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NK cell abnormality and its treatment in women with reproductive failures such as recurrent pregnancy loss, implantation failures, preeclampsia, and pelvic endometriosis

  • Review Article
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Reproductive Medicine and Biology

Abstract

The regulation of uterine and peripheral blood natural killer (NK) cells has been associated with problems related to reproductive immunology such as recurrent pregnancy loss (RPL), implantation failure or preeclampsia. NKp46, one of the natural cytotoxicity receptors (NCRs), is a unique marker that functions in NK cell cytotoxicity and cytokine production. Expression of NKp46 on NK cells is lower in women with recurrent pregnancy loss and pregnancy-induced hypertension. Moreover, expression of NKp46 on peritoneal fluid NK cells is lower in women with pelvic endometriosis. Therefore, evaluation of NKp46 on peripheral blood NK cells may provide a means of screening for reproductive abnormalities. Recently, a new type of NK cell, the NK22 cell, has been reported. This cell may be a regulator not only of the mucosal barrier but also of reproduction.For women with RPL showing abnormal uterine and/or peripheral blood NK cells, both intravenous immunoglobulin treatment and intralipid treatment have been reported. The effects of these treatments are still controversial, and further studies are needed in order to clarify their true impact. The present review examines variations in the expression of NCRs on NK cells, the participation of NK22 cells in reproduction, and the possible use of intravenous immunoglobulin or intralipid treatment for women with recurrent pregnancy loss and NK cell abnormality.

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References

  1. Norwitz ER, Schust DJ, Fisher SJ. Implantation and the survival of early pregnancy. N Engl J Med. 2001;345:1400–8.

    Article  CAS  PubMed  Google Scholar 

  2. Moffett A, Regan L, Braude P. Natural killer cells, miscarriage, and infertility. BMJ. 2004;329:1283–5.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Bhalla A, et al. Comparison of the expression of human leukocyte antigen (HLA)-G and HLA-E in women with normal pregnancy and those with recurrent miscarriage. Reproduction. 2006;131:583–9.

    Article  CAS  PubMed  Google Scholar 

  4. Katano K, et al. Peripheral natural killer cell activity as a predictor of recurrent pregnancy loss: a large cohort study. Fertil Steril. 2013;100:1629–34.

    Article  CAS  PubMed  Google Scholar 

  5. Tang AW, Alfirevic Z, Quenby S. Natural killer cells and pregnancy outcomes in women with recurrent miscarriage and infertility: a systematic review. Hum Reprod. 2011;26:1971–80.

    Article  CAS  PubMed  Google Scholar 

  6. Kwak-Kim J, Gilman-Sachs A. Clinical implication of natural killer cells and reproduction. Am J Reprod Immunol. 2008;59:388–400.

    Article  CAS  PubMed  Google Scholar 

  7. Kwak JY, et al. Up-regulated expression of CD56+, CD56+/CD16+, and CD19+ cells in peripheral blood lymphocytes in pregnant women with recurrent pregnancy losses. Am J Reprod Immunol. 1995;34:93–9.

    Article  CAS  PubMed  Google Scholar 

  8. Coulam CB, et al. Systemic CD56+ cells can predict pregnancy outcome. Am J Reprod Immunol. 1995;33:40–6.

    Article  CAS  PubMed  Google Scholar 

  9. Fukui A, et al. Natural killer cell subpopulations and cytotoxicity for infertile patients undergoing in vitro fertilization. Am J Reprod Immunol. 1999;41:413–22.

    Article  CAS  PubMed  Google Scholar 

  10. Fukui A, et al. Expression of natural cytotoxicity receptors and a2V-ATPase on peripheral blood NK cell subsets in women with recurrent spontaneous abortions and implantation failures. Am J Reprod Immunol. 2006;56:312–20.

    Article  CAS  PubMed  Google Scholar 

  11. Fukui A, et al. Intracellular cytokine expression of peripheral blood natural killer cell subsets in women with recurrent spontaneous abortions and implantation failures. Fertil Steril. 2008;89:157–65.

    Article  CAS  PubMed  Google Scholar 

  12. Fukui A, et al. Expression of natural cytotoxicity receptors and intracellular cytokine production of natural killer cell subsets in women with implantation failures. J Fertil Implant. 2009;26:341–7.

    Google Scholar 

  13. Fukui A, et al. Correlation between natural cytotoxicity receptors and intracellular cytokine expression of peripheral blood NK cells in women with recurrent pregnancy losses and implantation failures. Am J Reprod Immunol. 2009;62:371–80.

    Article  CAS  PubMed  Google Scholar 

  14. Fukui A, et al. Expression of natural cytotoxicity receptors on midsecretory endometrial or decidual natural killer cells. J Fertil Implant. 2010;27:369–74.

    Google Scholar 

  15. Fukui A, et al. Uterine and circulating natural killer cells and their roles in women with recurrent pregnancy loss, implantation failure and preeclampsia. J Reprod Immunol. 2011;90:105–10.

    Article  CAS  PubMed  Google Scholar 

  16. Chernyshov VP, et al. Elevated NK cell cytotoxicity, CD158a expression in NK cells and activated T lymphocytes in peripheral blood of women with IVF failures. Am J Reprod Immunol. 2010;64:58–67.

    CAS  PubMed  Google Scholar 

  17. Junovich G, et al. Endometrial CD16(+) and CD16(−) NK cell count in fertility and unexplained infertility. Am J Reprod Immunol. 2013;70:182–9.

    Article  CAS  PubMed  Google Scholar 

  18. Lachapelle MH, et al. Endometrial T, B, and NK cells in patients with recurrent spontaneous abortion. Altered profile and pregnancy outcome. J Immunol. 1996;156:4027–34.

    CAS  PubMed  Google Scholar 

  19. Arnon TI, et al. Recognition of viral hemagglutinins by NKp44 but not by NKp30. Eur J Immunol. 2001;31:2680–9.

    Article  CAS  PubMed  Google Scholar 

  20. Mandelboim O, et al. Recognition of haemagglutinins on virus-infected cells by NKp46 activates lysis by human NK cells. Nature. 2001;409:1055–60.

    Article  CAS  PubMed  Google Scholar 

  21. Halfteck GG, et al. Enhanced in vivo growth of lymphoma tumors in the absence of the NK-activating receptor NKp46/NCR1. J Immunol. 2009;182:2221–30.

    Article  CAS  PubMed  Google Scholar 

  22. Lakshmikanth T, et al. NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. J Clin Invest. 2009;119:1251–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Cagnano E, et al. Expression of ligands to NKp46 in benign and malignant melanocytes. J Invest Dermatol. 2008;128:972–9.

    Article  CAS  PubMed  Google Scholar 

  24. Yokota M, et al. Role of NKp46 expression in cytokine production by CD56-positive NK cells in the peripheral blood and the uterine endometrium. Am J Reprod Immunol. 2013;69:202–11.

    Article  CAS  PubMed  Google Scholar 

  25. Sivori S, et al. p46, a novel natural killer cell-specific surface molecule that mediates cell activation. J Exp Med. 1997;186:1129–36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Manaster I, et al. Endometrial NK cells are special immature cells that await pregnancy. J Immunol. 2008;181:1869–76.

    Article  CAS  PubMed  Google Scholar 

  27. Zhang Y, et al. Expressions of natural cytotoxicity receptors and NKG2D on decidual natural killer cells in patients having spontaneous abortions. Fertil Steril. 2008;90:1931–7.

    Article  PubMed  Google Scholar 

  28. Fukui A. NK cells and its role in reproduction. Am J Reprod Immunol. 2010;64:1.

    Article  Google Scholar 

  29. Fukui A. Uterine and circulating natural killer cells and their roles in women with recurrent pregnancy losses, implantation failures or preeclampsia. J Reprod Immunol. 2010;86:14.

    Article  Google Scholar 

  30. Fukui A, et al. Changes of NK cells in preeclampsia. Am J Reprod Immunol. 2012;67:278–86.

    Article  CAS  PubMed  Google Scholar 

  31. Moore Simas TA. Angiogenic factors for the prediction of preeclampsia in high-risk women. Am J Obstet Gynecol. 2007;197(244):e1–8.

    PubMed  Google Scholar 

  32. Poon LC, et al. First-trimester prediction of hypertensive disorders in pregnancy. Hypertension. 2009;53:812–8.

    Article  CAS  PubMed  Google Scholar 

  33. Funamizu A, et al. Expression of natural cytotoxicity receptors on peritoneal fluid natural killer cell and cytokine production by peritoneal fluid natural killer cell in women with endometriosis. Am J Reprod Immunol. 2014;71:359–67.

    Article  CAS  PubMed  Google Scholar 

  34. Cella M, et al. A human natural killer cell subset provides an innate source of IL-22 for mucosal immunity. Nature. 2009;457:722–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Colonna M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity. 2009;31:15–23.

    Article  CAS  PubMed  Google Scholar 

  36. Veiga-Fernandes H, Kioussis D, Coles M. Natural killer receptors: the burden of a name. J Exp Med. 2010;207:269–72.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Yang X, Zheng SG. Interleukin-22: a likely target for treatment of autoimmune diseases. Autoimmun Rev. 2014;13:615–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Brosnahan MM, et al. IL-22 is expressed by the invasive trophoblast of the equine (Equus caballus) chorionic girdle. J Immunol. 2012;188:4181–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Ghadially H, et al. NKp46 regulates allergic responses. Eur J Immunol. 2013;43:3006–16.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Wang Y, et al. IL-22 secreted by decidual stromal cells and NK cells promotes the survival of human trophoblasts. Int J Clin Exp Pathol. 2013;6:1781–90.

    PubMed Central  PubMed  Google Scholar 

  41. Kamoi M, et al. NK22 cells in the uterine mid-secretory endometrium and peripheral blood of women with recurrent pregnancy loss and unexplained infertility. Am J Reprod Immunol. 2015. doi:10.1111/aji.12356.

  42. Ata B, et al. A systematic review of intravenous immunoglobulin for treatment of unexplained recurrent miscarriage. Fertil Steril. 2011;95(1080–5):e1–2.

    PubMed  Google Scholar 

  43. Polanski LT, et al. Interventions to improve reproductive outcomes in women with elevated natural killer cells undergoing assisted reproduction techniques: a systematic review of literature. Hum Reprod. 2014;29:65–75.

    Article  CAS  PubMed  Google Scholar 

  44. Heilmann L, Schorsch M, Hahn T. CD3-CD56+CD16+ natural killer cells and improvement of pregnancy outcome in IVF/ICSI failure after additional IVIG-treatment. Am J Reprod Immunol. 2010;63:263–5.

    Article  CAS  PubMed  Google Scholar 

  45. Shimada S, et al. A high dose of intravenous immunoglobulin increases CD94 expression on natural killer cells in women with recurrent spontaneous abortion. Am J Reprod Immunol. 2009;62:301–7.

    Article  CAS  PubMed  Google Scholar 

  46. Aoki K, et al. Preconceptional natural-killer-cell activity as a predictor of miscarriage. Lancet. 1995;345:1340–2.

    Article  CAS  PubMed  Google Scholar 

  47. Hadinedoushan H, Mirahmadian M, Aflatounian A. Increased natural killer cell cytotoxicity and IL-2 production in recurrent spontaneous abortion. Am J Reprod Immunol. 2007;58:409–14.

    Article  CAS  PubMed  Google Scholar 

  48. Perricone R, et al. High levels of peripheral blood NK cells in women suffering from recurrent spontaneous abortion are reverted from high-dose intravenous immunoglobulins. Am J Reprod Immunol. 2006;55:232–9.

    Article  CAS  PubMed  Google Scholar 

  49. Katano K, et al. Clinical trial of immunostimulation with a biological response modifier in unexplained recurrent spontaneous abortion patients. J Clin Immunol. 1997;17:472–7.

    Article  CAS  PubMed  Google Scholar 

  50. Ndukwe G. Recurrent embryo implantation failure after in vitro fertilisation: improved outcome following intralipid infusion in women with elevated T Helper 1 response. Hum Fertil (Camb). 2011;14:131–46 Abstracts.

    Article  Google Scholar 

  51. Shreeve N, Sadek K. Intralipid therapy for recurrent implantation failure: new hope or false dawn? J Reprod Immunol. 2012;93:38–40.

    Article  CAS  PubMed  Google Scholar 

  52. Granato D, et al. Effects of parenteral lipid emulsions with different fatty acid composition on immune cell functions in vitro. JPEN J Parenter Enteral Nutr. 2000;24:113–8.

    Article  CAS  PubMed  Google Scholar 

  53. Roussev RG, et al. Duration of intralipid’s suppressive effect on NK cell’s functional activity. Am J Reprod Immunol. 2008;60:258–63.

    Article  PubMed  Google Scholar 

  54. Roussev RG, Ng SC, Coulam CB. Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G. Am J Reprod Immunol. 2007;57:262–9.

    Article  CAS  PubMed  Google Scholar 

  55. Coulam CB, Acacio B. Does immunotherapy for treatment of reproductive failure enhance live births? Am J Reprod Immunol. 2012;67:296–304.

    Article  CAS  PubMed  Google Scholar 

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Disclosures

Conflict of interest

Atsushi Fukui, Mai Kamoi, Ayano Funamizu, Kohei Fuchinoue, Hitomi Chiba, Megumi Yokota, Rie Fukuhara and Hideki Mizunuma declare that they have no conflict of interest.

Human rights statements and informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later amendments. Informed consent was obtained from all patients for being included in the study.

Animal rights

This article does not contain any studies with animal subjects performed by any of the authors.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan

    Atsushi Fukui, Mai Kamoi, Ayano Funamizu, Kohei Fuchinoue, Hitomi Chiba, Megumi Yokota, Rie Fukuhara & Hideki Mizunuma

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  1. Atsushi Fukui
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  2. Mai Kamoi
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Correspondence to Atsushi Fukui.

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Fukui, A., Kamoi, M., Funamizu, A. et al. NK cell abnormality and its treatment in women with reproductive failures such as recurrent pregnancy loss, implantation failures, preeclampsia, and pelvic endometriosis. Reprod Med Biol 14, 151–157 (2015). https://doi.org/10.1007/s12522-015-0207-7

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  • DOI: https://doi.org/10.1007/s12522-015-0207-7

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