Details

Autor(en) / Beteiligte

• 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

Titel

ERAP2 Increases the Abundance of a Peptide Submotif Highly Selective for the Birdshot Uveitis-Associated HLA-A29

Ist Teil von

• Frontiers in immunology, 2021-02, Vol.12, p.634441-634441

Ort / Verlag

Switzerland: Frontiers Media S.A

Erscheinungsjahr

2021

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked 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.