Exploration of Immunology

Table 1. Summary of suggested therapies according to the endometrial immune profile

Immune endometrial profile	GC	Intralipids	Luteal hCG	LMWH	Scratching	Supplementation in progesterone	Exposure to seminal plasma after ET
No dysregulation	-	-	-	-	-	-	-
Low immune activation	-	-	×	-	×	-	×
Over immune activation	×	×	-	×	-	×	-
Mixed profile	×	×	×	×	?	×	-

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GC: glucocorticoids; LMWH: low molecular weight heparin; hCG: human chorionic gonadotropin; -: not recommended; ×: recommended; ?: depending on the case

Declarations

Acknowledgments

We have written this article in memory of Gérard Chaouat, our mentor who passed away in 2021. He was one of those rare and pure men that it is an honor to know. As for all of us, his name evokes atypicality mixed with a dazzling intelligence in an eternally utopian spirit, generous and respectful of others. In our discipline of reproductive medicine, he fought against all odds to have the importance of innate immunity in reproduction accepted. He proved through his research the importance of the primordial immunological dialogue between the uterus and the embryo in the construction of our humanity (the placenta). His researches were decisive for the understanding of all obstetrical diseases and implantation disorders. Even today, if there is progress in our discipline, it will be by admitting, encompassing and overhanging the complexity of reproduction in order to go further.

Author contributions

AK and NL wrote this manuscript. NL interpreted the uterine immune profiles to personalize subsequent recommendations. AK performed the molecular analysis. MP and MR corrected the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

NL and MP are both inventors (PCT/EP2013/065355) and created the start-up MatriceLab Innove. The authors declare no other financial or commercial 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

Not applicable.

Copyright

References

Mascarenhas MN, Cheung H, Mathers CD, Stevens GA. Measuring infertility in populations: constructing a standard definition for use with demographic and reproductive health surveys. Popul Health Metr. 2012;10:17. [DOI] [PubMed] [PMC]

Cui W. Mother or nothing: the agony of infertility. Bull World Health Organ. 2010;88:881–2. [DOI] [PubMed] [PMC]

Chachamovich JR, Chachamovich E, Ezer H, Fleck MP, Knauth DR, Passos EP. Agreement on perceptions of quality of life in couples dealing with infertility. J Obstet Gynecol Neonatal Nurs. 2010;39:557–65. [DOI] [PubMed]

Gardner DK, Balaban B. Assessment of human embryo development using morphological criteria in an era of time-lapse, algorithms and ‘OMICS’: is looking good still important? Mol Hum Reprod. 2016;22:704–18. [DOI] [PubMed]

Giacomini E, Makieva S, Murdica V, Vago R, Viganó P. Extracellular vesicles as a potential diagnostic tool in assisted reproduction. Curr Opin Obstet Gynecol. 2020;32:179–84. [DOI] [PubMed]

Zhou W, Dimitriadis E. Secreted microRNA to predict embryo implantation outcome: from research to clinical diagnostic application. Front Cell Dev Biol. 2020;8:586510. [DOI] [PubMed] [PMC]

Cornelisse S, Zagers M, Kostova E, Fleischer K, van Wely M, Mastenbroek S. Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation. Cochrane Database Syst Rev. 2020:CD005291. [DOI] [PubMed] [PMC]

Guleria I, Sayegh MH. Maternal acceptance of the fetus: true human tolerance. J Immunol. 2007;178:3345–51. [DOI] [PubMed]

Medawar PB. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol. 1953;7:320–38.

10.

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

11.

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]

12.

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]

13.

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]

14.

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]

15.

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]

16.

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]

17.

Liu S, Diao L, Huang C, Li Y, Zeng Y, Kwak-Kim JYH. The role of decidual immune cells on human pregnancy. J Reprod Immunol. 2017;124:44–53. [DOI] [PubMed]

18.

Wilcox AJ, Baird DD, Weinberg CR. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med. 1999;340:1796–9. [DOI] [PubMed]

19.

Lee JY, Lee M, Lee SK. Role of endometrial immune cells in implantation. Clin Exp Reprod Med. 2011;38:119–25. [DOI] [PubMed] [PMC]

20.

Cooper MA, Fehniger TA, Caligiuri MA. The biology of human natural killer-cell subsets. Trends Immunol. 2001;22:633–40. [DOI] [PubMed]

21.

La Rocca C, Carbone F, Longobardi S, Matarese G. The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol Lett. 2014;162:41–8. [DOI] [PubMed]

22.

Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993;14:353–6. [DOI] [PubMed]

23.

Chaouat G. The Th1/Th2 paradigm: still important in pregnancy? Semin Immunopathol. 2007;29:95–113. [DOI] [PubMed]

24.

Chaouat G, Ledée-Bataille N, Dubanchet S, Zourbas S, Sandra O, Martal J. TH1/TH2 paradigm in pregnancy: paradigm lost? Cytokines in pregnancy/early abortion: reexamining the TH1/TH2 paradigm. Int Arch Allergy Immunol. 2004;134:93–119. [DOI] [PubMed]

25.

Kitaya K, Yamaguchi T, Honjo H. Central role of interleukin-15 in postovulatory recruitment of peripheral blood CD16^– natural killer cells into human endometrium. J Clin Endocrinol Metab. 2005;90:2932–40. [DOI] [PubMed]

26.

Verma S, Hiby SE, Loke YW, King A. Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15. Biol Reprod. 2000;62:959–68. [DOI] [PubMed]

27.

Croy BA, Esadeg S, Chantakru S, van den Heuvel M, Paffaro VA Jr, He H, et al. Update on pathways regulating the activation of uterine natural killer cells, their interactions with decidual spiral arteries and homing of their precursors to the uterus. J Reprod Immunol. 2003;59:175–91. [DOI] [PubMed]

28.

Goldman-Wohl DS, Ariel I, Greenfield C, Lavy Y, Yagel S. Tie-2 and angiopoietin-2 expression at the fetal-maternal interface: a receptor ligand model for vascular remodelling. Mol Hum Reprod. 2000;6:81–7. [DOI] [PubMed]

29.

Petitbarat M, Rahmati M, Sérazin V, Dubanchet S, Morvan C, Wainer R, et al. TWEAK appears as a modulator of endometrial IL-18 related cytotoxic activity of uterine natural killers. PLoS One. 2011;6:e14497. [DOI] [PubMed] [PMC]

30.

Mas AE, Petitbarat M, Dubanchet S, Fay S, Lédée N, Chaouat G. Immune regulation at the interface during early steps of murine implantation: involvement of two new cytokines of the IL-12 family (IL-23 and IL-27) and of TWEAK. Am J Reprod Immunol. 2008;59:323–38. [DOI] [PubMed]

31.

Petitbarat M, Serazin V, Dubanchet S, Wayner R, de Mazancourt P, Chaouat G, et al. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/fibroblast growth factor inducible-14 might regulate the effects of interleukin 18 and 15 in the human endometrium. Fertil Steril. 2010;94:1141–3. [DOI] [PubMed]

32.

Cheloufi M, Kazhalawi A, Pinton A, Rahmati M, Chevrier L, Prat-Ellenberg L, et al. The endometrial immune profiling may positively affect the management of recurrent pregnancy loss. Front Immunol. 2021;12:656701. [DOI] [PubMed] [PMC]

33.

Ledee N, Petitbarat M, Prat-Ellenberg L, Dray G, Cassuto GN, Chevrier L, et al. Endometrial immune profiling: a method to design personalized care in assisted reproductive medicine. Front Immunol. 2020;11:1032. [DOI] [PubMed] [PMC]

34.

Lédée N, Prat-Ellenberg L, Chevrier L, Balet R, Simon C, Lenoble C, et al. Uterine immune profiling for increasing live birth rate: a one-to-one matched cohort study. J Reprod Immunol. 2017;119:23–30. [DOI] [PubMed]

35.

Kalampokas T, Pandian Z, Keay SD, Bhattacharya S. Glucocorticoid supplementation during ovarian stimulation for IVF or ICSI. Cochrane Database Syst Rev. 2017:CD004752. [DOI] [PubMed] [PMC]

36.

Achilli C, Duran-Retamal M, Saab W, Serhal P, Seshadri S. The role of immunotherapy in in vitro fertilization and recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril. 2018;110:1089–100. [DOI] [PubMed]

37.

van Hoogenhuijze NE, Kasius JC, Broekmans FJM, Bosteels J, Torrance HL. Endometrial scratching prior to IVF; does it help and for whom? A systematic review and meta-analysis. Hum Reprod Open. 2019;2019:hoy025. [DOI] [PubMed] [PMC]

38.

Wong LF, Porter TF, Scott JR. Immunotherapy for recurrent miscarriage. Cochrane Database Syst Rev. 2014:CD000112. [DOI] [PubMed] [PMC]

39.

Moffett A, Shreeve N. First do no harm: uterine natural killer (NK) cells in assisted reproduction. Hum Reprod. 2015;30:1519–25. [DOI] [PubMed] [PMC]

40.

Robertson SA, Jin M, Yu D, Moldenhauer LM, Davies MJ, Hull ML, et al. Corticosteroid therapy in assisted reproduction—immune suppression is a faulty premise. Hum Reprod. 2016;31:2164–73. [DOI] [PubMed]

41.

Liu Y, Gao S, Zhao Y, Wang H, Pan Q, Shao Q. Decidual natural killer cells: a good nanny at the maternal-fetal interface during early pregnancy. Front Immunol. 2021;12:663660. [DOI] [PubMed] [PMC]

42.

Eddy JL, Krukowski K, Janusek L, Mathews HL. Glucocorticoids regulate natural killer cell function epigenetically. Cell Immunol. 2014;290:120–30. [DOI] [PubMed] [PMC]

43.

Moustaki A, Argyropoulos KV, Baxevanis CN, Papamichail M, Perez SA. Effect of the simultaneous administration of glucocorticoids and IL-15 on human NK cell phenotype, proliferation and function. Cancer Immunol Immunother. 2011;60:1683–95. [DOI] [PubMed]

44.

Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci. 2004;1024:138–46. [DOI] [PubMed]

45.

Girardi G, Salmon JE. The role of complement in pregnancy and fetal loss. Autoimmunity. 2003;36:19–26. [DOI] [PubMed]

46.

Oberkersch R, Attorresi AI, Calabrese GC. Low-molecular-weight heparin inhibition in classical complement activation pathway during pregnancy. Thromb Res. 2010;125:e240–5. [DOI] [PubMed]

47.

Lédée N, Prat-Ellenberg L, Petitbarat M, Chevrier L, Simon C, Irani EE, et al. Impact of prednisone in patients with repeated embryo implantation failures: beneficial or deleterious? J Reprod Immunol. 2018;127:11–5. [DOI] [PubMed]

48.

Lédée N, Vasseur C, Petitbarat M, Chevrier L, Vezmar K, Dray G, et al. Intralipid^® may represent a new hope for patients with reproductive failures and simultaneously an over-immune endometrial activation. J Reprod Immunol. 2018;130:18–22. [DOI] [PubMed]

49.

Granato D, Blum S, Rossle C, Le Boucher J, Malnoe A, Dutot G. 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. [DOI] [PubMed]

50.

Roussev RG, Acacio B, Ng SC, Coulam CB. Duration of intralipid’s suppressive effect on NK cell’s functional activity. Am J Reprod Immunol. 2008;60:258–63. [DOI] [PubMed]

51.

Yavangi M, Varmaghani N, Pirdehghan A, Varmaghani M, Faryadras M. Comparison of pregnancy outcome in intrauterine insemination-candidate women with and without endometrial scratch injury: an RCT. Int J Reprod Biomed. 2021;19:457–64. [DOI] [PubMed] [PMC]

52.

Izquierdo A, de la Fuente L, Spies K, Lora D, Galindo A. Is endometrial scratching beneficial for patients undergoing a donor-egg cycle with or without previous implantation failures? Results of a post-hoc analysis of an RCT. Diagnostics (Basel). 2021;11:1167. [DOI] [PubMed] [PMC]

53.

Mackens S, Racca A, Van de Velde H, Drakopoulos P, Tournaye H, Stoop D, et al. Follicular-phase endometrial scratching: a truncated randomized controlled trial. Hum Reprod. 2020;35:1090–8. [DOI] [PubMed]

54.

Gnainsky Y, Granot I, Aldo PB, Barash A, Or Y, Schechtman E, et al. Local injury of the endometrium induces an inflammatory response that promotes successful implantation. Fertil Steril. 2010;94:2030–6. [DOI] [PubMed] [PMC]

55.

Liang Y, Han J, Jia C, Ma Y, Lan Y, Li Y, et al. Effect of endometrial injury on secretion of endometrial cytokines and IVF outcomes in women with unexplained subfertility. Mediators Inflamm. 2015;2015:757184. [DOI] [PubMed] [PMC]

56.

Berndt S, Blacher S, Perrier d’Hauterive S, Thiry M, Tsampalas M, Cruz A, et al. Chorionic gonadotropin stimulation of angiogenesis and pericyte recruitment. J Clin Endocrinol Metab. 2009;94:4567–74. [DOI] [PubMed]

57.

Tsampalas M, Gridelet V, Berndt S, Foidart JM, Geenen V, Perrier d’Hauterive S. Human chorionic gonadotropin: a hormone with immunological and angiogenic properties. J Reprod Immunol. 2010;85:93–8. [DOI] [PubMed]

58.

Rienzi L, Vajta G, Ubaldi F. Predictive value of oocyte morphology in human IVF: a systematic review of the literature. Hum Reprod Update. 2011;17:34–45. [DOI] [PubMed] [PMC]

59.

Fragouli E, Spath K, Alfarawati S, Kaper F, Craig A, Michel CE, et al. Altered levels of mitochondrial DNA are associated with female age, aneuploidy, and provide an independent measure of embryonic implantation potential. PLoS Genet. 2015;11:e1005241. [DOI] [PubMed] [PMC]

60.

Huang Z, Wells D. The human oocyte and cumulus cells relationship: new insights from the cumulus cell transcriptome. Mol Hum Reprod. 2010;16:715–25. [DOI] [PubMed]

61.

Tural R, Karakaya C, Erdem M, Aykol Z, Karabacak RO, Kavutçu M. Investigation of oxidative stress status in cumulus cells in patients with in vitro fertilization. Turk J Med Sci. 2021;51:1969–75. [DOI] [PubMed]

62.

Tiegs AW, Titus S, Mehta S, Garcia-Milian R, Seli E, Scott RT Jr. Cumulus cells of euploid versus whole chromosome 21 aneuploid embryos reveal differentially expressed genes. Reprod Biomed Online. 2021;43:614–26. [DOI] [PubMed]

63.

Coticchio G, Sereni E, Serrao L, Mazzone S, Iadarola I, Borini A. What criteria for the definition of oocyte quality? Ann N Y Acad Sci. 2004;1034:132–44. [DOI] [PubMed]

64.

Patrizio P, Sakkas D. From oocyte to baby: a clinical evaluation of the biological efficiency of in vitro fertilization. Fertil Steril. 2009;91:1061–6. [DOI] [PubMed]

65.

Stoop D, Ermini B, Polyzos NP, Haentjens P, De Vos M, Verheyen G, et al. Reproductive potential of a metaphase II oocyte retrieved after ovarian stimulation: an analysis of 23 354 ICSI cycles. Hum Reprod. 2012;27:2030–5. [DOI] [PubMed]

66.

Noël L, Fransolet M, Jacobs N, Foidart JM, Nisolle M, Munaut C. A paracrine interaction between granulosa cells and leukocytes in the preovulatory follicle causes the increase in follicular G-CSF levels. J Assist Reprod Genet. 2020;37:405–16. [DOI] [PubMed] [PMC]

67.

Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood. 1991;78:2791–808. [PubMed]

68.

Franzke A. The role of G-CSF in adaptive immunity. Cytokine Growth Factor Rev. 2006;17:235–44. [DOI] [PubMed]

69.

Bendall LJ, Bradstock KF. G-CSF: from granulopoietic stimulant to bone marrow stem cell mobilizing agent. Cytokine Growth Factor Rev. 2014;25:355–67. [DOI] [PubMed]

70.

Makinoda S, Mikuni M, Sogame M, Kobamatsu Y, Furuta I, Yamada H, et al. Erythropoietin, granulocyte-colony stimulating factor, interleukin-1 beta and interleukin-6 during the normal menstrual cycle. Int J Gynaecol Obstet. 1996;55:265–71. [DOI] [PubMed]

71.

Salmassi A, Schmutzler AG, Schaefer S, Koch K, Hedderich J, Jonat W, et al. Is granulocyte colony-stimulating factor level predictive for human IVF outcome? Hum Reprod. 2005;20:2434–40. [DOI] [PubMed]

72.

Hock DL, Huhn RD, Kemmann E. Leukocytosis in response to exogenous gonadotrophin stimulation. Hum Reprod. 1997;12:2143–6. [DOI] [PubMed]

73.

Rutella S, Zavala F, Danese S, Kared H, Leone G. Granulocyte colony-stimulating factor: a novel mediator of T cell tolerance. J Immunol. 2005;175:7085–91. [DOI] [PubMed]

74.

Yannaki E, Athanasiou E, Xagorari A, Constantinou V, Batsis I, Kaloyannidis P, et al. G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs. Exp Hematol. 2005;33:108–19. [DOI] [PubMed]

75.

Cortez MA, Bueso-Ramos C, Ferdin J, Lopez-Berestein G, Sood AK, Calin GA. MicroRNAs in body fluids— the mix of hormones and biomarkers. Nature Rev Clin Oncol. 2011;8:467–77. [DOI] [PubMed] [PMC]

76.

Scalici E, Traver S, Mullet T, Molinari N, Ferrières A, Brunet C, et al. Circulating microRNAs in follicular fluid, powerful tools to explore in vitro fertilization process. Sci Rep. 2016;6:24976. [DOI] [PubMed] [PMC]

77.

Gross N, Kropp J, Khatib H. MicroRNA signaling in embryo development. Biology (Basel). 2017;6:34. [DOI] [PubMed] [PMC]

78.

Liu W, Niu Z, Li Q, Pang RTK, Chiu PCN, Yeung WSB. MicroRNA and embryo implantation. Am J Reprod Immunol. 2016;75:263–71. [DOI] [PubMed]

79.

Li Q, Wang H, Peng H, Huyan T, Cacalano NA. Exosomes: versatile nano mediators of immune regulation. Cancers (Basel). 2019;11:1557. [DOI] [PubMed] [PMC]

80.

Ng YH, Rome S, Jalabert A, Forterre A, Singh H, Hincks CL, et al. Endometrial exosomes/microvesicles in the uterine microenvironment: a new paradigm for embryo-endometrial cross talk at implantation. PLoS One. 2013;8:e58502. [DOI] [PubMed] [PMC]

81.

Gurung S, Greening DW, Catt S, Salamonsen L, Evans J. Exosomes and soluble secretome from hormone-treated endometrial epithelial cells direct embryo implantation. Mol Hum Reprod. 2020;26:510–20. [DOI] [PubMed]

82.

Bridi A, Perecin F, Silveira JCD. Extracellular vesicles mediated early embryo-maternal interactions. Int J Mol Sci. 2020;21:1163. [DOI] [PubMed] [PMC]

83.

Jones CJP, Aplin JD. Glycosylation at the fetomaternal interface: does the glycocode play a critical role in implantation? Glycoconj J. 2009;26:359–66. [DOI] [PubMed]