Exploration of Immunology

Table 6. Epidemiological risk factors in PE and miscarriage

	PE	Miscarriage
Inadequate induction of tolerance
First pregnancy	○	×
The second pregnancy reduces the risk, even if the first pregnancy is a miscarriage	○	×
First pregnancy with a new partner in multiparous women	○	×
More than 10 years after the last delivery, the risk increases even if adjusted by age	○	×
IVF-ET	○	×
Low or lack of semen exposure
Condom use	○	×
Short cohabitation	○	×
Sperm donation pregnancy	○	×
Egg donation pregnancy	○	○
Embryo donation pregnancy	○	○
Fetus is a complete allograft to maternal host
Egg donation pregnancy	○	○
Embryo donation pregnancy	○	○
Hydatidiform mole	○	○

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○:

risk factor; ×: not risk factor

Declarations

Author contributions

SS wrote the paper, and AN consulted on the content of the paper. TS did research on Treg and consulted on the content of the paper. ST submitted materials for the paper.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This study was supported by Japan Agency for Medical Research and Development (grant JP18gk0110018 and JP21gk0110047) and Japan Society for the Promotion of Science (KAKENHI grant JP19K09750, 20K09614, 19K18690 and 21K16764). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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References

Woods GM, Howson LJ, Brown GK, Tovar C, Kreiss A, Corcoran LM, et al. Immunology of a transmissible cancer spreading among Tasmanian devils. J Immunol. 2015;195:23–9. [DOI] [PubMed]

Samstein RM, Josefowicz SZ, Arvey A, Treuting PM, Rudensky AY. Extrathymic generation of regulatory T cells in placental mammals mitigates maternal-fetal conflict. Cell. 2012;150:29–38. [DOI] [PubMed] [PMC]

Tafuri A, Alferink J, Möller P, Hämmerling GJ, Arnold B. T cell awareness of paternal alloantigens during pregnancy. Science. 1995;270:630–3. [DOI] [PubMed]

Boid JB, Hamilton WJ. The human placenta. London and Basingstoke: Machilan Press; 1975. pp. 45–60.

Saito S, Nishikawa K, Morii T, Narita N, Enomoto M, Ichijo M. Expression of activation antigens CD69, HLA-DR, interleukin-2 receptor-alpha (IL-2R alpha) and IL-2R beta on T cells of human decidua at an early stage of pregnancy. Immunology. 1992;75:710–2. [PubMed] [PMC]

Nishikawa K, Saito S, Morii T, Hamada K, Ako H, Narita H, et al. Accumulation of CD16−CD56+ natural killer cells with high affinity interleukin 2 receptors in human early pregnancy decidua. Int Immunol. 1991;3:743–50. [DOI] [PubMed]

Morii T, Nishikawa K, Saito S, Enomoto M, Ito A, Kurai N, et al. T-cell receptors are expressed but down-regulated on intradecidual T lymphocytes. Am J Reprod Immunol. 1993;29:1–4. [DOI] [PubMed]

Saito S, Nishikawa K, Morii T, Narita N, Enomoto M, Ito A, et al. A study of CD45RO, CD45RA and CD29 antigen expression on human decidual T cells in an early stage of pregnancy. Immunol Lett. 1994;40:193–7. [DOI] [PubMed]

Saito S, Saito M, Enomoto M, Ito A, Motoyoshi K, Nakagawa T, et al. Human macrophage colony-stimulating factor induces the differentiation of trophoblast. Growth Factors. 1993;9:11–9. [DOI] [PubMed]

10.

Saito S, Nishikawa K, Morii T, Enomoto M, Narita N, Motoyoshi K, et al. Cytokine production by CD16-CD56^bright natural killer cells in the human early pregnancy decidua. Int Immunol. 1993;5:559–63. [DOI] [PubMed]

11.

Saito S, Kasahara T, Sakakura S, Umekage H, Harada N, Ichijo M. Detection and localization of interleukin-8 mRNA and protein in human placenta and decidual tissues. J Reprod Immunol. 1994;27:161–72. [DOI]

12.

Lash GE, Schiessl B, Kirkley M, Innes BA, Cooper A, Searle RF, et al. Expression of angiogenic growth factors by uterine natural killer cells during early pregnancy. J Leukoc Biol. 2006;80:572–80. [DOI] [PubMed]

13.

Fu B, Zhou Y, Ni X, Tong X, Xu X, Dong Z, et al. Natural killer cells promote fetal development through the secretion of growth-promoting factors. Immunity. 2017;47:1100–13.e6. [DOI] [PubMed]

14.

Saito S, Fukunaga R, Ichijo M, Nagata S. Expression of granulocyte colony-stimulating factor and its receptor at the fetomaternal interface in murine and human pregnancy. Growth Factors. 1994;10:135–43. [DOI] [PubMed]

15.

Drake BL, Head JR. GM-CSF and CSF-1 stimulate DNA synthesis but not cell proliferation in short-term cultures of mid-gestation murine trophoblast. J Reprod Immunol. 1994;26:41–56. [DOI] [PubMed]

16.

Murphy SP, Tayade C, Ashkar AA, Hatta K, Zhang J, Croy BA. Interferon gamma in successful pregnancies. Biol Reprod. 2009;80:848–59. [DOI] [PubMed] [PMC]

17.

Gamliel M, Goldman-Wohl D, Isaacson B, Gur C, Stein N, Yamin R, et al. Trained memory of human uterine NK cells enhances their function in subsequent pregnancies. Immunity. 2018;48:951–62.e5. [DOI] [PubMed]

18.

Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155:1151–64. [PubMed]

19.

Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol. 2004;5:266–71. [DOI] [PubMed]

20.

Sasaki Y, Sakai M, Miyazaki S, Higuma S, Shiozaki A, Saito S. Decidual and peripheral blood CD4+CD25+ regulatory T cells in early pregnancy subjects and spontaneous abortion cases. Mol Hum Reprod. 2004;10:347–53. [DOI] [PubMed]

21.

Shima T, Sasaki Y, Itoh M, Nakashima A, Ishii N, Sugamura K, et al. Regulatory T cells are necessary for implantation and maintenance of early pregnancy but not late pregnancy in allogeneic mice. J Reprod Immunol. 2010;85:121–9. [DOI] [PubMed]

22.

Shima T, Inada K, Nakashima A, Ushijima A, Ito M, Yoshino O, et al. Paternal antigen-specific proliferating regulatory T cells are increased in uterine-draining lymph nodes just before implantation and in pregnant uterus just after implantation by seminal plasma-priming in allogeneic mouse pregnancy. J Reprod Immunol. 2015;108:72–82. [DOI] [PubMed]

23.

Yasuda I, Shima T, Moriya T, Ikebuchi R, Kusumoto Y, Ushijima A, et al. Dynamic changes in the phenotype of dendritic cells in the uterus and uterine draining lymph nodes after coitus. Front Immunol. 2020;11:557720. [DOI] [PubMed] [PMC]

24.

Robertson SA, Guerin LR, Bromfield JJ, Branson KM, Ahlström AC, Care AS. Seminal fluid drives expansion of the CD4+CD25+ T regulatory cell pool and induces tolerance to paternal alloantigens in mice. Biol Reprod. 2009;80:1036–45. [DOI] [PubMed] [PMC]

25.

Koelman CA, Coumans AB, Nijman HW, Doxiadis II, Dekker GA, Claas FH. Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid? J Reprod Immunol. 2000;46:155–66. [DOI] [PubMed]

26.

Robertson SA, Ingman WV, O’Leary S, Sharkey DJ, Tremellen KP. Transforming growth factor beta—a mediator of immune deviation in seminal plasma. J Reprod Immunol. 2002;57:109–28. [DOI] [PubMed]

27.

Shima T, Nakashima A, Yasuda I, Ushijima A, Inada K, Tsuda S, et al. Uterine CD11c+ cells induce the development of paternal antigen-specific Tregs via seminal plasma priming. J Reprod Immunol. 2020;141:103165. [DOI] [PubMed]

28.

Crawford G, Ray A, Gudi A, Shah A, Homburg R. The role of seminal plasma for improved outcomes during in vitro fertilization treatment: review of the literature and meta–analysis. Hum Reprod Update. 2015;21:275–84. [DOI] [PubMed]

29.

Darrasse-Jèze G, Klatzmann D, Charlotte F, Salomon BL, Cohen JL. CD4⁺CD25⁺ regulatory/suppressor T cells prevent allogeneic fetus rejection in mice. Immunol Lett. 2006;102:106–9. [DOI] [PubMed]

30.

Zenclussen AC, Gerlof K, Zenclussen ML, Sollwedel A, Bertoja AZ, Ritter T, et al. Abnormal T-cell reactivity against paternal antigens in spontaneous abortion: adoptive transfer of pregnancy-induced CD4⁺CD25⁺ T regulatory cells prevents fetal rejection in a murine abortion model. Am J Pathol. 2005;166:811–22. [DOI] [PubMed] [PMC]

31.

Diao LH, Li GG, Zhu YC, Tu WW, Huang CY, Lian RC, et al. Human chorionic gonadotropin potentially affects pregnancy outcome in women with recurrent implantation failure by regulating the homing preference of regulatory T cells. Am J Reprod Immunol. 2017;77:e12618. [DOI] [PubMed]

32.

Plaks V, Birnberg T, Berkutzki T, Sela S, BenYashar A, Kalchenko V, et al. Uterine DCs are crucial for decidua formation during embryo implantation in mice. J Clin Invest. 2008;118:3954–65. [DOI] [PubMed] [PMC]

33.

Care AS, Diener KR, Jasper MJ, Brown HM, Ingman WV, Robertson SA. Macrophages regulate corpus luteum development during embryo implantation in mice. J Clin Invest. 2013;123:3472–87. [DOI] [PubMed] [PMC]

34.

Ono Y, Yoshino O, Hiraoka T, Sato E, Fukui Y, Ushijima A, et al. CD206+ M2-like macrophages are essential for successful implantation. Front Immunol. 2020;11:557184. [DOI] [PubMed] [PMC]

35.

Akaeda S, Hirota Y, Fukui Y, Aikawa S, Shimizu-Hirota R, Kaku T, et al. Retinoblastoma protein promotes uterine epithelial cell cycle arrest and necroptosis for embryo invasion. EMBO Rep. 2021;22:e50927. [DOI] [PubMed]

36.

Mor G, Cardenas I, Abrahams V, Guller S. Inflammation and pregnancy: the role of the immune system at the implantation site. Ann N Y Acad Sci. 2011;1221:80–7. [DOI] [PubMed] [PMC]

37.

Draijer C, Penke LRK, Peters-Golden M. Distinctive effects of GM-CSF and M-CSF on proliferation and polarization of two major pulmonary macrophage populations. J Immunol. 2019;202:2700–9. [DOI] [PubMed] [PMC]

38.

Wen Q, Kong Y, Zhao HY, Zhang YY, Han TT, Wang Y, et al. G-CSF-induced macrophage polarization and mobilization may prevent acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2019;54:1419–33. [DOI] [PubMed]

39.

Davari-Tanha F, Shahrokh Tehraninejad E, Ghazi M, Shahraki Z. The role of G-CSF in recurrent implantation failure: a randomized double blind placebo control trial. Int J Reprod Biomed. 2016;14:737–42. [DOI] [PubMed] [PMC]

40.

Kamath MS, Kirubakaran R, Sunkara SK. Granulocyte-colony stimulating factor administration for subfertile women undergoing assisted reproduction. Cochrane Database Syst Rev. 2020;1:CD013226. [DOI] [PubMed] [PMC]

41.

Nakagawa K, Kwak-Kim J, Ota K, Kuroda K, Hisano M, Sugiyama R, et al. Immunosuppression with tacrolimus improved reproductive outcome of women with repeated implantation failure and elevated peripheral blood TH1/TH2 cell ratios. Am J Reprod Immunol. 2015;73:353–61. [DOI] [PubMed]

42.

Winger EE, Reed JL, Ashoush S, El-Toukhy T, Ahuja S, Taranissi M. Degree of TNF-α/IL-10 cytokine elevation correlates with IVF success rates in women undergoing treatment with Adalimumab (Humira) and IVIG. Am J Reprod Immunol. 2011;65:610–8. [DOI] [PubMed]

43.

Paffoni A, Somigliana E, Sarais V, Ferrari S, Reschini M, Makieva S, et al. Effect of vitamin D supplementation on assisted reproduction technology (ART) outcomes and underlying biological mechanisms: protocol of a randomized clinical controlled trial. The “supplementation of vitamin D and reproductive outcome” (SUNDRO) study. BMC Pregnancy Childbirth. 2019;19:395. [DOI] [PubMed] [PMC]

44.

Abdolmohammadi-Vahid S, Pashazadeh F, Pourmoghaddam Z, Aghebati-Maleki L, Abdollahi-Fard S, Yousefi M. The effectiveness of IVIG therapy in pregnancy and live birth rate of women with recurrent implantation failure (RIF): a systematic review and meta-analysis. J Reprod Immunol. 2019;134–135:28–33. [DOI] [PubMed]

45.

Cicinelli E, Matteo M, Tinelli R, Lepera A, Alfonso R, Indraccolo U, et al. Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy. Hum Reprod. 2015;30:323–30. [DOI] [PubMed]

46.

Olesen MS, Hauge B, Ohrt L, Olesen TN, Roskær J, Bæk V, et al. Therapeutic endometrial scratching and implantation after in vitro fertilization: a multicenter randomized controlled trial. Fertil Steril. 2019;112:1015–21. [DOI] [PubMed]

47.

Dimitriadis E, Menkhorst E, Saito S, Kutteh WH, Brosens JJ. Recurrent pregnancy loss. Nat Rev Dis Primers. 2020;6:98. [DOI] [PubMed]

48.

Morita K, Ono Y, Takeshita T, Sugi T, Fujii T, Yamada H, et al. Risk factors and outcomes of recurrent pregnancy loss in Japan. J Obstet Gynaecol Res. 2019;45:1997–2006. [DOI] [PubMed]

49.

ESHRE Guideline Group on RPL; Bender Atik R, Christiansen OB, Elson J, Kolte AM, Lewis S, et al. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2018;2018:hoy004. [DOI] [PubMed] [PMC]

50.

Inada K, Shima T, Nakashima A, Aoki K, Ito M, Saito S. Characterization of regulatory T cells in decidua of miscarriage cases with abnormal or normal fetal chromosomal content. J Reprod Immunol. 2013;97:104–11. [DOI] [PubMed]

51.

Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional delineation and differentiation dynamics of human CD4⁺ T cells expressing the FoxP3 transcription factor. Immunity. 2009;30:899–911. [DOI] [PubMed]

52.

Inada K, Shima T, Ito M, Ushijima A, Saito S. Helios-positive functional regulatory T cells are decreased in decidua of miscarriage cases with normal fetal chromosomal content. J Reprod Immunol. 2015;107:10–9. [DOI] [PubMed]

53.

Tsuda S, Zhang X, Hamana H, Shima T, Ushijima A, Tsuda K, et al. Clonally expanded decidual effector regulatory T cells increase in late gestation of normal pregnancy, but not in preeclampsia, in humans. Front Immunol. 2018;9:1934. [DOI] [PubMed] [PMC]

54.

Tsuda S, Nakashima A, Shima T, Saito S. New paradigm in the role of regulatory T cells during pregnancy. Front Immunol. 2019;10:573. [DOI] [PubMed] [PMC]

55.

Tilburgs T, Schonkeren D, Eikmans M, Nagtzaam NM, Datema G, Swings GM, et al. Human decidual tissue contains differentiated CD8+ effector-memory T cells with unique properties. J Immunol. 2010;185:4470–7. [DOI] [PubMed]

56.

Morita K, Tsuda S, Kobayashi E, Hamana H, Tsuda K, Shima T, et al. Analysis of TCR repertoire and PD-1 expression in decidual and peripheral CD8+ T cells reveals distinct immune mechanisms in miscarriage and preeclampsia. Front Immunol. 2020;11:1082. [DOI] [PubMed] [PMC]

57.

Kinder JM, Turner LH, Stelzer IA, Miller-Handley H, Burg A, Shao TY, et al. CD8⁺ T cell functional exhaustion overrides pregnancy-induced fetal antigen alloimmunization. Cell Rep. 2020;31:107784. [DOI] [PubMed] [PMC]

58.

Christiansen OB, Kolte AM, Krog MC, Nielsen HS, Egerup P. Treatment with intravenous immunoglobulin in patients with recurrent pregnancy loss: an update. J Reprod Immunol. 2019;133:37–42. [DOI] [PubMed]

59.

Fu J, Li L, Qi L, Zhao L. A randomized controlled trial of etanercept in the treatment of refractory recurrent spontaneous abortion with innate immune disorders. Taiwan J Obstet Gynecol. 2019;58:621–5. [DOI] [PubMed]

60.

Zhao H, Wei X, Yang X. A novel update on vitamin D in recurrent pregnancy loss (Review). Mol Med Rep. 2021;23:382. [DOI] [PubMed] [PMC]

61.

Sasaki Y, Darmochwal-Kolarz D, Suzuki D, Sakai M, Ito M, Shima T, et al. Proportion of peripheral blood and decidual CD4+ CD25bright regulatory T cells in pre-eclampsia. Clin Exp Immunol. 2007;149:139–45. [DOI] [PubMed] [PMC]

62.

Toldi G, Vásárhelyi ZE, Rigó J Jr, Orbán C, Tamássy Z, Bajnok A, et al. Prevalence of regulatory T-cell subtypes in preeclampsia. Am J Reprod Immunol. 2015;74:110–15. [DOI] [PubMed]

63.

Nakabayashi Y, Nakashima A, Yoshino O, Shima T, Shiozaki A, Adachi T, et al. Impairment of the accumulation of decidual T cells, NK cells, and monocytes, and the poor vascular remodeling of spiral arteries, were observed in oocyte donation cases, regardless of the presence or absence of preeclampsia. J Reprod Immunol. 2016;114:65–74. [DOI] [PubMed]

64.

Robertson SA, Green ES, Care AS, Moldenhauer LM, Prins JR, Hull ML, et al. Therapeutic potential of regulatory T cells in preeclampsia-opportunities and challenges. Front Immunol. 2019;10:478. [DOI] [PubMed] [PMC]

65.

Staff AC, Fjeldstad HE, Fosheim IK, Moe K, Turowski G, Johnsen GM, et al. Failure of physiological transformation and spiral artery atherosis: their roles in preeclampsia. Am J Obstet Gynecol. 2020;[Epub ahead of print]. [DOI] [PubMed]

66.

Burbank F. History of uterine artery occlusion and subsequent pregnancy. AJR Am J Roentgenol. 2009;192:1593–600. [DOI] [PubMed]

67.

Cornelius DC, Amaral LM, Harmon A, Wallace K, Thomas AJ, Campbell N, et al. An increased population of regulatory T cells improves the pathophysiology of placental ischemia in a rat model of preeclampsia. Am J Physiol Regul Integr Comp Physiol. 2015;309:R884–91. [DOI] [PubMed] [PMC]

68.

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. [DOI] [PubMed] [PMC]

69.

Molvarec A, Ito M, Shima T, Yoneda S, Toldi G, Stenczer B, et al. Decreased proportion of peripheral blood vascular endothelial growth factor-expressing T and natural killer cells in preeclampsia. Am J Obstet Gynecol. 2010;203:567.e1–8. [DOI] [PubMed]

70.

Saito S, Takeda Y, Sakai M, Nakabayashi M, Hayakawa S. The incidence of pre-eclampsia among couples consisting of Japanese women and Caucasian men. J Reprod Immunol. 2006;70:93–8. [DOI] [PubMed]

71.

Saito S, Sakai M, Sasaki Y, Tanebe K, Tsuda H, Michimata T. Quantitative analysis of peripheral blood Th0, Th1, Th2 and the Th1:Th2 cell ratio during normal human pregnancy and preeclampsia. Clin Exp Immunol. 1999;117:550–5. [DOI] [PubMed] [PMC]

72.

Santner-Nanan B, Peek MJ, Khanam R, Richarts L, Zhu E, Fazekas de St Groth B, et al. Systemic increase in the ratio between Foxp3⁺ and IL-17-producing CD4⁺ T cells in healthy pregnancy but not in preeclampsia. J Immunol. 2009;183:7023–30. [DOI] [PubMed]

73.

Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T cell paradigm in pregnancy. Am J Reprod Immunol. 2010;63:601–10. [DOI] [PubMed]

74.

Harmon A, Cornelius D, Amaral L, Paige A, Herse F, Ibrahim T, et al. IL-10 supplementation increases Tregs and decreases hypertension in the RUPP rat model of preeclampsia. Hypertens Pregnancy. 2015;34:291–306. [DOI] [PubMed] [PMC]

75.

Cunningham MW, Jayaram A, Deer E, Amaral LM, Vaka VR, Ibrahim T, et al. Tumor necrosis factor alpha (TNF-α) blockade improves natural killer cell (NK) activation, hypertension, and mitochondrial oxidative stress in a preclinical rat model of preeclampsia. Hypertens Pregnancy. 2020;39:399–404. [DOI] [PubMed] [PMC]