Endometrial Immune Profiling: An Emerging Paradigm for Reproductive Disorders

  • Nathalie LéDée


A unique immune reaction occurs during the implantation window within the endometrium which is essential (1) to promote the embryo adhesion and (2) regulate the invasion phase. Disequilibrium of such a vital reaction may impede implantation. Documenting the immune environment before conception allows deciphering the immune mechanism able to generate or at least participate in the observed recurrent embryo implantation failures (RIF) and/or unexplained recurrent miscarriages (RM). To draw the most suitable personalized care, we hence propose to document the pre-conception endometrial immune environment. The objective is to identify the deregulations which can be corrected to enhance the chance of pregnancy following embryo transfer on the identified mechanism.

The immune profiling is a diagnostic method detailing from an endometrial biopsy collected in the mid-luteal phase, the uterine natural killer cell (uNK) mobilization/activation/maturation state, as well as the local immunoregulatory equilibrium between the Th-1 (cytotoxic) and the Th-2 (angiogenic/immunotropic) cytokines. The biomarkers such as IL-15/Fn-14 (maturation and hyper-activation state of uNK) and IL-18/TWEAK (Th-1/Th-2 equilibrium) mRNA ratios were determined by quantitative RT-PCR and CD56 mobilization by immunohistochemistry. An equilibrated endometrial environment at the time of uterine receptivity should be theoretically Th-2 dominant with an active mobilization of mature but not cytotoxic uterine NK cells. The objective is to understand if RIF and/or RM are the consequence of an over-immune activation (embryo rejection, apoptosis of the endometrium) or, the contrary, of an under-immune activation (no adhesion, low local angiogenesis, and immunotropic) or both (a Th-1 deviation of the endometrial environment with immature NK cells). In function of the immune profile, personalized care is suggested to counteract the identified mechanisms. The primary outcome evaluating the effectiveness of the diagnostic method is the live birth rate (LBR) at the first embryo transfer (fresh or freeze-thawed) following the immune evaluation.

In the chapter, we present the results in large longitudinal cohort studies and controlled cohort studies including RIF patients (after IVF/ICSI or oocyte donation) and unexplained RM. 70–80% of RIF and RM patients show an immune disequilibrium during the implantation window. These results suggest that personalization in function of the immune profile significantly increases the LBR while decreasing the miscarriage rate. We also detail the particularities of the immune profile in case of endometriosis. We also show how immunotherapy (corticoids and slow perfusion of diluted intralipids) in case of over-immune activation may impact adequately or not the immune profile.

Uterine immune profiling enables an integrated approach of infertility that includes endometrial immunity as a key factor in planning personalized IVF/ICSI treatments. Understanding the rationale leading to RIF/RM may be used as a guide to personalizing reproductive treatments accordingly. A randomized prospective cohort study is ongoing.


Endometrium Immune profile Implantation failures Recurrent miscarriages Personalized care 


  1. 1.
    Gellersen B, Brosens IA, Brosens JJ. Decidualization of the human endometrium: mechanisms, functions, and clinical perspectives. Semin Reprod Med. 2007;25(6):445–53.PubMedCrossRefGoogle Scholar
  2. 2.
    Ruiz-Alonso M, Blesa D, Diaz-Gimeno P, Gomez E, Fernandez-Sanchez M, Carranza F, et al. The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Fertil Steril. 2013;100(3):818–24.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Haouzi D, Dechaud H, Assou S, De Vos J, Hamamah S. Insights into human endometrial receptivity from transcriptomic and proteomic data. Reprod Biomed Online. 2012;24(1):23–34.PubMedCrossRefGoogle Scholar
  4. 4.
    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.PubMedCrossRefGoogle Scholar
  5. 5.
    Lee JY, Lee M, Lee SK. Role of endometrial immune cells in implantation. Clin Exp Reprod Med. 2011;38(3):119–25.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Voest EE, Kenyon BM, O’Reilly MS, Truitt G, D’Amato RJ, Folkman J. Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst. 1995;87(8):581–6.PubMedCrossRefGoogle Scholar
  7. 7.
    Croy BA, Esadeg S, Chantakru S, van den Heuvel M, Paffaro VA, 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(2):175–91.PubMedCrossRefGoogle Scholar
  8. 8.
    Simon C, Moreno C, Remohi J, Pellicer A. Cytokines and embryo implantation. J Reprod Immunol. 1998;39(1–2):117–31.PubMedCrossRefGoogle Scholar
  9. 9.
    Chaouat G. The Th1/Th2 paradigm: still important in pregnancy? Semin Immunopathol. 2007;29(2):95–113.PubMedCrossRefGoogle Scholar
  10. 10.
    Ledee-Bataille N, Bonnet-Chea K, Hosny G, Dubanchet S, Frydman R, Chaouat G. Role of the endometrial tripod interleukin-18, -15, and -12 in inadequate uterine receptivity in patients with a history of repeated in vitro fertilization-embryo transfer failure. Fertil Steril. 2005;83(3):598–605.PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang J, Chen Z, Smith GN, Croy BA. Natural killer cell-triggered vascular transformation: maternal care before birth? Cell Mol Immunol. 2010;8(1):1–11.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    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(1):81–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Petitbarat M, Rahmati M, Serazin 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(1):e14497.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    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. 2009;94(3):1141–3.PubMedCrossRefGoogle Scholar
  15. 15.
    Manaster I, Mizrahi S, Goldman-Wohl D, Sela HY, Stern-Ginossar N, Lankry D, et al. Endometrial NK cells are special immature cells that await pregnancy. J Immunol. 2008;181(3):1869–76.PubMedCrossRefGoogle Scholar
  16. 16.
    Blois SM, Barrientos G, Garcia MG, Orsal AS, Tometten M, Cordo-Russo RI, et al. Interaction between dendritic cells and natural killer cells during pregnancy in mice. J Mol Med (Berl). 2008;86(7):837–52.CrossRefGoogle Scholar
  17. 17.
    Ledee N, Petitbarat M, Chevrier L, Vitoux D, Vezmar K, Rahmati M, et al. The uterine immune profile may help women with repeated unexplained embryo implantation failure after in vitro fertilization. Am J Reprod Immunol. 2016;75(3):388–401.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Borghese B, Santulli P, Marcellin L, Chapron C. Definition, description, clinicopathological features, pathogenesis and natural history of endometriosis: CNGOF-HAS endometriosis guidelines. Gynecol Obstet Fertil Senol. 2018;46(3):156–67.PubMedGoogle Scholar
  19. 19.
    de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet. 2010;376(9742):730–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Simon C, Gutierrez A, Vidal A, de los Santos MJ, Tarin JJ, Remohi J, et al. Outcome of patients with endometriosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum Reprod. 1994;9(4):725–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Prapas Y, Goudakou M, Matalliotakis I, Kalogeraki A, Matalliotaki C, Panagiotidis Y, et al. History of endometriosis may adversely affect the outcome in menopausal recipients of sibling oocytes. Reprod Biomed Online. 2012;25(5):543–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Lessey BA, Lebovic DI, Taylor RN. Eutopic endometrium in women with endometriosis: ground zero for the study of implantation defects. Semin Reprod Med. 2013;31(2):109–24.PubMedCrossRefGoogle Scholar
  23. 23.
    Lessey BA, Kim JJ. Endometrial receptivity in the eutopic endometrium of women with endometriosis: it is affected, and let me show you why. Fertil Steril. 2017;108(1):19–27.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Garcia-Velasco JA, Fassbender A, Ruiz-Alonso M, Blesa D, D’Hooghe T, Simon C. Is endometrial receptivity transcriptomics affected in women with endometriosis? A pilot study. Reprod Biomed Online. 2015;31(5):647–54.PubMedCrossRefGoogle Scholar
  25. 25.
    Miravet-Valenciano J, Ruiz-Alonso M, Gomez E, Garcia-Velasco JA. Endometrial receptivity in eutopic endometrium in patients with endometriosis: it is not affected, and let me show you why. Fertil Steril. 2017;108(1):28–31.PubMedCrossRefGoogle Scholar
  26. 26.
    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(1):45–51.PubMedCrossRefGoogle Scholar
  27. 27.
    Tanaka E, Sendo F, Kawagoe S, Hiroi M. Decreased natural killer cell activity in women with endometriosis. Gynecol Obstet Investig. 1992;34(1):27–30.CrossRefGoogle Scholar
  28. 28.
    Fernandez-Shaw S, Clarke MT, Hicks B, Naish CE, Barlow DH, Starkey PM. Bone marrow-derived cell populations in uterine and ectopic endometrium. Hum Reprod. 1995;10(9):2285–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Jones RK, Bulmer JN, Searle RF. Immunohistochemical characterization of stromal leukocytes in ovarian endometriosis: comparison of eutopic and ectopic endometrium with normal endometrium. Fertil Steril. 1996;66(1):81–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Eddy JL, Krukowski K, Janusek L, Mathews HL. Glucocorticoids regulate natural killer cell function epigenetically. Cell Immunol. 2014;290(1):120–30.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    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(12):1683–95.PubMedCrossRefGoogle Scholar
  32. 32.
    Elenkov IJ. Glucocorticoids and the Th1/Th2 balance. Ann N Y Acad Sci. 2004;1024:138–46.PubMedCrossRefGoogle Scholar
  33. 33.
    Lunghi L, Pavan B, Biondi C, Paolillo R, Valerio A, Vesce F, et al. Use of glucocorticoids in pregnancy. Curr Pharm Des. 2010;16(32):3616–37.PubMedCrossRefGoogle Scholar
  34. 34.
    Boomsma CM, Keay SD, Macklon NS. Peri-implantation glucocorticoid administration for assisted reproductive technology cycles. Cochrane Database Syst Rev. 2012;6:CD005996.Google Scholar
  35. 35.
    Boomsma CM, Keay SD, Macklon NS. Peri-implantation glucocorticoid administration for assisted reproductive technology cycles. Cochrane Database Syst Rev. 2007;1:CD005996.Google Scholar
  36. 36.
    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(3):258–63.PubMedCrossRefGoogle Scholar
  37. 37.
    Coulam CB, Acacio B. Does immunotherapy for treatment of reproductive failure enhance live births? Am J Reprod Immunol. 2012;67(4):296–304.PubMedCrossRefGoogle Scholar
  38. 38.
    Szekeres-Bartho J, Par G, Dombay G, Smart YC, Volgyi Z. The antiabortive effect of progesterone-induced blocking factor in mice is manifested by modulating NK activity. Cell Immunol. 1997;177(2):194–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Szekeres-Bartho J, Halasz M, Palkovics T. Progesterone in pregnancy; receptor-ligand interaction and signaling pathways. J Reprod Immunol. 2009;83(1–2):60–4.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Blois SM, Ilarregui JM, Tometten M, Garcia M, Orsal AS, Cordo-Russo R, et al. A pivotal role for galectin-1 in fetomaternal tolerance. Nat Med. 2007;13(12):1450–7.PubMedCrossRefGoogle Scholar
  41. 41.
    Ledee N, Dubanchet S, Lombroso R, Ville Y, Chaouat G. Downregulation of human endometrial IL-18 by exogenous ovarian steroids. Am J Reprod Immunol. 2006;56(2):119–23.PubMedCrossRefGoogle Scholar
  42. 42.
    Robertson SA. Seminal plasma and male factor signalling in the female reproductive tract. Cell Tissue Res. 2005;322(1):43–52.PubMedCrossRefGoogle Scholar
  43. 43.
    Singh H, Aplin JD. Adhesion molecules in endometrial epithelium: tissue integrity and embryo implantation. J Anat. 2009;215(1):3–13.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    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(6):2030–6.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    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(4):959–68.PubMedCrossRefGoogle Scholar
  46. 46.
    Kane N, Kelly R, Saunders PT, Critchley HO. Proliferation of uterine natural killer cells is induced by human chorionic gonadotropin and mediated via the mannose receptor. Endocrinology. 2009;150(6):2882–8.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Perrier d’Hauterive S, Berndt S, Tsampalas M, Charlet-Renard C, Dubois M, Bourgain C, et al. Dialogue between blastocyst hCG and endometrial LH/hCG receptor: which role in implantation? Gynecol Obstet Investig. 2007;64(3):156–60.CrossRefGoogle Scholar
  48. 48.
    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(1–2):109–28.PubMedCrossRefGoogle Scholar
  49. 49.
    Sharkey DJ, Tremellen KP, Jasper MJ, Gemzell-Danielsson K, Robertson SA. Seminal fluid induces leukocyte recruitment and cytokine and chemokine mRNA expression in the human cervix after coitus. J Immunol. 2012;188(5):2445–54.PubMedCrossRefGoogle Scholar
  50. 50.
    Ledee 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.PubMedCrossRefGoogle Scholar
  51. 51.
    Kalampokas T, Pandian Z, Keay SD, Bhattacharya S. Glucocorticoid supplementation during ovarian stimulation for IVF or ICSI. Cochrane Database Syst Rev. 2017;3:CD004752.PubMedGoogle Scholar
  52. 52.
    Ledee 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.PubMedCrossRefGoogle Scholar
  53. 53.
    Ledee N, Vasseur C, Petitbarat M, Chevrier L, Vezmar K, Dray G, et al. Intralipid(R) may represent a new hope for patients with reproductive failures and simultaneously an over-immune endometrial activation. J Reprod Immunol. 2018;130:18–22.PubMedCrossRefGoogle Scholar
  54. 54.
    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(2):113–8.PubMedCrossRefGoogle Scholar
  55. 55.
    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(4):262–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Meng L, Lin J, Chen L, Wang Z, Liu M, Liu Y, et al. Effectiveness and potential mechanisms of intralipid in treating unexplained recurrent spontaneous abortion. Arch Gynecol Obstet. 2016;294(1):29–39.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Nathalie LéDée
    • 1
  1. 1.MatriceLab Innove, Pepinière Paris Santé Cochin, Hospital CochinParisFrance

Personalised recommendations