Abstract
Endometriosis (EDT) is an inflammatory disease characterized by implantation/growth of endometrial tissue, glands, and/or stroma, outside the uterus. Reduced NK cell cytotoxic activity has been implicated in its pathogenesis, together with other immunologic alterations. We investigated the influence of KIR gene polymorphisms and their HLA ligand combinations in deep endometriosis (DE) susceptibility. One hundred sixty women with a histological diagnosis of DE and 202 control women without the disease, who underwent laparoscopy, were enrolled. The DE group was subdivided into initial (I/II; n = 60) and advanced stages (III/IV, n = 100). KIR and HLA class I gene polymorphisms were typed by PCR-SSP and sequence-based-typing (SBT), respectively. We observed a significant association of KIR2DL2, an inhibitory gene of B haplotype, conferring risk for DE in Euro-descendants. Positive associations of Bx haplotype and centromeric AB segments were also found. However, no association with KIR-HLA ligand combination was observed. Our data suggest KIR2DL2 gene to be a relevant factor favoring NK inhibition in DE in Euro-descendants, contributing to the defective NK cytotoxic activity and impaired clearance of ectopic endometrial cells in the disease.
Similar content being viewed by others
References
Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364:1789–99.
Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril. 1997;68:585–96.
Cornillie FJ, Oosterlynck D, Lauweryns JM, Koninckx PR. Deeply infiltrating pelvic endometriosis: histology and clinical significance. Fertil Steril. 1990;53:978–83.
Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update. 2005;11:595–606.
Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98:511–9.
Oosterlynck DJ, Cornillie FJ, Waer M, Vandeputte M, Koninckx PR. Women with endometriosis show a defect in natural killer activity resulting in a decreased cytotoxicity to autologous endometrium. Fertil Steril. 1991;56:45–51.
Oosterlynck DJ, Meuleman C, Waer M, Vandeputte M, Koninckx PR. The natural killer activity of peritoneal fluid lymphocytes is decreased in women with endometriosis. Fertil Steril. 1992;58:290–5.
Garzetti GG, Ciavattini A, Provinciali M, Fabris N, Cignitti M, Romanini C. Natural killer cell activity in endometriosis: correlation between serum estradiol levels and cytotoxicity. Obstet Gynecol. 1993;81:665–8.
Colonna M, Borsellino G, Falco M, Ferrara GB, Strominger JL. HLA-C is the inhibitory ligand that determines dominant resistance to lysis by NK1- and NK2-specific natural killer cells. Proc Natl Acad Sci U S A. 1993;90:12000–4.
Valiante NM, Uhrberg M, Shilling HG, Lienert-Weidenbach K, Arnett KL, D'Andrea A, et al. Functionally and structurally distinct NK cell receptor repertoires in the peripheral blood of two human donors. Immunity. 1997;7:739–51.
Vilches C, Parham P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol. 2001;20:217–51.
Ljunggren HG, Kärre K. In search of the 'missing self': MHC molecules and NK cell recognition. Immunol Today. 1990;11:237–44.
Middleton D, Gonzelez F. The extensive polymorphism of KIR genes. Immunology. 2010;129:8–19.
Marsh SG, Parham P, Dupont B, Geraghty DE, Trowsdale J, Middleton D, et al. Killer-cell immunoglobulin-like receptor (KIR) nomenclature report, 2002. Tissue Antigens. 2003;62:79–86.
Augusto DG. The impact of KIR polymorphism on the risk of developing cancer: not as strong as imagined? Front Genet. 2016;7:121.
Uhrberg M, Valiante NM, Shum BP, Shilling HG, Lienert-Weidenbach K, Corliss B, et al. Human diversity in killer cell inhibitory receptor genes. Immunity. 1997;7:753–63.
Moesta AK, Parham P. Diverse functionality among human NK cell receptors for the C1 epitope of HLA-C: KIR2DS2, KIR2DL2, and KIR2DL3. Front Immunol. 2012;3:336.
Nowak I, Płoski R, Barcz E, Dziunycz P, Kamiński P, Kostrzewa G, et al. KIR2DS5 in the presence of HLA-C C2 protects against endometriosis. Immunogenetics. 2015;67:203–9.
Kitawaki J, Xu B, Ishihara H, Fukui M, Hasegawa G, Nakamura N, et al. Association of killer cell immunoglobulin-like receptor genotypes with susceptibility to endometriosis. Am J Reprod Immunol. 2007;58:481–6.
Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817–21
12th International Histocompatibility Conference. Genetic diversity of HLA: functional and medical implications. Paris, France, June 9–12, 1996. Abstracts. Hum Immunol. 1996;47:1–184
Winter CC, Long EO. A single amino acid in the p58 killer cell inhibitory receptor controls the ability of natural killer cells to discriminate between the two groups of HLA-C allotypes. J Immunol. 1997;158:4026–8.
Cooley S, Weisdorf DJ, Guethlein LA, Klein JP, Wang T, Le CT, et al. Donor selection for natural killer cell receptor genes leads to superior survival after unrelated transplantation for acute myelogenous leukemia. Blood. 2010;116:2411–9.
Sullivan KM, Dean A, Soe MM. OpenEpi: a web-based epidemiologic and statistical calculator for public health. Public Health Rep. 2009;124:471–4.
Excoffier L, Laval G, Schneider S. Arlequin (version 3.0): an integrated software package for population genetics data analysis. Evol Bioinformatics Online. 2007;1:47–50.
Hsu KC, Liu XR, Selvakumar A, Mickelson E, O'Reilly RJ, Dupont B. Killer Ig-like receptor haplotype analysis by gene content: evidence for genomic diversity with a minimum of six basic framework haplotypes, each with multiple subsets. J Immunol. 2002;169:5118–29.
Pyo CW, Guethlein LA, Vu Q, Wang R, Abi-Rached L, Norman PJ, et al. Different patterns of evolution in the centromeric and telomeric regions of group a and B haplotypes of the human killer cell Ig-like receptor locus. PLoS One. 2010;5:e15115.
Faure M, Long EO. KIR2DL4 (CD158d), an NK cell-activating receptor with inhibitory potential. J Immunol. 2002;168:6208–14.
Winter CC, Gumperz JE, Parham P, Long EO, Wagtmann N. Direct binding and functional transfer of NK cell inhibitory receptors reveal novel patterns of HLA-C allotype recognition. J Immunol. 1998;161:571–7.
Moesta AK, Norman PJ, Yawata M, Yawata N, Gleimer M, Parham P. Synergistic polymorphism at two positions distal to the ligand-binding site makes KIR2DL2 a stronger receptor for HLA-C than KIR2DL3. J Immunol. 2008;180:3969–79.
Parra FC, Amado RC, Lambertucci JR, Rocha J, Antunes CM, Pena SD. Color and genomic ancestry in Brazilians. Proc Natl Acad Sci U S A. 2002;100:177–82.
Kirshon B, Poindexter AN, Fast J. Endometriosis in multiparous women. J Reprod Med. 1989;34:215–7.
Arumugam K, Templeton AA. Endometriosis and race. Aust N Z J Obstet Gynaecol. 1992;32:164–5.
Missmer SA, Hankinson SE, Spiegelman D, Barbieri RL, Marshall LM, Hunter DJ. Incidence of laparoscopically confirmed endometriosis by demographic, anthropometric, and lifestyle factors. Am J Epidemiol. 2004;160:784–96.
Matalliotakis IM, Cakmak H, Fragouli YG, Goumenou AG, Mahutte NG, Arici A. Epidemiological characteristics in women with and without endometriosis in the Yale series. Arch Gynecol Obstet. 2007;277:389–93.
Naumova E, Mihaylova A, Stoitchkov K, Ivanova M, Quin L, Toneva M. Genetic polymorphism of NK receptors and their ligands in melanoma patients: prevalence of inhibitory over activating signals. Cancer Immunol Immunother. 2004;54:172–8.
Verheyden S, Bernier M, Demanet C. Identification of natural killer cell receptor phenotypes associated with leukemia. Leukemia. 2004;18:2002–7.
Hiby SE, Walker JJ, O'Shaughnessy KM, Redman CW, Carrington M, Trowsdale J, et al. Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success. J Exp Med. 2004;200:957–65.
Hiby SE, Apps R, Chazara O, Farrell LE, Magnus P, Trogstad L, et al. Maternal KIR in combination with paternal HLA-C2 regulate human birth weight. J Immunol. 2014;192:5069–73.
Martin MP, Gao X, Lee JH, Nelson GW, Detels R, Goedert JJ, et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet. 2002;31:429–34.
Suzuki Y, Hamamoto Y, Ogasawara Y, Ishikawa K, Yoshikawa Y, Sasazuki T, et al. Genetic polymorphisms of killer cell immunoglobulin-like receptors are associated with susceptibility to psoriasis vulgaris. J Invest Dermatol. 2004;122:1133–6.
Lowe DP, Cook MA, Bowman SJ, Briggs DC, Group UKSsI. Association of killer cell immunoglobulin-like receptors with primary Sjogren’s syndrome. Rheumatology (Oxford). 2009;48:359–62.
Ranstam J. Multiple P-values and Bonferroni correction. Osteoarthr Cartil. 2016;24:763–4.
Jh M (2014) Handbook of biological statistics. 3rd ed. ed, 3rd, editor. Baltimore: Sparky House Publishing
Armstrong RA. When to use the Bonferroni correction. Ophthalmic Physiol Opt. 2014;34:502–8.
Chou YC, Chen CH, Chen MJ, Chang CW, Chen PH, Yu MH, et al. Killer cell immunoglobulin-like receptors (KIR) and human leukocyte antigen-C (HLA-C) allorecognition patterns in women with endometriosis. Sci Rep. 2020;10:4897.
Lavender KJ, Chau HH, Kane KP. Distinctive interactions at multiple site 2 subsites by allele-specific rat and mouse ly49 determine functional binding and class I MHC specificity. J Immunol. 2007;179:6856–66.
Jonsson AH, Yang L, Kim S, Taffner SM, Yokoyama WM. Effects of MHC class I alleles on licensing of Ly49A+ NK cells. J Immunol. 2010;184:3424–32.
Ho HN, Chao KH, Chen HF, Wu MY, Yang YS, Lee TY. Peritoneal natural killer cytotoxicity and CD25+ CD3+ lymphocyte subpopulation are decreased in women with stage III-IV endometriosis. Hum Reprod. 1995;10:2671–5.
Montaldo E, Del Zotto G, Della Chiesa M, Mingari MC, Moretta A, De Maria A, et al. Human NK cell receptors/markers: a tool to analyze NK cell development, subsets and function. Cytometry A. 2013;83:702–13. https://doi.org/10.1002/cyto.a.22302.
Ivarsson MA, Stiglund N, Marquardt N, Westgren M, Gidlöf S, Björkström NK. Composition and dynamics of the uterine NK cell KIR repertoire in menstrual blood. Mucosal Immunol. 2016;10:322–31.
Feyaerts D, Kuret T, van Cranenbroek B, van der Zeeuw-Hingrez S, van der Heijden OWH, van der Meer A, et al. Endometrial natural killer (NK) cells reveal a tissue-specific receptor repertoire. Hum Reprod. 2018;33:441–51.
Rached MR, Coelho V, Marin MLC, Pincerato K, Fujita A, Kalil JE, et al. HLA-G is upregulated in advanced endometriosis. Eur J Obstet Gynecol Reprod Biol. 2019;235:36–41.
González-Foruria I, Santulli P, Chouzenoux S, Carmona F, Batteux F, Chapron C. Soluble ligands for the NKG2D receptor are released during endometriosis and correlate with disease severity. PLoS One. 2015;10:e0119961.
Acknowledgments
The authors thank Danilo Augusto Franceschi (State University of Maringá, PR, Brazil) and Claudia Borba Rosales (Heart Institute, Universidade de São Paulo, SP, Brazil) for their relevant technical KIR and HLA typing assistance and analyses of data.
Authors’ Collaborations
M.L.C.M.: conception and design; sample collection; technical processing; acquisition, analysis, and interpretation of data; drafting manuscript. V.C.: analysis and interpretation of data and drafting manuscript. J.E.L.V., H.V.A., and K.F.K.: analysis and interpretation of data. M.R.R.: sample collection and drafting manuscript. M.S.A. and J.K: conception and interpretation of data. All authors had revised for critical content and final approval of the submitted manuscript.
Funding
This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (grant number: 2010/10338-0).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
Abrão MS is a Consultant for Myovant Sciences and for Abbvie Pharmaceutical. The other authors declare that they have no conflict of interest.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic Supplementary Material
Supplementary Fig 1
Distribution of KIR genotypes according to AA and Bx haplotypes in women with DE and controls DE, deep endometriosis, including DE in the presence of endometrioma; KIR, killer cell immunoglobulin-like receptors. Hapl. G, Haplotype group; Gen. ID, Genotype ID assigned by the Allele Frequencies Net Database (http://www.allelefrequencies.net/kir60012.asp, April 2018); NAS, Not yet Assigned ID; ns, not significant; black box, gene detected; white box, gene absent/no detected. (DOCX 48 kb)
Rights and permissions
About this article
Cite this article
Marin, M.L.C., Coelho, V., Visentainer, J.E.L. et al. Inhibitory KIR2DL2 Gene: Risk for Deep Endometriosis in Euro-descendants. Reprod. Sci. 28, 291–304 (2021). https://doi.org/10.1007/s43032-020-00255-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s43032-020-00255-x