{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T12:50:45Z","timestamp":1791204645573,"version":"4.2.0"},"reference-count":36,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,25]],"date-time":"2022-12-25T00:00:00Z","timestamp":1671926400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hospital da Luz Lisboa"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Endometriosis is a chronic inflammatory disorder, characterized by the presence of endometrial cells outside the uterine cavity. An increasing number of studies correlate the immune system with endometriosis, particularly NK receptors (NKR), which have been suggested to play an essential role in the pathogenesis of the disease. This systematic review aims to enlighten the role of NKR in endometriosis. A literature search was performed independently by two reviewers, to identify studies assessing the role of NKR in endometriosis. In total, 18 studies were included. Endometriosis pathogenesis seems to be marked by the overexpression of NK inhibitor receptors (KIRS), namely, CD158a+, KIR2DL1, CD94\/NKG2A, PD-1, NKB1, and EB6, and inhibiting ligands such as PD-L1, HLA-E, HLA-G, and HLA-I. Concurrently, there is a decrease in NK-activating receptors and natural cytotoxicity receptors (NCRs), such as NKp46, NKp30, and NKG2D. The immune shift from NK surveillance to NK suppression is also apparent in the greater relative number of ITIM domains compared with ITAM domains in NKRs. In conclusion, NK receptor activity seems to dictate the immunocompetency of women to clear endometriotic cells from the peritoneal cavity. Future research could explore NKRs as therapeutic targets, such as that which is now well established in cancer therapy through immunotherapy.<\/jats:p>","DOI":"10.3390\/ijms24010331","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T04:40:39Z","timestamp":1672116039000},"page":"331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Natural Killer Cell Receptors and Endometriosis: A Systematic Review"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2537-7026","authenticated-orcid":false,"given":"Jos\u00e9 Louren\u00e7o","family":"Reis","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, LUZ SA\u00daDE, Hospital da Luz, 1500-650 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9583-2568","authenticated-orcid":false,"given":"Natacha Nurdine","family":"Rosa","sequence":"additional","affiliation":[{"name":"UCD School of Medicine, University College Dublin, D04 V1W8 Dublin, Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9933-4075","authenticated-orcid":false,"given":"Miguel","family":"\u00c2ngelo-Dias","sequence":"additional","affiliation":[{"name":"Comprehensive Health Research Centre (CHRC), NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas (NMS|FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal"},{"name":"Immunology Department, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas (NMS|FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catarina","family":"Martins","sequence":"additional","affiliation":[{"name":"Comprehensive Health Research Centre (CHRC), NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas (NMS|FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal"},{"name":"Immunology Department, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas (NMS|FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu\u00eds Miguel","family":"Borrego","sequence":"additional","affiliation":[{"name":"Comprehensive Health Research Centre (CHRC), NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas (NMS|FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal"},{"name":"Immunology Department, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas (NMS|FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal"},{"name":"Department of Imunoallergy, LUZ SA\u00daDE, Hospital da Luz, 1500-650 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0831-2741","authenticated-orcid":false,"given":"Jorge","family":"Lima","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, LUZ SA\u00daDE, Hospital da Luz, 1500-650 Lisboa, Portugal"},{"name":"Comprehensive Health Research Centre (CHRC), NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas (NMS|FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal"},{"name":"Immunology Department, NOVA Medical School|Faculdade de Ci\u00eancias M\u00e9dicas (NMS|FCM), Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bpobgyn.2018.06.001","article-title":"Risk for and consequences of endometriosis: A critical epidemiologic review","volume":"51","author":"Shafrir","year":"2018","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_2","first-page":"93","article-title":"Metastatic or Embolic Endometriosis, due to the Menstrual Dissemination of Endometrial Tissue into the Venous Circulation","volume":"3","author":"Sampson","year":"1927","journal-title":"Am. J. Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.bpobgyn.2018.01.010","article-title":"Immunology of endometriosis","volume":"50","author":"Riccio","year":"2018","journal-title":"Best Pract. Res. Clin. Obstet. Gynaecol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/aji.12408","article-title":"Natural Killer Cells: Key Players in Endometriosis","volume":"74","author":"Thiruchelvam","year":"2015","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/S0015-0282(00)01592-2","article-title":"Increase in the expression of killer cell inhibitory receptors on peritoneal natural killer cells in women with endometriosis","volume":"74","author":"Wu","year":"2000","journal-title":"Fertil. Steril."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/S0015-0282(00)01791-X","article-title":"Histocompatibility leukocyte antigen-G is not expressed by endometriosis or endometrial tissue","volume":"75","author":"Hornung","year":"2001","journal-title":"Fertil. Steril."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/S0015-0282(01)03249-6","article-title":"Aberrant expression of intercellular adhesion molecule-1 and killer inhibitory receptors induces immune tolerance in women with pelvic endometriosis","volume":"77","author":"Maeda","year":"2002","journal-title":"Fertil. Steril."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0015-0282(01)02964-8","article-title":"Increased killer inhibitory receptor KIR2DL1 expression among natural killer cells in women with pelvic endometriosis","volume":"77","author":"Maeda","year":"2002","journal-title":"Fertil. Steril."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/j.1600-0897.2004.00170.x","article-title":"Killer Inhibitory Receptor CD158a Overexpression Among Natural Killer Cells in Women With Endometriosis is Undiminished by Laparoscopic Surgery and Gonadotropin Releasing Hormone Agonist Treatment*","volume":"51","author":"Maeda","year":"2004","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/j.1600-0897.2005.00271.x","article-title":"Expression of Inhibitory-Motif Killer Immunoglobulin-Like Receptor, KIR2DL1, is Increased in Natural Killer Cells from Women with Pelvic Endometriosis","volume":"53","author":"Matsuoka","year":"2005","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1111\/j.1600-0897.2005.00360.x","article-title":"Aberrant Expression of CD95 and CD69 Molecules among CD56+ Cells in Women with Endometriosis","volume":"55","author":"Eidukaite","year":"2006","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1093\/humrep\/dei408","article-title":"HLA-G is expressed by the glandular epithelium of peritoneal endometriosis but not in eutopic endometrium","volume":"21","author":"Barrier","year":"2005","journal-title":"Hum. Reprod."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.fertnstert.2007.02.036","article-title":"Soluble HLA-G in the peritoneal fluid of women with endometriosis","volume":"89","author":"Eidukaite","year":"2008","journal-title":"Fertil. Steril."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1490","DOI":"10.1016\/j.fertnstert.2007.05.018","article-title":"Increased frequency of human leukocyte antigen-E inhibitory receptor CD94\/NKG2A-expressing peritoneal natural killer cells in patients with endometriosis","volume":"89","author":"Galandrini","year":"2008","journal-title":"Fertil. Steril."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"419","DOI":"10.3109\/09513590.2010.495429","article-title":"The expression of human leukocyte antigens class I and II in women with endometriosis or adenomyosis","volume":"27","author":"Baka","year":"2010","journal-title":"Gynecol. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1111\/aji.12206","article-title":"Expression of Natural Cytotoxicity Receptors on Peritoneal Fluid Natural Killer Cell and Cytokine Production by Peritoneal Fluid Natural Killer Cell in Women with Endometriosis","volume":"71","author":"Funamizu","year":"2014","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez-Foruria, I., Santulli, P., Chouzenoux, S., Carmona, F., Batteux, F., and Chapron, C. (2015). Soluble Ligands for the NKG2D Receptor Are Released during Endometriosis and Correlate with Disease Severity. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0119961"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.ejogrb.2019.01.030","article-title":"HLA-G is upregulated in advanced endometriosis","volume":"235","author":"Rached","year":"2019","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"102615","DOI":"10.1016\/j.jri.2019.102615","article-title":"Expressions of natural cytotoxicity receptor, NKG2D and NKG2D ligands in endometriosis","volume":"136","author":"Xu","year":"2019","journal-title":"J. Reprod. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-020-61702-y","article-title":"Killer cell immunoglobulin-like receptors (KIR) and human leukocyte antigen-C (HLA-C) allorecognition patterns in women with endometriosis","volume":"10","author":"Chou","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"105906","DOI":"10.1016\/j.ijsu.2021.105906","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"88","author":"Page","year":"2021","journal-title":"Int. J. Surg."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"n160","DOI":"10.1136\/bmj.n160","article-title":"PRISMA 2020 explanation and elaboration: Updated guidance and exemplars for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0015-0282(16)48430-X","article-title":"Revised American Fertility Society classification of endometriosis","volume":"43","author":"Andrews","year":"1985","journal-title":"Fertil. Steril."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1080\/09513590.2018.1519787","article-title":"Expression of programmed death-1 (PD-1) and its ligand PD-L1 is upregulated in endometriosis and promoted by 17beta-estradiol","volume":"35","author":"Wu","year":"2018","journal-title":"Gynecol. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"103765","DOI":"10.1016\/j.jri.2022.103765","article-title":"Co-expression of activating and inhibitory receptors on peritoneal fluid NK cells in women with endometriosis","volume":"155","author":"Saeki","year":"2022","journal-title":"J. Reprod. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"795976","DOI":"10.1155\/2015\/795976","article-title":"Pathophysiology and Immune Dysfunction in Endometriosis","volume":"2015","author":"Ahn","year":"2015","journal-title":"BioMed Res. Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e13342","DOI":"10.1111\/aji.13342","article-title":"Pelvic endometriosis and natural killer cell immunity","volume":"85","author":"Fukui","year":"2021","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_28","first-page":"433","article-title":"Natural killer cell recognition of HLA class I molecules","volume":"2","author":"Brooks","year":"2000","journal-title":"Rev. Immunogenet."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1379\/1466-1268(2000)005<0207:HSAAIE>2.0.CO;2","article-title":"Heat shock and arsenite induce expression of the nonclassical class I histocompatibility HLA-G gene in tumor cell lines","volume":"5","author":"Ibrahim","year":"2000","journal-title":"Cell Stress Chaperon."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Quatrini, L., Mariotti, F., Munari, E., Tumino, N., Vacca, P., and Moretta, L. (2020). The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy. Cancers, 12.","DOI":"10.3390\/cancers12113285"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"553","DOI":"10.20452\/pamw.2967","article-title":"Prognostic significance of PD-1 expression on peripheral blood CD4+ T cells in patients with newly diagnosed chronic lymphocytic leukemia","volume":"125","author":"Rusak","year":"2015","journal-title":"Pol. Arch. Intern. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.humpath.2016.02.007","article-title":"Expression and prognostic roles of PIK3CA, JAK2, PD-L1, and PD-L2 in Epstein-Barr virus-associated gastric carcinoma","volume":"53","author":"Dong","year":"2016","journal-title":"Hum. Pathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/j.ygyno.2016.03.008","article-title":"PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer","volume":"141","author":"Webb","year":"2016","journal-title":"Gynecol. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Chantalat, E., Valera, M.-C., Vaysse, C., Noirrit, E., Rusidze, M., Weyl, A., Vergriete, K., Buscail, E., Lluel, P., and Fontaine, C. (2020). Estrogen Receptors and Endometriosis. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082815"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3571","DOI":"10.1182\/blood-2007-07-100057","article-title":"Sustained NKG2D engagement induces cross-tolerance of multiple distinct NK cell activation pathways","volume":"111","author":"Coudert","year":"2008","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Evert, J.H.-V., Paap, R., Nap, A., and van der Molen, R. (2022). The Promises of Natural Killer Cell Therapy in Endometriosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105539"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/331\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:50:49Z","timestamp":1760147449000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/331"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,25]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24010331"],"URL":"https:\/\/doi.org\/10.3390\/ijms24010331","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,25]]}}}