Features of local immunity in women with endometriosis and genital infection

Introduction. External genital endometriosis is an inflammatory estrogen-dependent disease characterized by implantation and proliferation of endometrial tissue outside the uterus, accompanied by increased production of proinflammatory cytokines, prostaglandins, components of the complement, hydrolytic enzymes, increased angiogenesis and anomalies of ectopic endometrium. According to implantation theory, external genital endometriosis develops from viable endometrial cells transferred retrogradely through the fallopian tubes to the abdominal cavity during menstruation, while a disturbed local immunity is an important factor in its pathogenesis. Genital pathogens may be involved in the formation of the immune environment of the peritoneal cavity in women with endometriosis. Purpose. To study the peculiarities of local immunity in women with external genital endometriosis and genital infection pathogens.

and methods. 159 women with external genital endometriosis were examined. The total number of leukocytes, the absolute and relative number of viable cells, counts of neutrophils, macrophages and their functional activity, the level of IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IFNα, IFNγ, TNFα in the peritoneal fluid were evaluated. The study of local immunity was performed in women with endometriosis, stage 1—2 and 3—4, depending on detected genital pathogens. Chlamydia trachomatis, Ureaplasma spp., Mycoplasma genitalium, HSV1,2/CMV, high carcinogenic risk HPV were analyzed by using PCR in samples collected from the endometrium, peritoneal fluid, and endometrioid heterotopies. Statistical processing was performed by using the IBM SPSS Statistics Version 22.2 statistical analysis software package. Results. In the presence of HPV and Ureaplasma spp. in women with endometriosis, stage 1—2, the decreased functional activity of peritoneal neutrophils and macrophages was found. At 3—4 stage, a correlation analysis revealed that detected HPV and Ureaplasma spp. obtained increased both pro-inflammatory and anti-inflammatory cytokines in the peritoneum. However, the higher activity of Th-2 cells in the peritoneal fluid secreting IL-4 and IL-10 and suppressing cellular immunity, was observed in HPV-positive samples. In addition, HPV also correlated with a decreased IL-2 and IL-4 levels. Conclusions. The most prominent changes in the immunological parameters from peritoneal fluid samples were observed in case of detected genital infection pathogens, particularly HPV. Thus, immune disturbances emerged upon bacterial and viral pathogen detection may contribute to the implantation of endometrial cells in the pelvic organs and disease progression. About the authors L. F. Zaynetdinova South Ural State Medical University Email: [email protected] PhD, MD (Medicine), Associate Professor, Professor. Chelyabinsk L. F. Telesheva South Ural State Medical University Email: [email protected] PhD, MD (Medicine), Professor, Professor of the Department of Microbiology, Chelyabinsk A. V. Koryaushkina South Ural State Medical University Author for correspondence. Email: [email protected] Anna V. Koryaushkina - Obstetrician-Gynecologist. 454052, Chelyabinsk, Cherkasskaya str., 2, Phone: +7 908 047-62-67 (mobile), Fax: +7 (351) 721-82-44 Russian FederationReferences - Ашрафян Л.А., Бабаева Н.А., Антонова И.Б., Ивашин С.В., Моцкобили Т.А., Алешикова О.И., Кузнецов И.Н. Папилломавирусная инфекция и нарушение баланса эстрогеновых метаболитов как фактор риска развития рака органов женской репродуктивной системы // Онкология. Журнал им. П.А. Герцена. 2015. Т. 4, № 1. С. 5—12. - Бахтияров К.Р., Щукина А.С. Вирус папилломы человека—современный взгляд на проблему // Здоровье и образование в XXI веке. 2017. Т. 19, № 2. С. 37—42. - Глякин Д.С., Самойлова А.В., Гунин А.Г. Провоспалительные цитокины у больных раком эндометрия // Проблемы репродукции. 2012. Т. 18, № 1. С. 35—37. - Савченко А.А., Цхай В.Б., Круглова Д.Ю., Борисов А.Г. Иммунологические показатели при моноинфекции вирусом папилломы человека и сочетанной папилломавирусной и урогенитальной инфекции // Инфекция и иммунитет. 2014. Т. 4, № 3. С. 241—248. - Слесарева К.В., Ермолова Н.В., Линде В.А., Колесникова Л.В., Томай Л.Р. К вопросу о патогенезе наружного генитального эндометриоза // Журнал фундаментальной медицины и биологии. 2013. № 1. С. 18—22. - Соколов Д.И., Кондратьева П.Г., Ярмолинская М.И., Крамарева Н.Л., Селютин А.В., Рулев В.В., Ниаури Д.А., Сельков С.А. Содержание хемокинов и цитокинов в перитонеальной жидкости больных наружным генитальным эндометриозом различной степени тяжести // Медицинская иммунология. 2007. Т. 9, № 1. С. 85—90. - Тихомиров А.Л., Манухин И.Б., Батаева А.Е. Новая концепция возможного патогенеза эндометриоза. Обоснование профилактики // Русский медицинский журнал. 2012. Т. 20, № 1. С. 6—10. - Эндометриоз: диагностика, лечение и реабилитация. Федеральные клинические рекомендации по ведению больных. М., 2016. 66 с. - Ярмолинская М.И. Цитокиновый профиль перитонеальной жидкости и периферической крови больных с наружным генитальным эндометриозом // Журнал акушерства и женских болезней. 2008. № 3. С. 30—34. - Ярмолинская М.И., Сельков С.А. Иммунокорригирующая терапия наружного генитального эндометриоза: методическое пособие для врачей. СПб.: Тактик-Студио, 2007. 35 с. - Ярмолинская М.И., Сельков С.А., Мануйлова Т.Ю., Беженарь В.Ф., Рулев В.В., Селютин А.В., Тхазаплижева С.Ш. Эффективность применения протеолитического препарата «Лонгидаза» в комбинированном лечении спаечного процесса у больных наружным генитальным эндометриозом // Иммунология. 2015. Т. 36, № 2. С. 116—121. - Barcz E., Milewski E., Dziunycz P., Kaminski P., Ploski R., Malejczyk J. Peritoneal cytokines and adhesion formation in endometriosis: an inverse association with vascular endothelial growth factor concentration. Fertil. Steril., 2012, vol. 97, no. 6, pp. 1380-1386.e1. doi: 10.1016/j.fertnstert.2012.03.057 - Bulun S.E. Endometriosis. N. Engl. J. Med., 2009, vol. 360, no. 3, pp. 268—279. doi: 10.1056/NEJMra0804690 - Campos G.B., Marques L.M., Rezende I.S., Barbosa M.S., Abrao M.S., Timenetsky J. Mycoplasma genitalium can modulate the local immune response in patients with endometriosis. Fertil. Steril., 2018, vol. 109, no. 3, pp. 549—560. doi: 10.1016/j.fertns-tert.2017.11.009 - Heidarpour M., Derakhshan M., Derakhshan-Horeh M., Kheirollahi M., Dashti S. Prevalence of high-risk human papillomavirus infection in women with ovarian endometriosis. J. Obstet. Gynaecol. Res., 2017, vol. 43, no. 1, pp. 135—139. doi: 10.1111/jog.13188 - Hou Z., Sun L., Gao L., Liao L., Mao Y., Liu J. Cytokine array analysis of peritoneal fluid between women with endometriosis of different stages and those without endometriosis. Biomarkers, 2009, vol. 14, no. 8, pp. 604— 618. doi: 10.3109/13547500903183970 - Kalu E., Sumar N., Giannopoulos T., Patel P., Croucher C., Sherriff E., Bansal A. Cytocine profiles in serum and peritoneal fluid from infertile women with and without endometriosis. J. Obstet. Gynaecol. Research., 2007, vol. 33, no. 4, pp. 490—495. doi: 10.1111/j.1447-0756.2007.00569.x - Kobayashi H., Higashiura Y., Shigetomi H., Kajihara H. Pathogenesis of endometriosis: The role of initial infection and subsequent sterile inflammation (Review). Mol. Med. Rep., 2014, vol. 9, no. 1, pp. 9—15. doi: 10.3892/mmr.2013.1755 - Li J.X., Dai S.Z., Liu H., Cao Y.M., Liu S.Q. Study on the changes of T-lymphocyte subsets in the patients with endometriosis. Zhonghua Fu Chan Ke Za Zhi., 2005, vol. 40, no. 1, pp. 17—20. - Lousse J.C., Van Langendonckt A., Defrere S., Ramos R.G., Colette S., Donnez J. Peritoneal endometriosis is an inflammatory disease. Front Biosci. (Elite Ed.), 2012, vol. 4, pp. 23—40. doi: 10.2741/e358 - Lucidi R.S., Witz C.A., Chrisco M., Binkley P.A., Shain S.A., Schenken R.S. A novel in vitro model of the early endometriosis lesion demonstrates that attachment of endometrial cells to mesothelial cells is dependent on the source of endometrial cells. Fertil Steril., 2005, vol. 84, pp. 16—21. doi: 10.1016/j.fertnstert.2004.10.058 - Matarese G., De Placido G., Nicas Y., Alviggi C. Patogenesis of endometriosis: natural immunity disfunction or autoimmune disease. Trends Mol. Med., 2003, vol. 9, no. 5, pp. 223-228. doi: 10.1016/S1471-4914(03)00051-0 - Oppelt P., Renner S.P., Strick R., Valletta D., Mehlhorn G., Fasching P.A., Beckmann M.W., Strissel P.L. Correlation of high-risk human papilloma viruses but not of herpes viruses or Chlamydia trachomatis with endometriosis lesions. Fertil. Steril., 2010, vol. 93, no. 6, pp. 1778-1786. doi: 10.1016/j.fertnstert.2008.12.061 - Podgaec S., Dias Junior J.A., Chapron C., Oliveira R.M., Baracat E.C., Abrao M.S. Th1 and Th2 ummune responses related to pelvic endometriosis. Rev. Assoc. Med. Bras., 2010, vol. 56, no. 1, pp. 92—98. doi: 10.1590/s0104-42302010000100022 - Sampson J.A. Perforating hemorrhagic (chocolate) cysts of the ovary. Arch Surg, 1921, vol. 3, no. 2, pp. 245—323. doi: 10.1001/archsurg.1921.01110080003001 - Scholl B., Bersinger N.A., Kuhn A., Mueller M.D. Correlation between symptoms of pain and peritoneal fluid inflammatory cytokine concentrations in endometriosis. Gynecol., Endocrinol., 2009, vol. 25, no. 11, pp. 701—706. doi: 10.3109/09513590903159680 - Suen J.L., Chang Y., Chiu P.R., Hsieh T.H., Hsi E., Chen Y.C., Chen Y.F., Tsai E.M. Serum level of IL-10 is increased in patients with endometriosis, and IL-10 promotes the growth of lesions in a murine model. Am. J. Pathol., 2014, vol. 184, no. 2, pp. 464—471. doi: 10.1016/j.ajpath.2013.10.023 - Ulukus M., Ulukus E.C., Goker E.N.T., Tavmergen E., Zheng W., Arici A. Expression of interleukin-8 and monocyte chemotactic protein 1 in women with endometriosis. Fertil. Steril., 2009, vol. 91, no. 3, pp. 687—693. doi: 10.1016/j.fertnstert.2007.12.067 - Velasco I., Acien P, Campos A., Acien M.I., Ruiz-Macia E. Interleukin-6 and other soluble factors in peritoneal fluid and endome-triomas and their relation to pain and aromatase expression. J. Reprod. Immunol., 2010, vol. 84, no. 2, pp. 199—205. doi: 10.1016/j.jri.2009.11.004 - Vestergaard A.L., Knudsen U.B., Munk T., Rosbach H., Bialasiewicz S., Sloots T.P., Martensen P.M., Antonsson A. Low prevalence of DNA viruses in the human endometrium and endometriosis. Arch. Virol., 2010, vol. 155, no. 5, pp. 695—703. doi: 10.1007/s00705-010-0643-y