{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T16:43:22Z","timestamp":1768927402781,"version":"3.49.0"},"reference-count":51,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T00:00:00Z","timestamp":1560211200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004271","name":"Sapienza Universit\u00e0 di Roma","doi-asserted-by":"publisher","award":["Ateneo"],"award-info":[{"award-number":["Ateneo"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The human leukocyte antigen HLA-B27 is a strong risk factor for Ankylosing Spondylitis (AS), an immune-mediated disorder affecting axial skeleton and sacroiliac joints. Additionally, evidence exists sustaining a strong protective role for HLA-B27 in viral infections. These two aspects could stem from common molecular mechanisms. Recently, we have found that the HLA-B*2705 presents an EBV epitope (pEBNA3A-RPPIFIRRL), lacking the canonical B27 binding motif but known as immunodominant in the HLA-B7 context of presentation. Notably, 69% of B*2705 carriers, mostly patients with AS, possess B*2705-restricted, pEBNA3A-specific CD8+ T cells. Contrarily, the non-AS-associated B*2709 allele, distinguished from the B*2705 by the single His116Asp polymorphism, is unable to display this peptide and, accordingly, B*2709 healthy subjects do not unleash specific T cell responses. Herein, we investigated whether the reactivity towards pEBNA3A could be a side effect of the recognition of the natural longer peptide (pKEBNA3A) having the classical B27 consensus (KRPPIFIRRL). The stimulation of PBMC from B*2705 positive patients with AS in parallel with both pEBNA3A and pKEBNA3A did not allow to reach an unambiguous conclusion since the differences in the magnitude of the response measured as percentage of IFN\u03b3-producing CD8+ T cells were not statistically significant. Interestingly, computational analysis suggested a structural shift of pEBNA3A as well as of pKEBNA3A into the B27 grooves, leaving the A pocket partially unfilled. To our knowledge this is the first report of a viral peptide: HLA-B27 complex recognized by TCRs in spite of a partially empty groove. This implies a rethinking of the actual B27 immunopeptidome crucial for viral immune-surveillance and autoimmunity.<\/jats:p>","DOI":"10.3390\/cells8060572","type":"journal-article","created":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T10:55:44Z","timestamp":1560250544000},"page":"572","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Unusual Placement of an EBV Epitope into the Groove of the Ankylosing Spondylitis-Associated HLA-B27 Allele Allows CD8+ T Cell Activation"],"prefix":"10.3390","volume":"8","author":[{"given":"Valentina","family":"Tedeschi","sequence":"first","affiliation":[{"name":"Department of Biology and Biotechnology \u2018Charles Darwin\u2019, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josephine","family":"Alba","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1040-452X","authenticated-orcid":false,"given":"Fabiana","family":"Paladini","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u2018Charles Darwin\u2019, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7919-9128","authenticated-orcid":false,"given":"Marino","family":"Paroli","sequence":"additional","affiliation":[{"name":"Division of Clinical Immunology and Rheumatology, Department of Biotechnology and Medical Surgical Sciences, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Cauli","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Medical Sciences and Public Health, University and AOU of Cagliari, Monserrato, 09042 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessandro","family":"Mathieu","sequence":"additional","affiliation":[{"name":"Rheumatology Unit, Department of Medical Sciences and Public Health, University and AOU of Cagliari, Monserrato, 09042 Cagliari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Sorrentino","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u2018Charles Darwin\u2019, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6020-8581","authenticated-orcid":false,"given":"Marco","family":"D\u2019Abramo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6859-5851","authenticated-orcid":false,"given":"Maria Teresa","family":"Fiorillo","sequence":"additional","affiliation":[{"name":"Department of Biology and Biotechnology \u2018Charles Darwin\u2019, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1038\/nri3084","article-title":"Towards a systems understanding of MHC class I and MHC class II antigen presentation","volume":"11","author":"Neefjes","year":"2011","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1399-0039.2011.01735.x","article-title":"Running the gauntlet: From peptide generation to antigen presentation by MHC class I","volume":"78","author":"Saunders","year":"2011","journal-title":"Tissue Antigens"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/j.1600-065X.2012.01159.x","article-title":"A structural voyage toward an understanding of the MHC-I-restricted immune response: Lessons learned and much to be learned","volume":"250","author":"Gras","year":"2012","journal-title":"Immunol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2463","DOI":"10.3389\/fimmu.2018.02463","article-title":"How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins","volume":"9","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_5","unstructured":"Evnouchidou, I., and van Endert, P. (2019). Peptide trimming by endoplasmic reticulum aminopeptidases: Role of MHC class I binding and ERAP dimerization. Hum. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"6398","DOI":"10.4049\/jimmunol.164.12.6398","article-title":"The structure and stability of an HLA-A*0201\/octameric tax peptide complex with an empty conserved peptide-N-terminal binding site","volume":"164","author":"Khan","year":"2000","journal-title":"J. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/353321a0","article-title":"The structure of HLAB27 reveals nonomer self-peptides bound in an extended conformation","volume":"353","author":"Madden","year":"1991","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1515\/hsz-2016-0305","article-title":"Molecular challenges imposed by MHC-I restricted long epitopes on T cell immunity","volume":"398","author":"Josephs","year":"2017","journal-title":"Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Davies, M.N., Hattotuwagama, C.K., Moss, D.S., Drew, M.G., and Flower, D.R. (2006). Statistical deconvolution of enthalpic energetic contributions to MHC-peptide binding affinity. BMC Struct. Biol., 6.","DOI":"10.1186\/1472-6807-6-5"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrrheum.2015.133","article-title":"Genetics of ankylosing spondylitis\u2014Insights into pathogenesis","volume":"12","author":"Brown","year":"2016","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nrrheum.2017.56","article-title":"Pathogenesis of ankylosing spondylitis\u2014Recent advances and future directions","volume":"13","author":"Ranganathan","year":"2017","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1097\/BOR.0b013e328362018f","article-title":"HLA-B27-mediated protection in HIV and hepatitis C virus infection and pathogenesis in spondyloarthritis: Two sides of the same coin?","volume":"25","year":"2013","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.molimm.2013.06.017","article-title":"HLA-B27 and antigen presentation: At the crossroads between immune defense and autoimmunity","volume":"57","author":"Sorrentino","year":"2014","journal-title":"Mol. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1111\/cei.13020","article-title":"The interplay between HLA-B27 and ERAP1\/ERAP2 aminopeptidases: From anti-viral protection to spondyloarthritis","volume":"190","author":"Vitulano","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1329","DOI":"10.1038\/ng.2007.17","article-title":"Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants","volume":"39","author":"Burton","year":"2007","journal-title":"Nat. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1038\/ng.873","article-title":"Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility","volume":"43","author":"Evans","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1136\/annrheumdis-2015-207416","article-title":"ERAP2 is associated with ankylosing spondylitis in HLA-B27-positive and HLA-B27-negative patients","volume":"74","author":"Robinson","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1111\/j.1399-0039.2008.01051.x","article-title":"Peptides: The cornerstone of HLA-B27 biology and pathogenetic role in spondyloarthritis","volume":"71","author":"Marcilla","year":"2008","journal-title":"Tissue Antigens"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1007\/978-1-4419-0298-6_14","article-title":"HLA-B27-bound peptide repertoires: Their nature, origin and pathogenetic relevance","volume":"649","year":"2009","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10882","DOI":"10.1074\/jbc.M113.455352","article-title":"Natural HLA-B*2705 protein ligands with glutamine as anchor motif: Implications for HLA-B27 association with spondyloarthropathy","volume":"288","author":"Infantes","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e1700249","DOI":"10.1002\/pmic.201700249","article-title":"The Peptide Repertoire of HLA-B27 may include Ligands with Lysine at P2 Anchor Position","volume":"18","author":"Tedeschi","year":"2018","journal-title":"Proteomics"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1073\/pnas.91.4.1534","article-title":"A subset of HLA-B27 molecules contains peptides much longer than nonamers","volume":"91","author":"Urban","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/art.38249","article-title":"Critical role of endoplasmic reticulum aminopeptidase 1 in determining the length and sequence of peptides bound and presented by HLA-B27","volume":"66","author":"Chen","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s11926-017-0640-1","article-title":"An Update on the Genetic Polymorphism of HLA-B*27 With 213 Alleles Encompassing 160 Subtypes (and Still Counting)","volume":"19","author":"Khan","year":"2017","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3199","DOI":"10.1002\/eji.1830251133","article-title":"Relevance of residue 116 of HLA-B27 in determining susceptibility to ankylosing spondylitis","volume":"25","author":"Fiorillo","year":"1995","journal-title":"Eur. J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3319","DOI":"10.1002\/art.21308","article-title":"Distribution of HLA-B27 subtypes in Sardinia and continental Italy and their association with spondylarthropathies","volume":"52","author":"Paladini","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3389\/fimmu.2019.00035","article-title":"Ankylosing Spondylitis: A Trade Off of HLA-B27, ERAP, and Pathogen Interconnections? Focus on Sardinia","volume":"10","author":"Paladini","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1007\/978-1-4419-0298-6_19","article-title":"T cell responses against viral and self-epitopes and HLA-B27 subtypes differently associated with Ankylosing Spondylitis","volume":"649","author":"Fiorillo","year":"2009","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1002\/eji.1830270205","article-title":"Susceptibility to ankylosing spondylitis correlates with the C-terminal residue of peptides presented by various HLA-B27 subtypes","volume":"27","author":"Fiorillo","year":"1997","journal-title":"Eur. J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1097\/BOR.0b013e32836203ab","article-title":"Structural and dynamic features of HLA-B27 subtypes","volume":"25","author":"Ziegler","year":"2013","journal-title":"Curr. Opin. Rheumatol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"215","DOI":"10.2119\/molmed.2016.00031","article-title":"The Ankylosing Spondylitis-associated HLA-B*2705 presents a B*0702-restricted EBV epitope and sustains the clonal amplification of cytotoxic T cells in patients","volume":"22","author":"Tedeschi","year":"2016","journal-title":"Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1002\/eji.1830250105","article-title":"Characterization of two Epstein-Barr virus epitopes restricted by HLA-B7","volume":"25","author":"Hill","year":"1995","journal-title":"Eur. J. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1084\/jem.20031690","article-title":"Dual, HLA-B27 subtype-dependent conformation of a self-peptide","volume":"199","author":"Hulsmeyer","year":"2004","journal-title":"J. Exp. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"W294","DOI":"10.1093\/nar\/gks493","article-title":"GalaxyWEB server for protein structure prediction and refinement","volume":"40","author":"Ko","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6474","DOI":"10.1021\/jp003919d","article-title":"Evaluation and Reparametrization of the OPLS-AA Force Field for Proteins via Comparison with Accurate Quantum Chemical Calculations on Peptides","volume":"105","author":"Kaminski","year":"2001","journal-title":"J. Phys. Chem. B"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"9954","DOI":"10.1021\/jp003020w","article-title":"Structure and Dynamics of the TIP3P, SPC, and SPC\/E Water Models at 298 K","volume":"105","author":"Pekka","year":"2001","journal-title":"J. Phys. Chem. A"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/0009-2614(93)89366-P","article-title":"Estimation of absolute and relative entropies of macromolecules using the covariance matrix","volume":"215","author":"Schlitter","year":"1993","journal-title":"Chem. Phys. Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1002\/prot.340170408","article-title":"Essential dynamics of proteins","volume":"17","author":"Amadei","year":"1993","journal-title":"Proteins"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s00251-015-0849-y","article-title":"Zooming into the binding groove of HLA molecules: Which positions and which substitutions change peptide binding most?","volume":"67","year":"2015","journal-title":"Immunogenetics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/j.jmb.2011.11.021","article-title":"Dynamical characterization of two differentially disease associated MHC class I proteins in complex with viral and self-peptides","volume":"415","author":"Narzi","year":"2012","journal-title":"J. Mol. Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1002\/art.27316","article-title":"HLA-B27 heavy chains distinguished by a micropolymorphism exhibit differential flexibility","volume":"62","author":"Fabian","year":"2010","journal-title":"Arthritis Rheum."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1111\/j.1742-4658.2011.08097.x","article-title":"Influence of inflammation-related changes on conformational characteristics of HLA-B27 subtypes as detected by IR spectroscopy","volume":"278","author":"Fabian","year":"2011","journal-title":"FEBS J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.molimm.2013.07.013","article-title":"HLA-B27 misfolding and ankylosing spondylitis","volume":"57","author":"Colbert","year":"2014","journal-title":"Mol. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/tan.12410","article-title":"Endoplasmic reticulum aminopeptidase 1 function and its pathogenic role in regulating innate and adaptive immunity in cancer and major histocompatibility complex class I-associated autoimmune diseases","volume":"84","author":"Fruci","year":"2014","journal-title":"Tissue Antigens"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"10398","DOI":"10.1038\/s41598-018-28799-8","article-title":"An allelic variant in the intergenic region between ERAP1 and ERAP2 correlates with an inverse expression of the two genes","volume":"8","author":"Paladini","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1016\/j.jmb.2007.12.009","article-title":"HLA-B27 subtypes differentially associated with disease exhibit conformational differences in solution","volume":"376","author":"Fabian","year":"2008","journal-title":"J. Mol. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/nature08997","article-title":"Effects of thymic selection of the T-cell repertoire on HLA class I-associated control of HIV infection","volume":"465","author":"Kosmrlj","year":"2010","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5072","DOI":"10.1038\/s41598-017-05171-w","article-title":"Dual non-contiguous peptide occupancy of HLA class I evoke antiviral human CD8 T cell response and form neo-epitopes with self-antigens","volume":"7","author":"Xiao","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1002\/art.39430","article-title":"The Peptidome of Beh\u00e7et\u2019s Disease-Associated HLA-B*51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1","volume":"68","author":"Guasp","year":"2016","journal-title":"Arthritis Rheumatol."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/6\/572\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:57:29Z","timestamp":1760187449000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/8\/6\/572"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,11]]},"references-count":51,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2019,6]]}},"alternative-id":["cells8060572"],"URL":"https:\/\/doi.org\/10.3390\/cells8060572","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,11]]}}}