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

被引:16
|
作者
Venema, Wouter J. [1 ,2 ]
Hiddingh, Sanne [1 ,2 ]
de Boer, Joke H. [1 ]
Claas, Frans H. J. [3 ]
Mulder, Arend [3 ]
den Hollander, Anneke, I [4 ,5 ]
Stratikos, Efstratios [6 ]
Sarkizova, Siranush [7 ,8 ]
van der Veken, Lars T. [9 ]
Janssen, George M. C. [10 ]
van Veelen, Peter A. [10 ]
Kuiper, Jonas J. W. [1 ,2 ]
机构
[1] Univ Utrecht, Univ Med Ctr Utrecht, Dept Ophthalmol, Utrecht, Netherlands
[2] Univ Utrecht, Univ Med Ctr Utrecht, Ctr Translat Immunol, Utrecht, Netherlands
[3] Leiden Univ, Dept Immunol, Med Ctr, Leiden, Netherlands
[4] Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, Donders Inst Brain Cognit & Behav, Nijmegen, Netherlands
[5] Radboud Univ Nijmegen, Dept Human Genet, Med Ctr, Nijmegen, Netherlands
[6] Natl & Kapodistrian Univ Athens, Dept Chem, Panepistimiopolis, Greece
[7] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA
[8] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA
[9] Univ Utrecht, Univ Med Ctr Utrecht, Dept Genet, Div Labs,Pharm & Biomed Genet, Utrecht, Netherlands
[10] Leiden Univ, Ctr Prote & Metabol, Med Ctr, Leiden, Netherlands
来源
FRONTIERS IN IMMUNOLOGY | 2021年 / 12卷
关键词
Birdshot; HLA-A29; ERAP2; autoimmunity; immunopeptidome; PREDICTION; PRECURSORS;
D O I
10.3389/fimmu.2021.634441
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页数:15
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