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Behçet’s disease risk-variant HLA-B51/ERAP1-Hap10 alters human CD8 T cell immunity
  1. Ann Cavers1,
  2. Matthias Christian Kugler2,
  3. Yesim Ozguler1,3,4,
  4. Arshed Fahad Al-Obeidi5,
  5. Gulen Hatemi3,4,
  6. Beatrix M Ueberheide6,
  7. Didar Ucar4,7,
  8. Olivier Manches8,9,
  9. Johannes Nowatzky1,10
  1. 1Department of Medicine, Division of Rheumatology, NYU Langone Behçet’s Disease Program, NYU Langone Ocular Rheumatology Program, New York University Grossman School of Medicine, New York, NY, USA
  2. 2Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, New York University Grossman School of Medicine, New York, NY, USA
  3. 3Department of Internal Medicine, Division of Rheumatology, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
  4. 4Behçet's Disease Research Center, Istanbul University-Cerrahpasa, Istanbul, Turkey
  5. 5Department of Medicine, New York University Grossman School of Medicine, New York, NY, USA
  6. 6Department of Biochemistry and Molecular Pharmacology, Department of Neurology, Perlmutter Cancer Center, Proteomics Laboratory at the Division of Advanced Research Technologies, New York University Grossman School of Medicine, New York, NY, USA
  7. 7Department of Ophthalmology, Cerrahpasa Medical School, Istanbul University-Cerrahpasa, Istanbul, Turkey
  8. 8Immunobiology and Immunotherapy in Chronic Diseases, Institute for Advanced Biosciences, Inserm U 1209, Université Grenoble-Alpes, Grenoble, France
  9. 9Recherche et Développement, Etablissement Français du Sang Auvergne-Rhône-Alpes, La Tronche, France
  10. 10Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA
  1. Correspondence to Dr Johannes Nowatzky, Department of Medicine, Division of Rheumatology, NYU Langone Behçet's Disease Program, NYU Ocular Rheumatology Program, New York University Grossman School of Medicine, New York, NY 10016, USA; Johannes.Nowatzky{at}nyumc.org

Abstract

Objectives The endoplasmic reticulum aminopeptidase (ERAP1) haplotype Hap10 encodes for a variant allotype of the endoplasmic reticulum (ER)-resident peptide-trimming aminopeptidase ERAP1 with low enzymatic activity. This haplotype recessively confers the highest risk for Behçet’s diseases (BD) currently known, but only in carriers of HLA-B*51, the classical risk factor for the disease. The mechanistic implications and biological consequences of this epistatic relationship are unknown. Here, we aimed to determine its biological relevance and functional impact.

Methods We genotyped and immune phenotyped a cohort of 26 untreated Turkish BD subjects and 22 healthy donors, generated CRISPR-Cas9 ERAP1 KOs from HLA-B*51+ LCL, analysed the HLA class I-bound peptidome for peptide length differences and assessed immunogenicity of genome-edited cells in CD8 T cell co-culture systems.

Results Allele frequencies of ERAP1-Hap10 were similar to previous studies. There were frequency shifts between antigen-experienced and naïve CD8 T cell populations of carriers and non-carriers of ERAP1-Hap10 in an HLA-B*51 background. ERAP1 KO cells showed peptidomes with longer peptides above 9mer and significant differences in their ability to stimulate alloreactive CD8 T cells compared with wild-type control cells.

Conclusions We demonstrate that hypoactive ERAP1 changes immunogenicity to CD8 T cells, mediated by an HLA class I peptidome with undertrimmed peptides. Naïve/effector CD8 T cell shifts in affected carriers provide evidence of the biological relevance of ERAP1-Hap10/HLA-B*51 at the cellular level and point to an HLA-B51-restricted process. Our findings suggest that variant ERAP1-Hap10 partakes in BD pathogenesis by generating HLA-B51-restricted peptides, causing a change in immunodominance of the ensuing CD8 T cell response.

  • T Cells
  • T-Lymphocyte subsets
  • Systemic vasculitis
  • Behcet Syndrome

Data availability statement

Data are available upon reasonable request. Data and code we or others have deposited in publicly accessible repositories are cited in the text. We may not provide data to requesters with potential or actual conflicts of interest, including individuals requesting data for commercial, competitive or legal purposes.

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Data availability statement

Data are available upon reasonable request. Data and code we or others have deposited in publicly accessible repositories are cited in the text. We may not provide data to requesters with potential or actual conflicts of interest, including individuals requesting data for commercial, competitive or legal purposes.

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Footnotes

  • Handling editor Josef S Smolen

  • AC, MCK and YO contributed equally.

  • Contributors Conceptualisation, planning and implementation of the study: JN. Planning of study subject recruitment and design of data collection instruments: YO, GH, DU, JN. Study subject recruitment: YO, DU, GH. Native sample processing: YO, JN. Clinical data analysis: YO, JN. Genotyping (native and edited cells): MCK. Genome editing, cellular cloning and cell line generation: JN, AC. Flow cytometry: JN, AC, AFA-O, YO. Cell culture: JN, AC, AFA-O, YO. ELISA: AC, AFA-O. Immunoprecipitation: JN, AC. Mass spectrometry: BMU. Experimental design: JN, OM, BMU, MCK. Data analysis (genomic): MCK. Data analysis (post-translational applications): JN, BMU, OM. Data management: JN, YO, MCK. Writing (initial manuscript draft): JN. Manuscript editing: JN, OM. Funding acquisition: JN, GH. Approval of the final manuscript: all authors. Author acting as guarantor: JN.

  • Funding Research reported in this publication was supported by the National Eye Institute (NEI) of the National Institutes of Health (NIH) under award numbers R01EY031383 (Nowatzky), R01EY033495 (Nowatzky), the Istanbul University—Cerrahpaşa Research Fund (Hatemi), the Judith & Stewart Colton Centre for Autoimmunity (Nowatzky), and the NYU Department of Medicine (Nowatzky). More than 80% of the cost of this project was covered by US Federal funds.

  • Disclaimer The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • Competing interests GH, YO, and JN have received grant support as specified in the Funding section. GH has received research support from Celgene as well as speaker fees from Abbvie, Celgene, Novartis, and UCB Pharma, all paid to Istanbul University-Cerrahpasa. YO has received speaker fees from Pfizer, Novartis, and UCB Pharma, paid to Istanbul University-Cerrahpasa. JN has received lecture honoraria from Northwestern University, and Harvard University.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.