International Journal of Biomedicine. 2020;10(4):362-368.
Originally published December 10, 2020
The objective of our study was to investigate the specific features of immune status indicators in women of reproductive age with chronic endometritis (CE) and reproductive disorders.
Methods and Results: The observational study involved 81 women of reproductive age with reproductive disorders. The main group (MG) included 50 women with CE (mean age of 29.2±5.34 years). The control group (CG) consisted of 31 fertile women also of reproductive age(mean age of 30.7±5.9 years). MG was divided into the following subgroups: Subgroup A (SubA) included 31 patients with verified CE and an isolated infectious agent from endometrial tissue: Subgroup B (SubB) included 19 patients with verified CE and the absence of an infectious agent in the endometrial tissue. Endometrial aspiration pipe biopsy was performed on days 4-9 of the menstrual cycle (middle proliferative phase) using a disposable intrauterine probe (Taizhou Kechuang Medical Apparatus Co., Ltd, China) followed by histological examination of endometrial tissue. Laboratory diagnostics for sexually transmitted infections (STIs) was performed using the bacterial culture method. For the diagnosis of viral infection (HPV, HSV, CMV), cervical samples were studied using PCR. If STIs were detected, the patients were excluded from further research. Ultrasound examination of the pelvic organs was performed using the Aloka-5500 device with a 7MHz vaginal probe in two-dimensional visualization mode. The concentration of cytokines (IL-1β, INF-γ, TNF-α, ILs-4,6,8,10) in the endometrium was determined using the Protein Contour test systems (Saint Petersburg) and Multiskan EX ELISA Analyzer (Germany). The percentages and absolute counts of blood lymphocytes (CD3+, CD3+/CD8+/CD45+, CD19+/CD45+, and CD16+/CD56+/CD45+ cells) were determined by the method of indirect immunofluorescence with monoclonal antibodies using the BD FACSCalibur flow cytometer (USA).
We found a significant increase in the blood concentrations of CD3+ cells, CD3+/CD8+/CD45+ cells, and CD19+/CD45+ cells and a decrease in the levels of CD16+/CD56+/CD45+ cells, microbicidal activity of oxygen-dependent function of neutrophils, and phagocytic activity of neutrophils, as well as a significant decrease in the levels of IgA, IgM, and IRI in MG, compared to CG. In SubA, compared to SubB, we found a significant decrease in CD3+ cells and CD19+/C45+ cells and a slight increase in immunoregulatory index.
The concentrations of tissue cytokines in women of MG were characterized by a 3-fold increase in the level of pro- and anti-inflammatory cytokines (IL-1β, ILs - 4, 6, 10, and INF-γ), and a 4-fold increase in the levels of TNF-α and IL-8, compared to CG.
In SubA, in comparison with SubB, a significant decrease in anti-inflammatory cytokines (ILs-4,10) and chemokine IL-8 was revealed against the background of a significant increase in the concentrations of INF–γ and TNF–α.
Conclusion: The results obtained indicate changes in the reactivity of the immune system in women with reproductive disorders and chronic inflammation in the endometrium. The most pronounced changes in the local immunity indicators are observed when opportunistic pathogens are detected in the endometrial tissue.
- Korsak VS, Zabelkina OV, Isakova EV, Popov EN. [Diagnosis of pathology of the uterine cavity in patients suffering from tubal-peritoneal infertility]. Journal of Obstetrics and Women's Diseases. 2005;54(3):50-53. [Article in Russian].
- Kiryushchenkov PA, Belousov DM, Veryasov VN, Menzhinskaya IV, Alekseeva MS. [Significance of uterine pathology and peculiarities of pre-gestational preparation of women with the syndrome of habitual early pregnancy loss]. Journal of Obstetrics and Gynecology. 2009;5:15-19. [Article in Russian].
- Rudakova EB, Luzin AA, Bogdanova ON, Mozgovoy SI, Loboda OA, Pilipenko MA, Burova OM. [Chronic endometritis: from improving the diagnostic approach to optimizing treatment]. Lechaschi Vrach. 2008;10:6-10. [Article in Russian].
- Eckert LO, Hawes SE, Wölner-Hanssen PK, Kiviat NB, Wasserheit JN, Paavonen JA, Eschenbach DA, Holmes KK. Endometritis: the clinical-pathologic syndrome. Am J Obstet Gynecol. 2002;186(4):690-5. doi: 10.1067/mob.2002.121728.
- Campos-Outcalt D. CDC update: Guidelines for treating STDs. J Fam Pract. 2011 Mar;60(3):143-6.
- Dubnitskaya LV, Nazarenko TA. [Chronic endometritis: diagnostic and treatment options]. Consilium Medicum. 2007;9(6):25–28. [Article in Russian].
- Zdanovskiĭ VM, Buravchenko NB. [Results of using assisted reproductive technologies in infertile patients with endometrial pathology]. Russian Bulletin of Obstetrician-Gynecologist. 2010;10(2):39-42. [Article in Russian].
- Kulakov VI, Ankirskaya AS, Beloborodov SM. [Antibacterial therapy of inflammatory diseases of the pelvic organs: tasks, solutions, mistakes]. Gynecology. 2004;7:3-5. [Article in Russian].
- Rudakova EB, Besman IV. [Assisted reproductive technologies. Problems of pregnancy loss]. Lechaschi Vrach. 2010;3:46–49. [Article in Russian].
- Radzinsky VE, Kozlov RS, Dukhin AO. Antibacterial therapy of pelvic inflammatory diseases without mistakes and experiments: a methodological guide for doctors. M.: StatusPraesens, 2013:16. [In Russian].
- Sidelnikova VM, Sukhikh GT. Miscarriage: A Guide for Physicians. M., 2011:534. [In Russian].
- Andrews WW, Hauth JC, Cliver SP, Conner MG, Goldenberg RL, Goepfert AR. Association of asymptomatic bacterial vaginosis with endometrial microbial colonization and plasma cell endometritis in nonpregnant women. Am J Obstet Gynecol. 2006;195(6):1611-6. doi: 10.1016/j.ajog.2006.04.010.
- Cicinelli E, De Ziegler D, Nicoletti R, Colafiglio G, Saliani N, Resta L, Rizzi D, De Vito D. Chronic endometritis: correlation among hysteroscopic, histologic, and bacteriologic findings in a prospective trial with 2190 consecutive office hysteroscopies. Fertil Steril. 2008 Mar;89(3):677-84. doi: 10.1016/j.fertnstert.2007.03.074.
- Eckert LO, Moore DE, Patton DL, Agnew KJ, Eschenbach DA. Relationship of vaginal bacteria and inflammation with conception and early pregnancy loss following in-vitro fertilization. Infect Dis Obstet Gynecol. 2003;11(1):11-7. doi: 10.1155/S1064744903000024.
- Matteo M, Cicinelli E, Greco P, Massenzio F, Baldini D, Falagario T, Rosenberg P, Castellana L, Specchia G, Liso A. Abnormal pattern of lymphocyte subpopulations in the endometrium of infertile women with chronic endometritis. Am J Reprod Immunol. 2009 May;61(5):322-9. doi: 10.1111/j.1600-0897.2009.00698.x.
- Kitaya K, Yasuo T. Immunohistochemistrical and clinicopathological characterization of chronic endometritis. Am J Reprod Immunol. 2011 Nov;66(5):410-5. doi: 10.1111/j.1600-0897.2011.01051.x.
- Tortorella C, Piazzolla G, Matteo M, Pinto V, Tinelli R, Sabbà C, Fanelli M, Cicinelli E. Interleukin-6, interleukin-1β, and tumor necrosis factor α in menstrual effluents as biomarkers of chronic endometritis. Fertil Steril. 2014 Jan;101(1):242-7. doi: 10.1016/j.fertnstert.2013.09.041.
- Maybin JA, Critchley HO, Jabbour HN. Inflammatory pathways in endometrial disorders. Mol Cell Endocrinol. 2011;335(1):42-51. doi: 10.1016/j.mce.2010.08.006.
- Kungurtseva EA, Darenskaya MA, Nemchenko UM, Leshchenko OYa. [Oropharyngeal biocenosis in women with chronic endometrial inflammation and reproductive disorders]. Infectious Diseases. 2019;17(4): 92-97. [Article in Russian].
- Sidorova IS, Makarov IO, Unanyan AL, Vlasov RS, Karpov DV. [Pathogenesis and pathogenetically based therapy of chronic endometritis (Clinical lecture)].Obstetrics, Gynecology and Reproduction. 2010;3:21-24. [Article in Russian].
- Nalaboff KM, Pellerito JS, Ben-Levi E. Imaging the endometrium: disease and normal variants. Radiographics. 2001 Nov-Dec;21(6):1409-24. doi: 10.1148/radiographics.21.6.g01nv211409.
- Kuznetsova AV. Khronicheskiĭ éndometrit [Chronic endometritis]. Arkh Patol. 2000 May-Jun;62(3):48-52. [Article in Russian].
- Greenwood SM, Moran JJ. Chronic endometritis: morphologic and clinical observations. Obstet Gynecol. 1981 Aug;58(2):176-84. .
- Bayer-Garner IB, Korourian S. Plasma cells in chronic endometritis are easily identified when stained with syndecan-1. Mod Pathol. 2001 Sep;14(9):877-9. doi: 10.1038/modpathol.3880405.
- Kasius JC, Fatemi HM, Bourgain C, Sie-Go DM, Eijkemans RJ, Fauser BC, Devroey P, Broekmans FJ. The impact of chronic endometritis on reproductive outcome. Fertil Steril. 2011;96(6):1451-6. doi: 10.1016/j.fertnstert.2011.09.039.
- Smith M, Hagerty KA, Skipper B, Bocklage T. Chronic endometritis: a combined histopathologic and clinical review of cases from 2002 to 2007. Int J Gynecol Pathol. 2010 Jan;29(1):44-50. doi: 10.1097/PGP.0b013e3181ae81bb.
- Inoue T, Moran I, Shinnakasu R, Phan TG, Kurosaki T. Generation of memory B cells and their reactivation. Immunol Rev. 2018 May;283(1):138-149. doi: 10.1111/imr.12640.
- Hoyer BF, Radbruch A. Protective and pathogenic memory plasma cells. Immunol Lett. 2017 Sep;189:10-12. doi: 10.1016/j.imlet.2017.04.014. Epub 2017 Apr 25.
- Kolesnikova LI, Grebenkina LA, Darenskaya MA, Vlasov BYa. [Oxidative stress as nonspecific pathogenetic link of reproductive disorders (systematic review)]. Bulletin of the Siberian Branch of the Russian Academy of Medical Sciences. 2012;32(1):58-66. [Article in Russian].
- Kozlov VA. [Selection of cells in the thymus and homeostatic cell proliferation in the periphery during infectious processes]. Infection and Immunity. 2019; 9(5–6):629-638. [Article in Russian].
- Trunova LA, Gorbenko OM, Shvayuk AP, Obukhova OO, Trunov AN. [Features of the immune response in pubertal girls with chronic infectious and inflammatory diseases of the pelvic organs in remission]. International Journal on Immunorehabilitation. 2010;12(2):93-96. [Article in Russian].
- Moskalev AV, Sboychakov VB, Rudoy AS. General immunology with the basics of clinical immunology. Moscow; 2015:352. [In Russian].
- Joyce S. Natural T cells: cranking up the immune system by prompt cytokine secretion. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):6933-5. doi: 10.1073/pnas.97.13.6933.
- Yarilin AA. Immunology: textbook. M.: GEOTAR-Media. 2010:749. [In Russian].
- Johnston-MacAnanny EB, Hartnett J, Engmann LL, Nulsen JC, Sanders MM, Benadiva CA. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil Steril. 2010 Feb;93(2):437-41. doi: 10.1016/j.fertnstert.2008.12.131.
- Danusevich I.N. [Cytokine-hormonal interactions in chronic endometritis in women with reproductive disorders]. Voprosy Ginekologii Akusherstva i Perinatologii. 2015;14(4):42-48. [Article in Russian].
- Wira CR, Rossoll RM. Oestradiol regulation of antigen presentation by uterine stromal cells: role of transforming growth factor-beta production by epithelial cells in mediating antigen-presenting cell function. Immunology. 2003 Jul;109(3):398-406. doi: 10.1046/j.1365-2567.2003.01670.x.
- Herath S, Fischer DP, Werling D, Williams EJ, Lilly ST, Dobson H, Bryant CE, Sheldon IM. Expression and function of Toll-like receptor 4 in the endometrial cells of the uterus. Endocrinology. 2006 Jan;147(1):562-70. doi: 10.1210/en.2005-1113.
- Tanikawa M, Acosta TJ, Fukui T, Murakami S, Korzekwa A, Skarzynski DJ, Piotrowska KK, Park CK, Okuda K. Regulation of prostaglandin synthesis by interleukin-1alpha in bovine endometrium during the estrous cycle. Prostaglandins Other Lipid Mediat. 2005 Dec;78(1-4):279-90. doi: 10.1016/j.prostaglandins.2005.09.003.
- Simbirtsev AS. Cytokines: classification and biological functions. [Cytokines and Inflammation]. 2004; 3(2):16-22. [Article in Russian].
- Kungurtseva EA, Belkova NL, Prefix AA, Ivanova EI, Darenskaya MA, Serdyuk LV, Leshchenko OYa. [The structure of opportunistic microbiota of nasopharynx and vaginal tract in women with reproduction disorders and chronic endometritis]. Russian Clinical Laboratory Diagnostics. 2017;62(4):252-256. [Article in Russian].
- Bukharin OV. [From persistence to symbiosis of microorganisms]. Zhurnal Mikrobiologii, Epidemiologii i Immunobiologii. 2012;4:4-9. [Article in Russian].
- Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006 Feb 24;124(4):783-801. doi: 10.1016/j.cell.2006.02.015.
- Beutler B. Inferences, questions and possibilities in Toll-like receptor signalling. Nature. 2004 Jul 8;430(6996):257-63. doi: 10.1038/nature02761.
- Burger D, Dayer JM. Cytokines, acute-phase proteins, and hormones: IL-1 and TNF-alpha production in contact-mediated activation of monocytes by T lymphocytes. Ann N Y Acad Sci. 2002 Jun;966:464-73. doi: 10.1111/j.1749-6632.2002.tb04248.x.
- Cole AM, Ganz T, Liese AM, Burdick MD, Liu L, Strieter RM. Cutting edge: IFN-inducible ELR- CXC chemokines display defensin-like antimicrobial activity. J Immunol. 2001 Jul 15;167(2):623-7. doi: 10.4049/jimmunol.167.2.623.
- Fournier B, Philpott DJ. Recognition of Staphylococcus aureus by the innate immune system. Clin Microbiol Rev. 2005 Jul;18(3):521-40. doi: 10.1128/CMR.18.3.521-540.2005.
- Wang JE, Jørgensen PF, Almlöf M, Thiemermann C, Foster SJ, Aasen AO, Solberg R. Peptidoglycan and lipoteichoic acid from Staphylococcus aureus induce tumor necrosis factor alpha, interleukin 6 (IL-6), and IL-10 production in both T cells and monocytes in a human whole blood model. Infect Immun. 2000 Jul;68(7):3965-70. doi: 10.1128/iai.68.7.3965-3970.2000.
- Terzieva VI, Popova DN, Elenkov II. IFN-γ Attenuates Spontaneous Lymphocyte Proliferation by Fuelling Regulatory T Cells in HIV-1-Infected Patients. Viral Immunol. 2017 Apr;30(3):157-166. doi: 10.1089/vim.2016.0075.
- Conti P, DiGioacchino M. MCP-1 and RANTES are mediators of acute and chronic inflammation. Allergy Asthma Proc. 2001 May-Jun;22(3):133-7. doi: 10.2500/108854101778148737.
- Zhu D, Yang DY, Guo YY, Zheng YF, Li JL, Wang B, Tao Y, Jonas JB. Intracameral interleukin 1β, 6, 8, 10, 12p, tumor necrosis factor α and vascular endothelial growth factor and axial length in patients with cataract. PLoS One. 2015 Feb 13;10(2):e0117777. doi: 10.1371/journal.pone.0117777.
- Tagashira Y, Taniguchi F, Harada T, Ikeda A, Watanabe A, Terakawa N. Interleukin-10 attenuates TNF-alpha-induced interleukin-6 production in endometriotic stromal cells. Fertil Steril. 2009 May;91(5 Suppl):2185-92. doi: 10.1016/j.fertnstert.2008.04.052.
- Marth CD, Firestone SM, Glenton LY, Browning GF, Young ND, Krekeler N. Oestrous cycle-dependent equine uterine immune response to induced infectious endometritis. Vet Res. 2016 Nov 8;47(1):110. doi: 10.1186/s13567-016-0398-x.
- Medvedeva PA, Dzhioev YuP, Popkova SM, Danusevich IN. [The structure of species diversity of lactobacilli from the vaginal biotope of women living in Irkutsk]. Izvestia Irkutsk State University, 2012;5(1):11-17. [Article in Russian].
Received September 27, 2020.
Accepted November 15, 2020.
©2020 International Medical Research and Development Corporation.