Endometrial Immune-Inflammatory Gene Signatures in Endometriosis

  • Jessica E. Miller
  • Lindsey K. Symons
  • Ryan M. Marks
  • Chandrakant TayadeEmail author


Endometriosis affects 176 million women worldwide and is defined by the growth of endometrial (uterine) tissue outside of the uterus. Endometriosis is considered a multifactorial disease known for chronic inflammation and estrogen dependence; however, there is no consensus as to the cause. An overall lack of knowledge surrounding the disease has led to substantial challenges in classification, diagnosis, and treatment for endometriosis patients. The use of large-scale molecular profiles, including genomic, epigenetic, transcriptomic, and proteomic profiles, has been conducted to further understand the pathology of endometriosis with the hopes that this information could help improve the current challenges. Interestingly, these studies have clearly revealed unique immune-inflammatory gene signatures in endometriosis patients compared to healthy fertile women. Since immune pathways are redundant and converge at multiple cellular and molecular levels, further study is required to carefully dissect how these specific immune pathways are contributing to the disease and if therapeutic targets can be revealed. Additionally, further study of specific lesion types, disease stage, and associated symptoms in the context of an immune gene signature could lead to the design of novel classification systems and diagnostic procedures. Here, we provide a comprehensive overview of the alterations in immune-inflammatory gene signatures and their functional significance in endometriosis.


Endometriosis Cytokines and chemokines Gene expression Inflammation Immune response 


  1. 1.
    Levy AR, Osenenko KM, Lozano-Ortega G, Sambrook R, Jeddi M, Bélisle S, Reid RL. Economic burden of surgically confirmed endometriosis in Canada. J Obstet Gynaecol Can. 2011;33:830–7.PubMedCrossRefGoogle Scholar
  2. 2.
    Fuldeore M, Yang H, Du EX, Soliman AM, Wu EQ, Winkel C. Healthcare utilization and costs in women diagnosed with endometriosis before and after diagnosis: a longitudinal analysis of claims databases. Fertil Steril. 2015;103:163–71.PubMedCrossRefGoogle Scholar
  3. 3.
    McKinnon BD, Bertschi D, Bersinger NA, Mueller MD. Inflammation and nerve fiber interaction in endometriotic pain. Trends Endocrinol Metab. 2015;26:1–10.PubMedCrossRefGoogle Scholar
  4. 4.
    Anaf V, Simon P, El Nakadi I, Fayt I, Buxant F, Simonart T, Peny MO, Noel JC. Relationship between endometriotic foci and nerves in rectovaginal endometriotic nodules. Hum Reprod. 2000;15:1744–50.PubMedCrossRefGoogle Scholar
  5. 5.
    Khan KN, Kitajima M, Hiraki K, Fujishita A, Nakashima M, Masuzaki H. Visible and occult microscopic lesions of endometriosis. Gynecol Minim Invasive Ther. 2014;3:109–14.CrossRefGoogle Scholar
  6. 6.
    Aghajanova L, Tatsumi K, Horcajadas JA, Zamah AM, Esteban FJ, Herndon CN, Conti M, Giudice LC. Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011;84:801–15.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Klemmt PAB, Starzinski-Powitz A. Molecular and cellular pathogenesis of endometriosis. Curr Womens Health Rev. 2018;14:106–16.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:422–69.CrossRefGoogle Scholar
  9. 9.
    Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364:1789–99.CrossRefGoogle Scholar
  10. 10.
    Jerman LF, Hey-Cunningham AJ. The role of the lymphatic system in endometriosis: a comprehensive review of the Literature. Biol Reprod. 2015;92:64. Scholar
  11. 11.
    Beavis AL, Matsuo K, Grubbs BH, Srivastava SA, Truong CM, Moffitt MN, Maliglig AM, Lin YG. Endometriosis in para-aortic lymph nodes during pregnancy: case report and review of literature. Fertil Steril. 2011;95:2429.e9–2429.e13.CrossRefGoogle Scholar
  12. 12.
    Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927;3:93–110.43.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Matsuura K, Ohtake H, Katabuchi H, Okamura H. Coelomic metaplasia theory of endometriosis: evidence from in vivo studies and an in vitro experimental model. Gynecol Obstet Investig. 1999;47:18–22.CrossRefGoogle Scholar
  14. 14.
    Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362:2389–98.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    BALLARD K, LOWTON K, WRIGHT J. What’s the delay? A qualitative study of women’s experiences of reaching a diagnosis of endometriosis. Fertil Steril. 2006;86:1296–301.PubMedCrossRefGoogle Scholar
  16. 16.
    Nnoaham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco NF, de Cicco NC, Jenkinson C, Kennedy SH, Zondervan KT, World Endometriosis Research Foundation Global Study of Women’s Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96:366–373.e8.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Nisenblat V, Bossuyt PM, Shaikh R, Farquhar C, Jordan V, Scheffers CS, Mol BWJ, Johnson N, Hull ML. Blood biomarkers for the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev. 2016;
  18. 18.
    May KE, Conduit-Hulbert SA, Villar J, Kirtley S, Kennedy SH, Becker CM. Peripheral biomarkers of endometriosis: a systematic review. Hum Reprod Update. 2010;16:651–74.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Fassbender A, Burney RO, O DF, D’Hooghe T, Giudice L. Update on biomarkers for the detection of endometriosis. Biomed Res Int. 2015;2015:1–14.CrossRefGoogle Scholar
  20. 20.
    Schenken RS, Guzick DS. Endometriosis classification and infertility. Fertil Steril. 1997;67(5):815–6.PubMedCrossRefGoogle Scholar
  21. 21.
    Johnson NP, Hummelshoj L, Adamson GD, et al. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod. 2017;32:315–24.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    Bertschi D, McKinnon BD, Evers J, Bersinger NA, Mueller MD. Enhanced inflammatory activity of endometriotic lesions from the rectovaginal septum. Mediat Inflamm. 2013;2013:450950.CrossRefGoogle Scholar
  24. 24.
    Chapron C, Fauconnier A, Dubuisson J-B, Barakat H, Vieira M, Bréart G. Deep infiltrating endometriosis: relation between severity of dysmenorrhoea and extent of disease. Hum Reprod. 2003;18:760–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Koninckx PR, Meuleman C, Demeyere S, Lesaffre E, Cornillie FJ. Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril. 1991;55:759–65.PubMedCrossRefGoogle Scholar
  26. 26.
    Tosti C, Pinzauti S, Santulli P, Chapron C, Petraglia F. Pathogenetic mechanisms of deep infiltrating endometriosis. Reprod Sci. 2015;22:1053–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Kvaskoff M, Horne AW, Missmer SA. Informing women with endometriosis about ovarian cancer risk. Lancet. 2017;390:2433–4.PubMedCrossRefGoogle Scholar
  28. 28.
    Wendel JRH, Wang X, Hawkins SM. The Endometriotic tumor microenvironment in ovarian cancer. Cancers (Basel). 2018;10 Scholar
  29. 29.
    Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril. 2014;101:927–35.CrossRefGoogle Scholar
  30. 30.
    Vignali M, Bianchi S, Candiani M, Spadaccini G, Oggioni G, Busacca M. Surgical treatment of deep endometriosis and risk of recurrence. J Minim Invasive Gynecol. 2005;12:508–13.PubMedCrossRefGoogle Scholar
  31. 31.
    Marcoux S, Maheux R, Bérubé S, Endometriosis the CCG on. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Engl J Med. 1997;337:217–22.CrossRefGoogle Scholar
  32. 32.
    Jacobson TZ, Duffy JM, Barlow DH, Farquhar C, Koninckx PR, Olive D. Laparoscopic surgery for subfertility associated with endometriosis. Cochrane Database Syst Rev. 2010;
  33. 33.
    Monsanto SP, Edwards AK, Zhou J, Nagarkatti P, Nagarkatti M, Young SL, Lessey BA, Tayade C. Surgical removal of endometriotic lesions alters local and systemic proinflammatory cytokines in endometriosis patients. Fertil Steril. 2016;105:968–977.e5.PubMedCrossRefGoogle Scholar
  34. 34.
    Dun EC, Taylor HS. Elagolix: a promising oral GnRH antagonist for endometriosis-associated pain. Oncotarget. 2017;8:99219–20.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Symons LK, Miller JE, Kay VR, Marks RM, Liblik K, Koti M, Tayade C. The immunopathophysiology of endometriosis. Trends Mol Med. 2018;24:748–62.PubMedCrossRefGoogle Scholar
  36. 36.
    Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984;64:151–4.PubMedGoogle Scholar
  37. 37.
    Kvaskoff M, Mu F, Terry KL, Harris HR, Poole EM, Farland L, Missmer SA. Endometriosis: a high-risk population for major chronic diseases? Hum Reprod Update. 2015;21:500–16.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Bungum HF, Vestergaard C, Knudsen UB. Endometriosis and type 1 allergies/immediate type hypersensitivity: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2014;179:209–15.PubMedCrossRefGoogle Scholar
  39. 39.
    Capobianco A, Rovere-Querini P. Endometriosis, a disease of the macrophage. Front Immunol. 2013;4:9.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Han SJ, Jung SY, Wu S-P, et al. Estrogen receptor β modulates apoptosis complexes and the Inflammasome to drive the pathogenesis of endometriosis. Cell. 2015;163:960–74.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Fox C, Morin S, Jeong J-W, Scott RT, Lessey BA. Local and systemic factors and implantation: what is the evidence? Fertil Steril. 2016;105:873–84.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Miller JE, Ahn SH, Monsanto SP, Khalaj K, Koti M, Tayade C. Implications of immune dysfunction on endometriosis associated infertility. Oncotarget. 2016;8(4):7138–47. Scholar
  43. 43.
    Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, Osteen K, Lessey BA, Giudice LC. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology. 2003;144:2870–81.PubMedCrossRefGoogle Scholar
  44. 44.
    Gashaw I, Hastings JM, Jackson KS, Winterhager E, Fazleabas AT. Induced endometriosis in the baboon (Papio anubis) increases the expression of the proangiogenic factor CYR61 (CCN1) in eutopic and ectopic endometria. Biol Reprod. 2006;74:1060–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Afshar Y, Hastings J, Roqueiro D, Jeong J-W, Giudice LC, Fazleabas AT. Changes in Eutopic endometrial gene expression during the progression of experimental endometriosis in the baboon, Papio Anubis. Biol Reprod. 2013;88:44.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Ahn SH, Khalaj K, Young SL, Lessey BA, Koti M, Tayade C. Immune-inflammation gene signatures in endometriosis patients. Fertil Steril. 2016;106:1420–1431.e7. Scholar
  47. 47.
    Tamaresis JS, Irwin JC, Goldfien GA, Rabban JT, Burney RO, Nezhat C, DePaolo LV, Giudice LC. Molecular classification of endometriosis and disease stage using high-dimensional genomic data. Endocrinology. 2014;155:4986–99.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kopelman A, Girão MJBC, Bonetti TCS, Carvalho CV, da Silva IDCG, Schor E. Analysis of gene expression in the endocervical epithelium of women with deep endometriosis. Reprod Sci. 2016;23:1269–74.PubMedCrossRefGoogle Scholar
  49. 49.
    Nikoo S, Ebtekar M, Jeddi-Tehrani M, Shervin A, Bozorgmehr M, Vafaei S, Kazemnejad S, Zarnani A-H. Menstrual blood-derived stromal stem cells from women with and without endometriosis reveal different phenotypic and functional characteristics. Mol Hum Reprod. 2014;20:905–18.PubMedCrossRefGoogle Scholar
  50. 50.
    Barragan F, Irwin JC, Balayan S, et al. Human endometrial fibroblasts derived from mesenchymal progenitors inherit progesterone resistance and acquire an inflammatory phenotype in the endometrial niche in endometriosis1. Biol Reprod. 2016;94:118. Scholar
  51. 51.
    Fassbender A, Verbeeck N, Börnigen D, et al. Combined mRNA microarray and proteomic analysis of eutopic endometrium of women with and without endometriosis. Hum Reprod. 2012;27:2020–9.PubMedCrossRefGoogle Scholar
  52. 52.
    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;31:647–54.CrossRefGoogle Scholar
  53. 53.
    Brunham RC, Gottlieb SL, Paavonen J. Pelvic inflammatory disease. N Engl J Med. 2015;372:2039–48.PubMedCrossRefGoogle Scholar
  54. 54.
    Gentilini D, Perino A, Vigano P, Chiodo I, Cucinella G, Vignali M, Di Blasio AM, Busacca M. Gene expression profiling of peripheral blood mononuclear cells in endometriosis identifies genes altered in non-gynaecologic chronic inflammatory diseases. Hum Reprod. 2011;26:3109–17.PubMedCrossRefGoogle Scholar
  55. 55.
    Salmeri FM, Laganà AS, Sofo V, Triolo O, Sturlese E, Retto G, Pizzo A, D’Ascola A, Campo S. Behavior of tumor necrosis factor-α and tumor necrosis factor receptor 1/tumor necrosis factor receptor 2 system in mononuclear cells recovered from peritoneal fluid of women with endometriosis at different stages. Reprod Sci. 2015;22:165–72.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Suryawanshi S, Huang X, Elishaev E, et al. Complement pathway is frequently altered in endometriosis and endometriosis-associated ovarian cancer. Clin Cancer Res. 2014;20:6163–74.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Borrelli GM, Carvalho KI, Kallas EG, Mechsner S, Baracat EC, Abrão MS. Chemokines in the pathogenesis of endometriosis and infertility. J Reprod Immunol. 2013;98:1–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Ahn SH, Monsanto SP, Miller C, Singh SS, Thomas R, Tayade C. Pathophysiology and immune dysfunction in endometriosis. Biomed Res Int. 2015;2015:1. Scholar
  59. 59.
    Podgaec S, Abrao MS, Dias JA, Rizzo LV, de Oliveira RM, Baracat EC. Endometriosis: an inflammatory disease with a Th2 immune response component. Hum Reprod. 2007;22:1373–9.PubMedCrossRefGoogle Scholar
  60. 60.
    Chegini N, Roberts M, Ripps B. Differential expression of interleukins (IL)-13 and IL-15 in ectopic and eutopic endometrium of women with endometriosis and normal fertile women. Am J Reprod Immunol. 2003;49:75–83.PubMedCrossRefGoogle Scholar
  61. 61.
    Beste MT, Pfäffle-Doyle N, Prentice EA, Morris SN, Lauffenburger DA, Isaacson KB, Griffith LG. Molecular network analysis of endometriosis reveals a role for c-Jun–regulated macrophage activation. Sci Transl Med. 2014;6:222ra16.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Bakhtiarizadeh MR, Hosseinpour B, Shahhoseini M, Korte A, Gifani P. Weighted gene co-expression network analysis of endometriosis and identification of functional modules associated with its main hallmarks. Front Genet. 2018;9:453.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Ahn SH, Singh V, Tayade C. Biomarkers in endometriosis: challenges and opportunities. Fertil Steril. 2017;107:523–32.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    McArdel SL, Terhorst C, Sharpe AH. Roles of CD48 in regulating immunity and tolerance. Clin Immunol. 2016;164:10–20.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Takamura M, Koga K, Izumi G, Hirata T, Harada M, Hirota Y, Hiraike O, Fujii T, Osuga Y. Simultaneous detection and evaluation of four subsets of CD4+ T lymphocyte in lesions and peripheral blood in endometriosis. Am J Reprod Immunol. 2015;74:480–6.PubMedCrossRefGoogle Scholar
  66. 66.
    Olkowska-Truchanowicz J, Bocian K, Maksym RB, Bialoszewska A, Wlodarczyk D, Baranowski W, Zabek J, Korczak-Kowalska G, Malejczyk J. CD4+ CD25+ FOXP3+ regulatory T cells in peripheral blood and peritoneal fluid of patients with endometriosis. Hum Reprod. 2013;28:119–24.PubMedCrossRefGoogle Scholar
  67. 67.
    Tariverdian N, Siedentopf F, Rücke M, Blois SM, Klapp BF, Kentenich H, Arck PC. Intraperitoneal immune cell status in infertile women with and without endometriosis. J Reprod Immunol. 2009;80:80–90.PubMedCrossRefGoogle Scholar
  68. 68.
    Paula R, Oliani AH, Vaz-Oliani DCM, D’Ávila SCGP, Oliani SM, Gil CD. The intricate role of mast cell proteases and the annexin A1-FPR1 system in abdominal wall endometriosis. J Mol Histol. 2015;46:33–43.PubMedCrossRefGoogle Scholar
  69. 69.
    Binda MM, Donnez J, Dolmans M-M. Targeting mast cells: a new way to treat endometriosis. Expert Opin Ther Targets. 2017;21:67–75.PubMedCrossRefGoogle Scholar
  70. 70.
    Jeung I, Cheon K, Kim M-R, Jeung I, Cheon K, Kim M-R. Decreased cytotoxicity of peripheral and peritoneal natural killer cell in endometriosis. Biomed Res Int. 2016;2016:1–6.CrossRefGoogle Scholar
  71. 71.
    Ota H, Igarashi S. Expression of major histocompatibility complex class II antigen in endometriotic tissue in patients with endometriosis and adenomyosis. Fertil Steril. 1993;60:834–8.PubMedCrossRefGoogle Scholar
  72. 72.
    Sobalska-Kwapis M, Smolarz B, Słomka M, et al. New variants near RHOJ and C2, HLA-DRA region and susceptibility to endometriosis in the Polish population—The genome-wide association study. Eur J Obstet Gynecol Reprod Biol. 2017;217:106–12.PubMedCrossRefGoogle Scholar
  73. 73.
    Cavalli G, Hayashi M, Jin Y, et al. MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo. Proc Natl Acad Sci U S A. 2016;113:1363–8.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Wild RA, Shivers CA. Antiendometrial antibodies in patients with endometriosis. Am J Reprod Immunol Microbiol. 1985;8:84–6.PubMedCrossRefGoogle Scholar
  75. 75.
    Fernández-Shaw S, Hicks BR, Yudkin PL, Kennedy S, Barlow DH, Starkey PM. Anti-endometrial and anti-endothelial auto-antibodies in women with endometriosis. Hum Reprod. 1993;8:310–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Lee K-S, Baek D-W, Kim K-H, Shin B-S, Lee D-H, Kim J-W, Hong Y-S, Bae Y-S, Kwak J-Y. IL-10-dependent down-regulation of MHC class II expression level on monocytes by peritoneal fluid from endometriosis patients. Int Immunopharmacol. 2005;5:1699–712.PubMedCrossRefGoogle Scholar
  77. 77.
    Na Y-J, Jin J-O, Lee M-S, Song M-G, Lee K-S, Kwak J-Y. Peritoneal fluid from endometriosis patients switches differentiation of monocytes from dendritic cells to macrophages. J Reprod Immunol. 2008;77:63–74.PubMedCrossRefGoogle Scholar
  78. 78.
    McGranahan N, Rosenthal R, Hiley CT, et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell. 2017;171:1259–1271.e11.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Campos GB, Marques LM, Rezende IS, Barbosa MS, Abrão MS, Timenetsky J. Mycoplasma genitalium can modulate the local immune response in patients with endometriosis. Fertil Steril. 2018;109:549–560.e4.PubMedCrossRefGoogle Scholar
  80. 80.
    Yeo SG, Won YS, Lee HY, Kim YI, Lee J-W, Park DC. Increased expression of pattern recognition receptors and nitric oxide synthase in patients with endometriosis. Int J Med Sci. 2013;10:1199–208.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Hayashi C, Chishima F, Sugitani M, Ichikawa G, Nakazawa-Watanabe T, Sugita K, Suzuki M, Nemoto N, Yamamoto T. Relationship between toll-like receptor-4 and mPGES-1 gene expression in local lesions of endometriosis patients. Am J Reprod Immunol. 2013;69:231–9.PubMedCrossRefGoogle Scholar
  82. 82.
    Chang C-M, Wang M-L, Lu K-H, Yang Y-P, Juang C-M, Wang P-H, Hsu R-J, Yu M-H, Chang C-C. Integrating the dysregulated inflammasome-based molecular functionome in the malignant transformation of endometriosis-associated ovarian carcinoma. Oncotarget. 2018;9:3704–26.PubMedGoogle Scholar
  83. 83.
    Tao XJ, Sayegh RA, Isaacson KB. Increased expression of complement component 3 in human ectopic endometrium compared with the matched eutopic endometrium. Fertil Steril. 1997;68:460–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Kajihara H, Yamada Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, Yoshida S, Sado T, Oi H, Kobayashi H. New insights into the pathophysiology of endometriosis: from chronic inflammation to danger signal. Gynecol Endocrinol. 2011;27:73–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Khan KN, Kitajima M, Hiraki K, Yamaguchi N, Katamine S, Matsuyama T, Nakashima M, Fujishita A, Ishimaru T, Masuzaki H. Escherichia coli contamination of menstrual blood and effect of bacterial endotoxin on endometriosis. Fertil Steril. 2010;94:2860–3-3.PubMedCrossRefGoogle Scholar
  86. 86.
    Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11:785–97.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Reis ES, Mastellos DC, Ricklin D, Mantovani A, Lambris JD. Complement in cancer: untangling an intricate relationship. Nat Rev Immunol. 2018;18:5–18.PubMedCrossRefGoogle Scholar
  88. 88.
    Ricklin D, Lambris JD. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J Immunol. 2013;190:3831–8.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Rekker K, Saare M, Eriste E, et al. High-throughput mRNA sequencing of stromal cells from endometriomas and endometrium. Reproduction. 2017;154:93–100.PubMedCrossRefGoogle Scholar
  90. 90.
    Aslan C, Ak H, Askar N, Ozkaya AB, Ergenoglu AM, Yeniel AO, Akdemir A, Aydin HH. Overexpression of complement C5 in endometriosis. Clin Biochem. 2014;47:496–8.PubMedCrossRefGoogle Scholar
  91. 91.
    Wu J, Xie H, Yao S, Liang Y. Macrophage and nerve interaction in endometriosis. J Neuroinflammation. 2017;14:53.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Bałkowiec M, Maksym RB, Włodarski PK. The bimodal role of matrix metalloproteinases and their inhibitors in etiology and pathogenesis of endometriosis (Review). Mol Med Rep. 2018;18:3123–36.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Wu Y, Kajdacsy-Balla A, Strawn E, Basir Z, Halverson G, Jailwala P, Wang Y, Wang X, Ghosh S, Guo S-W. Transcriptional characterizations of differences between eutopic and ectopic endometrium. Endocrinology. 2006;147:232–46.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Desai O, Winkler J, Minasyan M, Herzog EL. The role of immune and inflammatory cells in idiopathic pulmonary fibrosis. Front Med. 2018;5:43.CrossRefGoogle Scholar
  95. 95.
    Gieseck RL, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol. 2017;18:62. Scholar
  96. 96.
    Tang PM-K, Nikolic-Paterson DJ, Lan H-Y. Macrophages: versatile players in renal inflammation and fibrosis. Nat Rev Nephrol. 2019;15(3):144–58.PubMedCrossRefGoogle Scholar
  97. 97.
    Guo S-W. Cancer driver mutations in endometriosis: variations on the major theme of fibrogenesis. Reprod Med Biol. 2018;17:369–97.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Treloar SA, O’Connor DT, O’Connor VM, Martin NG. Genetic influences on endometriosis in an Australian twin sample. Fertil Steril. 1999;71:701–10.PubMedCrossRefGoogle Scholar
  99. 99.
    Saha R, Pettersson HJ, Svedberg P, Olovsson M, Bergqvist A, Marions L, Tornvall P, Kuja-Halkola R. Heritability of endometriosis. Fertil Steril. 2015;104:947–52.PubMedCrossRefGoogle Scholar
  100. 100.
    Nyholt DR, Low S-K, Anderson CA, et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat Genet. 2012;44:1355–9.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Uno S, Zembutsu H, Hirasawa A, Takahashi A, Kubo M, Akahane T, Aoki D, Kamatani N, Hirata K, Nakamura Y. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat Genet. 2010;42:707–10.PubMedCrossRefGoogle Scholar
  102. 102.
    Uimari O, Rahmioglu N, Nyholt DR, Vincent K, Missmer SA, Becker C, Morris AP, Montgomery GW, Zondervan KT. Genome-wide genetic analyses highlight mitogen-activated protein kinase (MAPK) signaling in the pathogenesis of endometriosis. Hum Reprod. 2017;32:780–93.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Rahmioglu N, Macgregor S, Drong AW, et al. Genome-wide enrichment analysis between endometriosis and obesity-related traits reveals novel susceptibility loci. Hum Mol Genet. 2015;24:1185–99.PubMedCrossRefGoogle Scholar
  104. 104.
    Pagliardini L, Gentilini D, Vigano’ P, Panina-Bordignon P, Busacca M, Candiani M, Di Blasio AM. An Italian association study and meta-analysis with previous GWAS confirm WNT4, CDKN2BAS and FN1 as the first identified susceptibility loci for endometriosis. J Med Genet. 2013;50:43–6.PubMedCrossRefGoogle Scholar
  105. 105.
    Gajbhiye R, McKinnon B, Mortlock S, Mueller M, Montgomery G. Genetic variation at chromosome 2q13 and its potential influence on endometriosis susceptibility through effects on the IL-1 family. Reprod Sci. 2018;25:1307–17.PubMedCrossRefGoogle Scholar
  106. 106.
    Sapkota Y, Steinthorsdottir V, Morris AP, et al. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat Commun. 2017;8:15539.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Zondervan KT, Rahmioglu N, Morris AP, Nyholt DR, Montgomery GW, Becker CM, Missmer SA. Beyond endometriosis genome-wide association study: from genomics to phenomics to the patient. Semin Reprod Med. 2016;34:242–54.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Sapkota Y, Low S-K, Attia J, et al. Association between endometriosis and the interleukin 1A (IL1A) locus. Hum Reprod. 2015;30:239–48.PubMedCrossRefGoogle Scholar
  109. 109.
    Chae W-J, Bothwell ALM. Canonical and non-canonical Wnt signaling in immune cells. Trends Immunol. 2018;39:830–47.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Jessica E. Miller
    • 1
  • Lindsey K. Symons
    • 1
  • Ryan M. Marks
    • 1
  • Chandrakant Tayade
    • 1
    Email author
  1. 1.Department of Biomedical and Molecular SciencesQueen’s UniversityKingstonCanada

Personalised recommendations