{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T09:12:28Z","timestamp":1775034748556,"version":"3.50.1"},"reference-count":26,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2016,12,16]],"date-time":"2016-12-16T00:00:00Z","timestamp":1481846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is characterized by a low percentage of neoplastic lymphocyte predominant (LP) cells in a background of lymphocytes. The goal of this study is to characterize the microenvironment in NLPHL. Ten NLPHL cases and seven reactive lymph nodes (RLN) were analyzed by flow cytometry for the main immune cells and multiple specific subpopulations. To discriminate between cells in or outside the tumor cell area, we used CD26. We observed significantly lower levels of CD20+ B-cells and CD56+ NK cells and higher levels of CD4+ T-cells in NLPHL in comparison to RLN. In the subpopulations, we observed increased numbers of PD-1+CD4+ T follicular helper cells (TFH), CD69+CD4+ and CD69+CD8+ T-cells and CCR7-CD45RA-CD4+ effector memory T-cells, while FoxP3+CD4+ T regulatory cells (Tregs) and CCR7-CD45RA+ terminally differentiated CD4+ T-cells were decreased in NLPHL compared to RLN. CD69+ cells were increased in the tumor cell area in CD4+ and CD8+ T-cells, while FoxP3+CD25+CD4+ Tregs and CD25+CD8+ T-cells were significantly increased outside the tumor area. Thus, we show a markedly altered microenvironment in NLPHL, with lower numbers of NK cells and Tregs. PD-1+CD4+ and CD69+ T-cells were located inside, and Tregs and CD25+CD8+ cells outside the tumor cell area.<\/jats:p>","DOI":"10.3390\/ijms17122127","type":"journal-article","created":{"date-parts":[[2016,12,16]],"date-time":"2016-12-16T10:55:28Z","timestamp":1481885728000},"page":"2127","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Characterization of the Microenvironment of Nodular Lymphocyte Predominant Hodgkin Lymphoma"],"prefix":"10.3390","volume":"17","author":[{"given":"Ahmad","family":"Sattarzadeh","sequence":"first","affiliation":[{"name":"Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lydia","family":"Visser","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bea","family":"Rutgers","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9239-1050","authenticated-orcid":false,"given":"Arjan","family":"Diepstra","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8894-2638","authenticated-orcid":false,"given":"Anke","family":"Berg","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, 9700RB Groningen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2016,12,16]]},"reference":[{"key":"ref_1","unstructured":"Swerdlow, S.H., Campo, E., Harris, N.L., Jaffe, E.S., Pileri, S.A., Stein, H., Thiele, J., and Vardiman, J.W. (2008). WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization. [4th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.semcancer.2013.07.002","article-title":"The microenvironment in classical Hodgkin lymphoma: An actively shaped and essential tumor component","volume":"24","author":"Liu","year":"2014","journal-title":"Semin. Cancer Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1002\/path.1894","article-title":"Cytokine gene expression profile distinguishes CD4+\/CD57+ T-cells of nodular lymphocyte predominance type of Hodgkin lymphoma from their tonsillar counterparts","volume":"208","author":"Atayar","year":"2006","journal-title":"J. Pathol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1097\/PAS.0b013e318165b0d6","article-title":"PD-1, a follicular T-cell marker useful for recognizing nodular lymphocyte-predominant Hodgkin lymphoma","volume":"32","author":"Roncador","year":"2008","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s40164-015-0022-1","article-title":"CD57+ T-cells are a subpopulation of T-follicular helper cells in nodular lymphocyte predominant Hodgkin lymphoma","volume":"4","author":"Sattarzadeh","year":"2015","journal-title":"Exp. Hematol. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1870","DOI":"10.1080\/10428190802308728","article-title":"Beyond the lymphocyte predominant cell: CD4+CD8+ T-cells in nodular lymphocyte predominant Hodgkin lymphoma","volume":"49","author":"Rahemtullah","year":"2008","journal-title":"Leuk Lymphoma"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1002\/cyto.b.20407","article-title":"Detection of T-regulatory cells has a potential role in the diagnosis of classical Hodgkin lymphoma","volume":"74","author":"Bosler","year":"2008","journal-title":"Cytometry B Clin. Cytom."},{"key":"ref_8","first-page":"13241","article-title":"Expression of Sirt1 and FoxP3 in classical Hodgkin lymphoma and tumor infiltrating lymphocytes: Implications for immune dysregulation, prognosis and potential therapeutic targeting","volume":"8","author":"Quesada","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2856","DOI":"10.1182\/blood-2013-06-508044","article-title":"Defining characteristics of classical Hodgkin lymphoma microenvironment T-helper cells","volume":"122","author":"Greaves","year":"2013","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1006\/scbi.2000.0327","article-title":"Interaction between host T cells and Reed-Sternberg cells in Hodgkin lymphomas","volume":"10","author":"Poppema","year":"2000","journal-title":"Seminars Cancer Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1002\/cyto.b.21261","article-title":"Reactive T cells by flow cytometry distinguish Hodgkin lymphomas from T cell\/histiocyte-rich large B cell lymphoma","volume":"90","author":"Wu","year":"2016","journal-title":"Cytometry B Clin. Cytom."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1084\/jem.20080809","article-title":"Origin and pathogenesis of nodular lymphocyte-predominant Hodgkin lymphoma as revealed by global gene expression analysis","volume":"205","author":"Brune","year":"2008","journal-title":"J. Exp. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2597","DOI":"10.1002\/eji.201242616","article-title":"Expansion of follicular helper T cells in the absence of Treg cells: implications for loss of B-cell anergy","volume":"42","author":"Leonardo","year":"2012","journal-title":"Eur. J. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Hartmann, S., Doring, C., Jakobus, C., Rengstl, B., Newrzela, S., Tousseyn, T., Sagaert, X., Ponzoni, M., Facchetti, F., and de Wolf-Peeters, C. (2013). Nodular lymphocyte predominant Hodgkin lymphoma and T cell\/histiocyte rich large B cell lymphoma\u2013endpoints of a spectrum of one disease?. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0078812"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1084\/jem.20141432","article-title":"ICOS maintains the T follicular helper cell phenotype by down-regulating Kruppel-like factor 2","volume":"212","author":"Weber","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1038\/ni.3050","article-title":"A p85\u03b1-osteopontin axis couples the receptor ICOS to sustained BCL-6 expression by follicular helper and regulatory T cells","volume":"16","author":"Leavenworth","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa1411087","article-title":"PD-1 blockade with nivolumab in relapsed or refractory Hodgkin\u2019s lymphoma","volume":"372","author":"Ansell","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3462","DOI":"10.1158\/1078-0432.CCR-13-0855","article-title":"PD-L1 expression is characteristic of a subset of aggressive B-cell lymphomas and virus-associated malignancies","volume":"19","author":"Chen","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e281","DOI":"10.1038\/bcj.2015.1","article-title":"PD-1 expression defines two distinct T-cell sub-populations in follicular lymphoma that differentially impact patient survival","volume":"5","author":"Yang","year":"2015","journal-title":"Blood Cancer J."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1097\/TP.0b013e318290de18","article-title":"Elevation of CD4+ differentiated memory T cells is associated with acute cellular and antibody-mediated rejection after liver transplantation","volume":"95","author":"Gerlach","year":"2013","journal-title":"Transplantation"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1038\/44385","article-title":"Two subsets of memory T lymphocytes with distinct homing potentials and effector functions","volume":"401","author":"Sallusto","year":"1999","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.immuni.2014.12.007","article-title":"Tissue-resident memory T cells","volume":"41","author":"Schenkel","year":"2014","journal-title":"Immunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/nature04606","article-title":"CD69 acts downstream of interferon-\u03b1\/\u03b2 to inhibit S1P1 and lymphocyte egress from lymphoid organs","volume":"440","author":"Shiow","year":"2006","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1172\/JCI200319112","article-title":"CD69 downregulates autoimmune reactivity through active transforming growth factor-\u03b2 production in collagen-induced arthritis","volume":"112","author":"Sancho","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1084\/jem.20021337","article-title":"Enhanced antitumor immunity in mice deficient in CD69","volume":"197","author":"Esplugues","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e417","DOI":"10.1038\/bcj.2016.26","article-title":"The microenvironment of classical Hodgkin lymphoma: heterogeneity by Epstein-Barr virus presence and location within the tumor","volume":"6","author":"Wu","year":"2016","journal-title":"Blood Cancer J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/12\/2127\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:28:45Z","timestamp":1760210925000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/17\/12\/2127"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,16]]},"references-count":26,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2016,12]]}},"alternative-id":["ijms17122127"],"URL":"https:\/\/doi.org\/10.3390\/ijms17122127","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,16]]}}}