Skip to main content

Advertisement

Log in

High Levels of Anti-GM-CSF Antibodies in Deep Infiltrating Endometriosis

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Endometriosis is a chronic hormono-dependent inflammatory gynecological disease. Endometriosis can be subdivided into three forms: superficial peritoneal implants, endometrioma, and deep infiltrating endometriosis (DIE). Inflammation is a typical feature of endometriosis with overproduction of prostaglandins, chemokines, and cytokines, like granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF is a hematopoietic growth factor and immune modulator which belongs to the group of cytokines that actively participate in inflammatory reactions. GM-CSF autoantibodies (Ab) are described in inflammatory diseases such as Crohn disease and ulcerative colitis where high concentrations of anti-GM-CSF Ab are correlated with severity, complications, and relapses. We have evaluated the presence of anti-GM-CSF Ab in the serum of 106 patients with endometriosis and 92 controls using a home-made enzyme-linked immunosorbent assay (ELISA) and correlated the results with the form and severity of the disease. We found that anti-GM-CSF Ab level is significantly increased in the sera of patients with endometriosis compared to controls and is associated with the severity of the disease especially in patients with deep endometriosis (p < 0.0001) with the highest number of lesions (p = 0.0034), including digestive involvement (p = 0.0041). We also found a correlation between these levels of anti-GM-CSF Ab and the number of lesions in DIE patients (r = 0.913). In this way, searching anti-GM-CSF Ab in endometriosis patient sera could be of value for patient follow-up and put further insight into the role of inflammation and of GM-CSF in endometriosis pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Borghese B, Santulli P, Marcellin L, Chapron C. Définition, description, formes anatomo-cliniques, pathogenèse et histoire naturelle de l’endométriose, RPC Endométriose CNGOF-HAS. Gynécologie Obstétrique Fertil Sénologie. 2018;46(3):156–67. https://doi.org/10.1016/j.gofs.2018.02.017.

    Article  CAS  Google Scholar 

  2. Riccio LGC, Baracat EC, Chapron C, Batteux F, Abrão MS. The role of the B lymphocytes in endometriosis: a systematic review. J Reprod Immunol. 2017;123:29–34. https://doi.org/10.1016/j.jri.2017.09.001.

    Article  CAS  PubMed  Google Scholar 

  3. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10(5):261–75. https://doi.org/10.1038/nrendo.2013.255.

    Article  CAS  PubMed  Google Scholar 

  4. Guo S-W. Recurrence of endometriosis and its control. Hum Reprod Update. 2009;15(4):441–61. https://doi.org/10.1093/humupd/dmp007.

    Article  PubMed  Google Scholar 

  5. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–9. https://doi.org/10.1016/j.fertnstert.2012.06.029.

    Article  CAS  PubMed  Google Scholar 

  6. Yu J, Wang Y, Zhou W-H, Wang L, He Y-Y, Li D-J. Combination of estrogen and dioxin is involved in the pathogenesis of endometriosis by promoting chemokine secretion and invasion of endometrial stromal cells. Hum Reprod. 2008;23(7):1614–26. https://doi.org/10.1093/humrep/den125.

    Article  CAS  PubMed  Google Scholar 

  7. Kyama CM, Overbergh L, Mihalyi A, Meuleman C, Mwenda JM, Mathieu C, et al. Endometrial and peritoneal expression of aromatase, cytokines, and adhesion factors in women with endometriosis. Fertil Steril. 2008;89(2):301–10. https://doi.org/10.1016/j.fertnstert.2007.02.057.

    Article  CAS  PubMed  Google Scholar 

  8. Rasko J, Gough N. Granulocyte macrophage-colony stimulating factor. In: The Cytokine Handbook. 2nd ed. New York: A Thomson: Academic Press; 1994. p. 342–69.

    Google Scholar 

  9. Shi Y, Liu CH, Roberts AI, et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don’t know. Cell Res. 2006;16(2):126–33. https://doi.org/10.1038/sj.cr.7310017.

    Article  CAS  PubMed  Google Scholar 

  10. Zhao Y, Chegini N. The expression of granulocyte macrophage-Colony stimulating factor (GM-CSF) and receptors in human endometrium*. Am J Reprod Immunol. 1999;42(5):303–11. https://doi.org/10.1111/j.1600-0897.1999.tb00106.x.

    Article  CAS  PubMed  Google Scholar 

  11. Monsanto SP, Edwards AK, Zhou J, et al. Surgical removal of endometriotic lesions alters local and systemic proinflammatory cytokines in endometriosis patients. Fertil Steril. 2016;105(4):968–77.e5. https://doi.org/10.1016/j.fertnstert.2015.11.047.

    Article  CAS  PubMed  Google Scholar 

  12. Miyajima A. Molecular structure of the IL-3, GM-CSF and IL-5 receptors. Int J Cell Cloning. 1992;10(3):126–34. https://doi.org/10.1002/stem.5530100302.

    Article  CAS  PubMed  Google Scholar 

  13. Dijkers PF, van Dijk TB, de Groot RP, Raaijmakers JAM, Lammers JWJ, Koenderman L, et al. Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor. Oncogene. 1999;18(22):3334–42. https://doi.org/10.1038/sj.onc.1202678.

    Article  CAS  PubMed  Google Scholar 

  14. Jenkins BJ, Blake TJ, Gonda TJ. Saturation mutagenesis of the β subunit of the human granulocyte-macrophage colony-stimulating factor receptor shows clustering of constitutive mutations, activation of erk map kinase and stat pathways, and differential β subunit tyrosine phosphorylation. Blood. 1998;92(6):1989–2002.

    Article  CAS  PubMed  Google Scholar 

  15. Shibata Y, Berclaz P-Y, Chroneos ZC, Yoshida M, Whitsett JA, Trapnell BC. GM-CSF regulates alveolar macrophage differentiation and innate immunity in the lung through PU.1. Immunity. 2001;15(4):557–67. https://doi.org/10.1016/S1074-7613(01)00218-7.

    Article  CAS  PubMed  Google Scholar 

  16. Wang Y, Thomson CA, Allan LL, Jackson LM, Olson M, Hercus TR, et al. Characterization of pathogenic human monoclonal autoantibodies against GM-CSF. Proc Natl Acad Sci. 2013;110(19):7832–7. https://doi.org/10.1073/pnas.1216011110.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Piccoli L, Campo I, Fregni CS, et al. Neutralization and clearance of GM-CSF by autoantibodies in pulmonary alveolar proteinosis. Nat Commun. 2015;6(1):7375. https://doi.org/10.1038/ncomms8375.

  18. Browne SK. Anticytokine autoantibody–associated immunodeficiency. Annu Rev Immunol. 2014;32(1):635–57. https://doi.org/10.1146/annurev-immunol-032713-120222.

    Article  CAS  PubMed  Google Scholar 

  19. Kuo C-Y, Wang S-Y, Shih H-P, Tu KH, Huang WC, Ding JY, et al. Disseminated Cryptococcosis due to anti-granulocyte-macrophage Colony-stimulating factor autoantibodies in the absence of pulmonary alveolar Proteinosis. J Clin Immunol. 2017;37(2):143–52. https://doi.org/10.1007/s10875-016-0364-4.

    Article  CAS  PubMed  Google Scholar 

  20. Uchida K, Beck DC, Yamamoto T, et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar Proteinosis. N Engl J Med. 2007;356(6):567–79. https://doi.org/10.1056/NEJMoa062505.

    Article  CAS  PubMed  Google Scholar 

  21. Bonneau J, Dumestre-Perard C, Rinaudo-Gaujous M, et al. Systematic review: new serological markers (anti-glycan, anti-GP2, anti-GM-CSF Ab) in the prediction of IBD patient outcomes. Autoimmun Rev. 2015;14(3):231–45. https://doi.org/10.1016/j.autrev.2014.11.004.

    Article  CAS  PubMed  Google Scholar 

  22. Iwasaki H. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood. 2005;106(5):1590–600. https://doi.org/10.1182/blood-2005-03-0860.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Somigliana E, Vercellini P, Gattei U, Chopin N, Chiodo I, Chapron C. Bladder endometriosis: getting closer and closer to the unifying metastatic hypothesis. Fertil Steril. 2007;87(6):1287–90. https://doi.org/10.1016/j.fertnstert.2006.11.090.

    Article  PubMed  Google Scholar 

  24. Chapron C, Pietin-Vialle C, Borghese B, Davy C, Foulot H, Chopin N. Associated ovarian endometrioma is a marker for greater severity of deeply infiltrating endometriosis. Fertil Steril. 2009;92(2):453–7. https://doi.org/10.1016/j.fertnstert.2008.06.003.

    Article  PubMed  Google Scholar 

  25. Chapron C, Chopin N, Borghese B, Foulot H, Dousset B, Vacher-Lavenu MC, et al. Deeply infiltrating endometriosis: pathogenetic implications of the anatomical distribution. Hum Reprod. 2006;21(7):1839–45. https://doi.org/10.1093/humrep/del079.

    Article  PubMed  Google Scholar 

  26. Chapron C, Souza C, de Ziegler D, et al. Smoking habits of 411 women with histologically proven endometriosis and 567 unaffected women. Fertil Steril. 2010;94(6):2353–5. https://doi.org/10.1016/j.fertnstert.2010.04.020.

    Article  PubMed  Google Scholar 

  27. Chapron C, Bourret A, Chopin N, Dousset B, Leconte M, Amsellem-Ouazana D, et al. Surgery for bladder endometriosis: long-term results and concomitant management of associated posterior deep lesions. Hum Reprod. 2010;25(4):884–9. https://doi.org/10.1093/humrep/deq017.

    Article  PubMed  Google Scholar 

  28. Dousset B, Leconte M, Borghese B, Millischer AE, Roseau G, Arkwright S, et al. Complete surgery for low rectal endometriosis: long-term results of a 100-case prospective study. Ann Surg. 2010;251(5):887–95. https://doi.org/10.1097/SLA.0b013e3181d9722d.

    Article  PubMed  Google Scholar 

  29. Fauconnier A, Chapron C, Dubuisson J-B, Vieira M, Dousset B, Bréart G. Relation between pain symptoms and the anatomic location of deep infiltrating endometriosis. Fertil Steril. 2002;78(4):719–26. https://doi.org/10.1016/S0015-0282(02)03331-9.

    Article  PubMed  Google Scholar 

  30. Huskisson EC. Measurement of pain. Lancet. 1974;9:1127–31.

    Article  Google Scholar 

  31. Uchida K, Nakata K, Carey B, Chalk C, Suzuki T, Sakagami T, et al. Standardized serum GM-CSF autoantibody testing for the routine clinical diagnosis of autoimmune pulmonary alveolar proteinosis. J Immunol Methods. 2014;402(1–2):57–70. https://doi.org/10.1016/j.jim.2013.11.011.

    Article  CAS  PubMed  Google Scholar 

  32. Svenson M, Hansen MB, Ross C, et al. Antibody to granulocyte-macrophage colony-stimulating factor is a dominant anti-cytokine activity in human igg preparations. Blood. 1998;91(6):2054–61.

    Article  CAS  PubMed  Google Scholar 

  33. Hamilton JA. GM-CSF in inflammation and autoimmunity. Trends Immunol. 2002;23(8):403–8. https://doi.org/10.1016/S1471-4906(02)02260-3.

    Article  CAS  PubMed  Google Scholar 

  34. Sun Y, Shao J, Jiang F, et al. CD33+CD14+CD11b+HLA-DR− monocytic myeloid-derived suppressor cells recruited and activated by CCR9/CCL25 are crucial for the pathogenic progression of endometriosis. Am J Reprod Immunol. 2019;81:e13067. https://doi.org/10.1111/aji.13067.

    Article  PubMed  Google Scholar 

  35. Eylenstein R, Weinfurtner D, Härtle S, et al. Molecular basis of in vitro affinity maturation and functional evolution of a neutralizing anti-human GM-CSF antibody. MAbs. 2016;8(1):176–86. https://doi.org/10.1080/19420862.2015.1099774.

    Article  CAS  PubMed  Google Scholar 

  36. Finkelman FD, Madden KB, Morris SC, Holmes JM, Katona IM, Maliszewski CR. Anti-cytokine antibodies as carrier proteins. Prolongation of in vivo effects of exogenous cytokines by injection of cytokine-anti-cytokine antibody complexes. J Immunol Res. 1993;151(3)1235–1244.

  37. Matalliotakis I, Goumenou A, Koumantakis G, Neonaki MA, Koumantakis EE, Dionyssopoulou E, et al. Serum concentrations of growth factors in women with and without endometriosis: the action of anti-endometriosis medicines. Int Immunopharmacol. 2003;3(1):81–9. https://doi.org/10.1016/S1567-5769(02)00216-3.

    Article  CAS  PubMed  Google Scholar 

  38. Othman EE-DR, Hornung D, Salem HT, Khalifa EA, El-Metwally TH, Al-Hendy A. Serum cytokines as biomarkers for nonsurgical prediction of endometriosis. Eur J Obstet Gynecol Reprod Biol. 2008;137(2):240–6. https://doi.org/10.1016/j.ejogrb.2007.05.001.

    Article  CAS  Google Scholar 

  39. Tanaka Y, Mori T, Ito F, Koshiba A, Takaoka O, Kataoka H, et al. Exacerbation of endometriosis due to regulatory T-cell dysfunction. J Clin Endocrinol Metab. 2017;102(9):3206–17. https://doi.org/10.1210/jc.2017-00052.

    Article  PubMed  Google Scholar 

  40. Robertson SA. Ovarian steroid hormones regulate granulocyte-macrophage colony- stimulating factor synthesis by uterine epithelial cells in the mouse. Biol Reprod. 1996;54(1):183–96. https://doi.org/10.1095/biolreprod54.1.183.

    Article  CAS  PubMed  Google Scholar 

  41. Revoltella RP, Laricchia-Robbio L, Moscato S, Genua A, Liberati AM. Natural and Therapy-Induced Anti-GM-CSF and Anti-G-CSF Antibodies in Human Serum. Leuk Lymphoma. 1997;26(sup1):29–34. https://doi.org/10.3109/10428199709058597.

    Article  CAS  PubMed  Google Scholar 

  42. Uchida K, Nakata K, Suzuki T, et al. Granulocyte/macrophage–colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. 2009;113(11):11.

Download references

Acknowledgments

The authors like to thank Dr. Sophie Candon for her ELISA protocol version and Catherine Dehoulle for her technical assistance.

Author information

Authors and Affiliations

Authors

Contributions

Laurie Toullec, Frédéric Batteux, Pietro Santulli, Sandrine Chouzenoux, Mohamed Jeljeli, Thibaut Belmondo, Sophie Hüe, and Charles Chapron have substantial contributions to the conception and design, the acquisition of data, or the analysis and interpretation of data. Laurie Toullec, Sophie Hüe, Frédéric Batteux, and Charles Chapron contributed to the drafting and critically revising the article for important intellectual content. Laurie Toullec, Sophie Hüe, Frédéric Batteux, and Charles Chapron approved the final version to be published.

Corresponding authors

Correspondence to Frédéric Batteux, Sophie Hue or Charles Chapron.

Ethics declarations

Conflict of Interest

The authors declare that there is no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Toullec, L., Batteux, F., Santulli, P. et al. High Levels of Anti-GM-CSF Antibodies in Deep Infiltrating Endometriosis. Reprod. Sci. 27, 211–217 (2020). https://doi.org/10.1007/s43032-019-00021-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-019-00021-8

Keywords

Navigation