikos, Efstratios Sarkizova, Siranush van der Veken, Lars T. Janssen, George M. C. van Veelen, Peter A. Kuiper, Jonas J. W. Front Immunol Immunology Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent peptide presentation by HLA-A29 drives the pathogenesis of BU. However, it remains poorly understood whether the effects of ERAP2 on the HLA-A29 peptidome are distinct from its effect on other HLA allotypes. To address this, we focused on the effects of ERAP2 on the immunopeptidome in patient-derived antigen presenting cells. Using complementary HLA-A29-based and pan-class I immunopurifications, isotope-labeled naturally processed and presented HLA-bound peptides were sequenced by mass spectrometry. We show that the effects of ERAP2 on the N-terminus of ligands of HLA-A29 are shared across endogenous HLA allotypes, but discover and replicate that one peptide motif generated in the presence of ERAP2 is specifically bound by HLA-A29. This motif can be found in the amino acid sequence of putative autoantigens. We further show evidence for internal sequence specificity for ERAP2 imprinted in the immunopeptidome. These results reveal that ERAP2 can generate an HLA-A29-specific antigen repertoire, which supports that antigen presentation is a key disease pathway in BU. Frontiers Media S.A. 2021-02-25 /pmc/articles/PMC7950316/ /pubmed/33717175 http://dx.doi.org/10.3389/fimmu.2021.634441 Text en Copyright © 2021 Venema, Hiddingh, de Boer, Claas, Mulder, den Hollander, Stratikos, Sarkizova, van der Veken, Janssen, van Veelen and Kuiper http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Venema, Wouter J. Hiddingh, Sanne de Boer, Joke H. Claas, Frans H. J. Mulder, Arend den Hollander, Anneke I. Stratikos, Efstratios Sarkizova, Siranush van der Veken, Lars T. Janssen, George M. C. van Veelen, Peter A. Kuiper, Jonas J. W. ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29 |
title | ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29 |
title_full | ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29 |
title_fullStr | ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29 |
title_full_unstemmed | ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29 |
title_short | ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29 |
title_sort | erap2 increases the abundance of a peptide submotif highly selective for the birdshot uveitis-associated hla-a29 |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7950316/ https://www.ncbi.nlm.nih.gov/pubmed/33717175 http://dx.doi.org/10.3389/fimmu.2021.634441 |
work_keys_str_mv | AT venemawouterj erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 AT hiddinghsanne erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 AT deboerjokeh erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 AT claasfranshj erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 AT mulderarend erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 AT denhollanderannekei erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 AT stratikosefstratios erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 AT sarkizovasiranush erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 AT vandervekenlarst erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 AT janssengeorgemc erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 AT vanveelenpetera erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 AT kuiperjonasjw erap2increasestheabundanceofapeptidesubmotifhighlyselectiveforthebirdshotuveitisassociatedhlaa29 |