{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T14:50:21Z","timestamp":1787496621165,"version":"build-2736575974"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T00:00:00Z","timestamp":1643241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Tumor cells of classic Hodgkin lymphoma (cHL) are derived from antigen presenting B cells that are infected by Epstein Barr virus (EBV) in ~30% of patients. Polymorphic Killer cell immunoglobulin-like receptors (KIRs) expressed on NK cells interact with human leukocyte antigen (HLA) class I and play a key role in immune surveillance against virally infected cells and tumor cells. We investigated the effect of KIR types on cHL susceptibility overall (n=211) and in EBV-stratified subgroups using the Dutch GoNL cohort as controls (n=498). The frequency of the KIR haplotype B subgroup was significantly different between EBV+ and EBV\u2212 cHL patients (62% vs. 77%, p=0.04) and this difference was more pronounced in nodular sclerosis (NS) cHL (49% vs. 79%, p=0.0003). The frequency of KIR haplotype B subgroup was significantly lower in EBV+ NS cHL compared to controls (49% vs. 67%, p=0.01). Analyses of known KIR \u2013 HLA interaction pairs revealed lower carrier frequencies of\n                    <jats:italic>KIR2DS2<\/jats:italic>\n                    \u2013 HLA-C1 (29% vs. 46%, p=0.03) and\n                    <jats:italic>KIR2DL2<\/jats:italic>\n                    \u2013 HLA-C1 (29% vs. 45%, p=0.04) in EBV+ NS cHL patients compared to controls. Carriers of the KIR haplotype B subgroup are less likely to develop EBV+ NS cHL, probably because of a more efficient control over EBV-infected B cells.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.829943","type":"journal-article","created":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T06:06:40Z","timestamp":1643263600000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Killer Cell Immunoglobulin-Like Receptor Haplotype B Modulates Susceptibility to EBV-Associated Classic Hodgkin Lymphoma"],"prefix":"10.3389","volume":"13","author":[{"given":"Peijia","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilja M.","family":"Nolte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bouke G.","family":"Hepkema","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marijke","family":"Stulp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"van den Berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan","family":"Diepstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,1,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21438","article-title":"Hodgkin Lymphoma: A Review and Update on Recent Progress","volume":"68","author":"Shanbhag","year":"2018","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arcmed.2014.06.001","article-title":"Prevalence and Prognostic Significance of Epstein-Barr Virus Infection in Classical Hodgkin\u2019s Lymphoma: A Meta-Analysis","volume":"45","author":"Lee","year":"2014","journal-title":"Arch Med Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1136\/jcp.56.11.811","article-title":"The Scotland and Newcastle Epidemiological Study of Hodgkin\u2019s Disease: Impact of Histopathological Review and EBV Status on Incidence Estimates","volume":"56","author":"Jarrett","year":"2003","journal-title":"J\u00a0Clin Pathol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdg065","article-title":"The Effect of Epstein-Barr Virus Status on Outcome in Age- and Sex-Defined Subgroups of Patients With Advanced Hodgkin\u2019s Disease","volume":"14","author":"Flavell","year":"2003","journal-title":"Ann Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/sj.leu.2401097","article-title":"Epstein-Barr Virus and Hodgkin\u2019s Disease: Further Evidence for the Three Disease Hypothesis","volume":"12","author":"Armstrong","year":"1998","journal-title":"Leukemia"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.32.8401","article-title":"Molecular Pathogenesis of Hodgkin\u2019s Lymphoma: Increasing Evidence of the Importance of the Microenvironment","volume":"29","author":"Steidl","year":"2011","journal-title":"J Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2016.08.010","article-title":"Present Yourself! By MHC Class I and MHC Class II Molecules","volume":"37","author":"Rock","year":"2016","journal-title":"Trends Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2017.12.001","article-title":"Natural Killer Cell Education and the Response to Infection and Cancer Therapy: Stay Tuned","volume":"39","author":"Boudreau","year":"2018","journal-title":"Trends Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-06-855296","article-title":"Genome-Wide Association Study Implicates Immune Dysfunction in the Development of Hodgkin Lymphoma","volume":"132","author":"Sud","year":"2018","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","first-page":"3856","DOI":"10.1038\/ncomms4856","article-title":"A Meta-Analysis of Hodgkin Lymphoma Reveals 19p13.3 TCF3 as a Novel Susceptibility Locus","volume":"5","author":"Cozen","year":"2014","journal-title":"Nat Commun"},{"key":"B11","doi-asserted-by":"publisher","first-page":"e39986","DOI":"10.1371\/journal.pone.0039986","article-title":"HLA Associations in Classical Hodgkin Lymphoma: EBV Status Matters","volume":"7","author":"Huang","year":"2012","journal-title":"PloS One"},{"key":"B12","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1111\/j.1600-0609.2005.00452.x","article-title":"Genetic Susceptibility to Hodgkin\u2019s Lymphoma Associated With the Human Leukocyte Antigen Region","author":"Diepstra","year":"2005","journal-title":"Eur J Haematol Suppl"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/cei.12716","article-title":"The Impact of HLA Class I and EBV Latency-II Antigen-Specific CD8(+) T Cells on the Pathogenesis of EBV(+) Hodgkin Lymphoma","volume":"183","author":"Jones","year":"2016","journal-title":"Clin Exp Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-06-162883","article-title":"A Mechanism for the HLA-A*01-Associated Risk for EBV+ Hodgkin Lymphoma and Infectious Mononucleosis","volume":"112","author":"Brennan","year":"2008","journal-title":"Blood"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.14.1.619","article-title":"Receptors for HLA Class-I Molecules in Human Natural Killer Cells","volume":"14","author":"Moretta","year":"1996","journal-title":"Annu Rev Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/0167-5699(90)90097-s","article-title":"In Search of the \u2018Missing Self\u2019: MHC Molecules and NK Cell Recognition","volume":"11","author":"Ljunggren","year":"1990","journal-title":"Immunol Today"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01179","article-title":"Killer Ig-Like Receptors (KIRs): Their Role in NK Cell Modulation and Developments Leading to Their Clinical Exploitation","volume":"10","author":"Pende","year":"2019","journal-title":"Front Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.6.3969","article-title":"Synergistic Polymorphism at Two Positions Distal to the Ligand-Binding Site Makes KIR2DL2 a Stronger Receptor for HLA-C Than KIR2DL3","volume":"180","author":"Moesta","year":"2008","journal-title":"J\u00a0Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1101\/gr.137976.112","article-title":"Copy Number Variation Leads to Considerable Diversity for B But Not A Haplotypes of the Human KIR Genes Encoding NK Cell Receptors","volume":"22","author":"Jiang","year":"2012","journal-title":"Genome Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12316","article-title":"Human KIR Repertoires: Shaped by Genetic Diversity and Evolution","volume":"267","author":"Manser","year":"2015","journal-title":"Immunol Rev"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3513","article-title":"Open Conformers of HLA-F Are High-Affinity Ligands of the Activating NK-Cell Receptor KIR3DS1","volume":"17","author":"Garcia-Beltran","year":"2016","journal-title":"Nat Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00298","article-title":"Modulation of Human Leukocyte Antigen-C by Human Cytomegalovirus Stimulates KIR2DS1 Recognition by Natural Killer Cells","volume":"8","author":"van der Ploeg","year":"2017","journal-title":"Front Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aal5296","article-title":"KIR2DS2 Recognizes Conserved Peptides Derived From Viral Helicases in the Context of HLA-C","volume":"2","author":"Naiyer","year":"2017","journal-title":"Sci Immunol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.1053\/j.gastro.2018.07.019","article-title":"Interactions Between KIR3DS1 and HLA-F Activate Natural Killer Cells to Control HCV Replication in Cell Culture","volume":"155","author":"Lunemann","year":"2018","journal-title":"Gastroenterology"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3967\/bes2015.042","article-title":"Novel Association of Killer Cell Immunoglobulin-Like Receptor Genes With EBV-Infectious Diseases in Children","volume":"28","author":"Huo","year":"2015","journal-title":"BioMed Environ Sci"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/tan.13770","article-title":"Epstein-Barr Virus Infections Are Strongly Dependent on Activating and Inhibitory KIR-HLA Pairs After T-Cell Replate Unrelated Hematopoietic Stem Cell Transplantation, the Principles, and Method of Pairing Analysis","author":"Nowak","year":"2019","journal-title":"HLA"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-016-0255-4","article-title":"The Favorable Role of Homozygosity for Killer Immunoglobulin-Like Receptor (KIR) A Haplotype in Patients With Advanced-Stage Classic Hodgkin Lymphoma","volume":"9","author":"La Nasa","year":"2016","journal-title":"J Hematol Oncol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.mgene.2015.02.004","article-title":"KIR Genotype Distribution Among Lebanese Patients With Hodgkin\u2019s Lymphoma","volume":"4","author":"Hoteit","year":"2015","journal-title":"Meta Gene"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000406","article-title":"Association of Killer Cell Immunoglobulin-Like Receptor Genes With Hodgkin\u2019s Lymphoma in a Familial Study","volume":"2","author":"Besson","year":"2007","journal-title":"PloS One"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13030414","article-title":"Interaction Between ERAP Alleles and HLA Class I Types Support a Role of Antigen Presentation in Hodgkin Lymphoma Development","volume":"13","author":"Jiang","year":"2021","journal-title":"Cancers"},{"key":"B31","author":"Swerdlow","year":"2017","journal-title":"WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Revised 4th edition)"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3021","article-title":"Whole-Genome Sequence Variation, Population Structure and Demographic History of the Dutch Population","volume":"46","year":"2014","journal-title":"Nat Genet"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.583013","article-title":"Accurate and Efficient KIR Gene and Haplotype Inference From Genome Sequencing Reads With Novel K-Mer Signatures","volume":"11","author":"Roe","year":"2020","journal-title":"Front Immunol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/tpj.2013.18","article-title":"HIBAG\u2013HLA Genotype Imputation With Attribute Bagging","volume":"14","author":"Zheng","year":"2014","journal-title":"Pharmacogenom J"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.29467","article-title":"Modeling HLA Associations With EBV-Positive and -Negative Hodgkin Lymphoma Suggests Distinct Mechanisms in Disease Pathogenesis","volume":"137","author":"Johnson","year":"2015","journal-title":"Int J Cancer"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1991.281","article-title":"Viral Involvement in Hodgkin\u2019s Disease: Detection of Clonal Type A Epstein-Barr Virus Genomes in Tumour Samples","volume":"64","author":"Gledhill","year":"1991","journal-title":"Br J Cancer"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/s1074-7613(00)80493-8","article-title":"Is EBV Persistence In Vivo a Model for B Cell Homeostasis","volume":"5","author":"Khan","year":"1996","journal-title":"Immunity"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198903163201103","article-title":"Hodgkin\u2019s Disease and Epstein-Barr Virus. Altered Antibody Pattern Before\u00a0Diagnosis","volume":"320","author":"Mueller","year":"1989","journal-title":"N Engl J Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-3566","article-title":"Infectious Mononucleosis, Childhood Social Environment, and Risk of Hodgkin Lymphoma","volume":"67","author":"Hjalgrim","year":"2007","journal-title":"Cancer Res"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa023141","article-title":"Characteristics of Hodgkin\u2019s Lymphoma After Infectious Mononucleosis","volume":"349","author":"Hjalgrim","year":"2003","journal-title":"N Engl J Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20161017","article-title":"Two Alternate Strategies for Innate Immunity to Epstein-Barr Virus: One Using NK Cells and the Other NK Cells and Gammadelta T Cells","volume":"214","author":"Djaoud","year":"2017","journal-title":"J Exp Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.11.041","article-title":"Human Natural Killer Cells Prevent Infectious Mononucleosis Features by Targeting Lytic Epstein-Barr Virus Infection","volume":"5","author":"Chijioke","year":"2013","journal-title":"Cell Rep"},{"key":"B43","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1007\/s00262-021-02956-x","article-title":"Reduced Frequency of Cytotoxic CD56(dim) CD16(+) NK Cells Leads to Impaired Antibody-Dependent Degranulation in EBV-Positive Classical Hodgkin Lymphoma","volume":"71","author":"Panisova","year":"2022","journal-title":"Cancer Immunol Immunother"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-07-796342","article-title":"Immune Evasion via PD-1\/PD-L1 on NK Cells and Monocyte\/Macrophages Is More Prominent in Hodgkin Lymphoma Than DLBCL","volume":"131","author":"Vari","year":"2018","journal-title":"Blood"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3800","article-title":"Tumor Immunoevasion by the Conversion of Effector NK Cells Into Type 1 Innate Lymphoid Cells","volume":"18","author":"Gao","year":"2017","journal-title":"Nat Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.12.7335","article-title":"Elevated TGF-Beta1 Secretion and Down-Modulation of NKG2D Underlies Impaired NK Cytotoxicity in Cancer Patients","volume":"172","author":"Lee","year":"2004","journal-title":"J Immunol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20190103","article-title":"Transforming Growth Factor-Beta in Tissue Fibrosis","volume":"217","author":"Frangogiannis","year":"2020","journal-title":"J Exp Med"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2018-08-870915","article-title":"Serum Levels of TARC, MDC, IL-10, and Soluble CD163 in Hodgkin Lymphoma: A SWOG S0816 Correlative Study","volume":"133","author":"Hsi","year":"2019","journal-title":"Blood"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0039.2008.01005.x","article-title":"HLA-G Protein Expression as a Potential Immune Escape Mechanism in Classical Hodgkin\u2019s Lymphoma","volume":"71","author":"Diepstra","year":"2008","journal-title":"Tissue Antigens"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2016.66.4482","article-title":"PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome","volume":"34","author":"Roemer","year":"2016","journal-title":"J Clin Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.829943\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,27]],"date-time":"2022-01-27T06:06:46Z","timestamp":1643263606000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.829943\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,27]]},"references-count":50,"alternative-id":["10.3389\/fimmu.2022.829943"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.829943","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,27]]},"article-number":"829943"}}