Skip to main content

Inhibitory KIR2DL2 Gene: Risk for Deep Endometriosis in Euro-descendants

Reproductive Sciences volume 28, pages 291–304 (2021)Cite this article

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.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Fig. 1

References

  1. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364:1789–99.

    PubMed  Google Scholar 

  2. 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.

    CAS  PubMed  Google Scholar 

  3. Cornillie FJ, Oosterlynck D, Lauweryns JM, Koninckx PR. Deeply infiltrating pelvic endometriosis: histology and clinical significance. Fertil Steril. 1990;53:978–83.

    CAS  PubMed  Google Scholar 

  4. Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications. Hum Reprod Update. 2005;11:595–606.

    CAS  PubMed  Google Scholar 

  5. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98:511–9.

    CAS  PubMed  Google Scholar 

  6. 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.

    CAS  PubMed  Google Scholar 

  7. 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.

    CAS  PubMed  Google Scholar 

  8. 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.

    CAS  PubMed  Google Scholar 

  9. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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.

    CAS  PubMed  Google Scholar 

  11. Vilches C, Parham P. KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol. 2001;20:217–51.

    PubMed  Google Scholar 

  12. Ljunggren HG, Kärre K. In search of the 'missing self': MHC molecules and NK cell recognition. Immunol Today. 1990;11:237–44.

    CAS  PubMed  Google Scholar 

  13. Middleton D, Gonzelez F. The extensive polymorphism of KIR genes. Immunology. 2010;129:8–19.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 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.

    CAS  PubMed  Google Scholar 

  15. Augusto DG. The impact of KIR polymorphism on the risk of developing cancer: not as strong as imagined? Front Genet. 2016;7:121.

    PubMed  PubMed Central  Google Scholar 

  16. 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.

    CAS  PubMed  Google Scholar 

  17. 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.

    PubMed  PubMed Central  Google Scholar 

  18. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 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.

    PubMed  Google Scholar 

  20. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817–21

  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

  22. 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.

    CAS  PubMed  Google Scholar 

  23. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Sullivan KM, Dean A, Soe MM. OpenEpi: a web-based epidemiologic and statistical calculator for public health. Public Health Rep. 2009;124:471–4.

    PubMed  PubMed Central  Google Scholar 

  25. 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.

    Google Scholar 

  26. 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.

    PubMed  Google Scholar 

  27. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Faure M, Long EO. KIR2DL4 (CD158d), an NK cell-activating receptor with inhibitory potential. J Immunol. 2002;168:6208–14.

    CAS  PubMed  Google Scholar 

  29. 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.

    CAS  PubMed  Google Scholar 

  30. 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.

    CAS  PubMed  Google Scholar 

  31. 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.

    PubMed  PubMed Central  Google Scholar 

  32. Kirshon B, Poindexter AN, Fast J. Endometriosis in multiparous women. J Reprod Med. 1989;34:215–7.

    CAS  PubMed  Google Scholar 

  33. Arumugam K, Templeton AA. Endometriosis and race. Aust N Z J Obstet Gynaecol. 1992;32:164–5.

    CAS  PubMed  Google Scholar 

  34. 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.

    PubMed  Google Scholar 

  35. 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.

    PubMed  Google Scholar 

  36. 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.

    PubMed  Google Scholar 

  37. Verheyden S, Bernier M, Demanet C. Identification of natural killer cell receptor phenotypes associated with leukemia. Leukemia. 2004;18:2002–7.

    CAS  PubMed  Google Scholar 

  38. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 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.

    CAS  PubMed  Google Scholar 

  40. 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.

    CAS  PubMed  Google Scholar 

  41. 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.

    CAS  PubMed  Google Scholar 

  42. 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.

    CAS  Google Scholar 

  43. Ranstam J. Multiple P-values and Bonferroni correction. Osteoarthr Cartil. 2016;24:763–4.

    CAS  Google Scholar 

  44. Jh M (2014) Handbook of biological statistics. 3rd ed. ed, 3rd, editor. Baltimore: Sparky House Publishing

  45. Armstrong RA. When to use the Bonferroni correction. Ophthalmic Physiol Opt. 2014;34:502–8.

    PubMed  Google Scholar 

  46. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 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.

    CAS  PubMed  Google Scholar 

  48. 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.

    CAS  PubMed  Google Scholar 

  49. 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.

    CAS  PubMed  Google Scholar 

  50. 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.

    Article  PubMed  Google Scholar 

  51. 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.

    PubMed  Google Scholar 

  52. 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.

    CAS  PubMed  Google Scholar 

  53. 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.

    CAS  PubMed  Google Scholar 

  54. 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.

    PubMed  PubMed Central  Google Scholar 

Download references

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

Author notes

  1. Mauricio Simões Abrão and Jorge Kalil contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Immunology, Heart Institute (InCor), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

    Maria Lucia Carnevale Marin, Verônica Coelho, Karen Francine Köhler, Marici Rached Rached & Jorge Kalil

  2. Histocompatibility and Cellular Immunology Laboratory, LIM-19, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

    Maria Lucia Carnevale Marin, Verônica Coelho & Jorge Kalil

  3. Institute for Investigation in Immunology, National Institute of Science and Technology (iii-INCT), São Paulo, SP, Brazil

    Verônica Coelho & Jorge Kalil

  4. Division of Clinical Immunology and Allergy, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

    Verônica Coelho & Jorge Kalil

  5. Laboratory of Immunogenetics, Department of Basic Health Sciences, State University of Maringá, Maringá, PR, Brazil

    Jeane Eliete Laguila Visentainer & Hugo Vicentin Alves

  6. Obstetrics and Gynecology Department, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil

    Mauricio Simões Abrão

  7. Gynecologic Division, BP - A Beneficência Portuguesa de São Paulo, São Paulo, SP, Brazil

    Mauricio Simões Abrão

  8. Rua São Sebastião 550, São Paulo, 04708-001, Brazil

    Mauricio Simões Abrão

Authors
  1. Maria Lucia Carnevale Marin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Verônica Coelho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeane Eliete Laguila Visentainer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hugo Vicentin Alves
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karen Francine Köhler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marici Rached Rached
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mauricio Simões Abrão
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jorge Kalil
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mauricio Simões Abrão.

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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-020-00255-x

Keywords

  • Endometriosis
  • NK cells
  • Killer cell immunoglobulin-like receptors
  • KIR-HLA ligand combinations