Актуальность. ВИЧ-инфекция является независимым фактором снижения фертильности, а также фактором риска невынашивания беременности. Имеются данные о нарушении процессов инвазии трофобласта в эндометрий, однако истинные причины снижения фертильности при ВИЧ-инфекции остаются неизвестными. Цель. Изучение экспрессии антигенов CD20, CD56 и TLR9 в биоптатах эндометрия у ВИЧ-инфицированных пациенток и эффективности нуклеоспермата натрия в качестве иммуномодулирующего средства. Материалы и методы. В исследование включены ВИЧ-инфицированные (n=12) и ВИЧ-негативные (n=22) пациентки в возрасте от 26 до 49 лет (средний возраст – 33,35±2,9 года). Проведено иммуноцитохимическое исследование (ИЦХИ) биоптатов эндометрия, взятых на 7–10-й день менструального цикла до и после лечения нуклеосперматом натрия. Курс лечения нуклеосперматом натрия составил 42 дня. Результаты. Уровни экспрессии CD56 и TLR9 у ВИЧ-инфицированных пациенток составили 7,64±0,92 и 0,33±0,18% соответственно и достоверно отличались от уровней экспрессии у серонегативных пациенток. После лечения нуклеосперматом натрия произошло снижение уровней экспрессии CD20 и CD56 и повышение уровней экспрессии TLR9 у пациенток обеих групп. Заключение. Снижение экспрессии TLR9 у ВИЧ-инфицированных пациенток может свидетельствовать об отсутствии способности врожденного иммунитета элиминировать патогены, ассоциированные с субклиническим воспалением, что коррелирует с повышением экспрессии маркеров хронического эндометрита.
Relevance. Human immunodeficiency virus (HIV) infection is an independent factor in reduced fertility and a risk factor for miscarriage. There are some date an endometrial receptivity of HIV-infected patients has changed that plays an important role in embryo invasion, but the true reasons for the decrease in fertility rate in HIV infection remain unknown. Aim. Study of the expression of CD20, CD56 and TLR9 antigens on uterine epithelial cells of HIV-infected patients and the effectiveness of treatment for chronic endometritis by sodium nucleospermate. Materials and methods. This parallel-group study was done at two centres in the Russia. Participants were adults women aged 26 to 49 years (mean age 33.35±2.9 years), who were HIV-infected (n=12) and HIV-negative (22). An immunocytochemical study of endometrial biopsies taken on the 7–10th day of the menstrual cycle before and after treatment was done. The course of treatment with sodium nucleospermate was 42 days. Results. The expression level of CD56 and TLR9 in HIV-infected patients was 7.64±0.92% and 0.33±0.18%, respectively, and significantly differed from the expression levels in HIV-seronegative patients. There was a decrease in the expression levels of CD20 and CD56 and an increase in the expression levels of TLR9 in all groups of patients after treatment with sodium nucleospermate. Conclusion. A decrease TLR9 expression on uterine epithelial cells in HIV-infected patients showing lack of ability of innate immunity to eliminate pathogens associated with subclinical inflammation and it correlates with an increase in the expression of markers of chronic endometritis. Key words: HIV-infected women, endometrium, TLR9.
1. Zaba B, Gregson S. Measuring the impact of HIV on fertility in Africa. AIDS 1998; 12 (Suppl. 1): 41–50. PubMed PMID: 9677188.
2. Favot I, Ngalula J, Mgalla Z et al. HIV infection and sexual behaviour among women with infertility in Tanzania: a hospital-based study. Int J Epidemiol 1997; 26 (2): 414–9. DOI: 10.1093/ije/26.2.414
3 Massad LS, Springer G, Jacobson L et al. Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV. AIDS 2004; 18 (2): 281–6. DOI: 10.1097/00002030-200401230-00018
4. Chirgwin KD, Feldman J, Muneyyirci-Delale O et al. Menstrual function in human immunodeficiency virus-infected women without acquired immunodeficiency syndrome. J Acquir Immune Defic Syndr Hum Retrovirol 1996; (5): 489–94. DOI: 10.1097/00042560-199608150-00008
5. Cejtin HE, Kalinowski A, Bacchetti P et al. Effects of human immunodeficiency virus on protracted amenorrhea and ovarian dysfunction. Obstet Gynecol 2006; 108 (6): 1423–31. DOI: 10.1097/01.AOG.0000245442.29969.5c
6. Clark RA, Mulligan K, Stamenovic E et al. Frequency of anovulation and early menopause among women enrolled in selected adult AIDS clinical trials group studies. J Infect Dis 2001; 184 (10): 1325–7. DOI: 10.1086/323999
7. Seifer DB, Golub ET, Lambert-Messerlian G et al. Biologic markers of ovarian reserve and reproductive aging: application in a cohort study of HIV infection in women. Fertil Steril 2007; 88 (6): 1645–52. DOI: 10.1016/j.fertnstert.2007.01.122
8. Coll O, Lopez M, Vidal R et al. Fertility assessment in non-infertile HIV-infected women and their partners. Reprod Biomed Online 2007; 14 (4): 488–94. DOI: 10.1016/s1472-6483(10)60897-8
9. Gilbert RO. Symposium review: Mechanisms of disruption of fertility by infectious diseases of the reproductive tract. J Dairy Sci 2019; 102 (4): 3754–65. DOI: 10.3168/jds.2018-15602
10. Тапильская Н.И. Роль иммунной системы в патогенезе невынашивания беременности. Предпосылки для фармакологической коррекции. Обзоры по клинической фармакологии и лекарственной терапии. 2002; 1 (2): 15–26.
[Tapil'skaia N.I. Rol' immunnoi sistemy v patogeneze nevynashivaniia beremennosti. Predposylki dlia farmakologicheskoi korrektsii. Obzory po klinicheskoi farmakologii i lekarstvennoi terapii. 2002; 1 (2): 15–26 (in Russian).]
11. Тапильская Н.И., Савичева А.М., Рыжкова О.С., Синицына О.В. Эффективность препарата ВирутерR в лечении хронического эндометрита. Мед. алфавит. 2016; 1 (7): 10–4.
[Tapil'skaia N.I., Savicheva A.M., Ryzhkova O.S., Sinitsyna O.V. Effektivnost' preparata ViruterR v lechenii khronicheskogo endometrita. Med. alfavit. 2016; 1 (7): 10–4 (in Russian).]
12. Прошин С.Н., Глушаков Р.И., Семенова И.В. и др. Клинико-иммунологические критерии эффективности нуклеоспермата натрия в лечении хронического эндометрита у пациенток с бесплодием и папилломавирусной инфекцией. Экспер. и клин. фармакология. 2013; 76 (3): 27–30. DOI: 10.30906/0869-2092-2013-76-3-27-30
[Proshin S.N., Glushakov R.I., Semenova I.V. et al. Kliniko-immunologicheskie kriterii effektivnosti nukleospermata natriia v lechenii khronicheskogo endometrita u patsientok s besplodiem i papillomavirusnoi infektsiei. Eksper. i kiln. farmakologiia. 2013; 76 (3): 27–30. DOI: 10.30906/0869-2092-2013-76-3-27-30 (in Russian).]
13. Савичева А.М., Тапильская Н.И., Шипицына Е.В., Воробьева Н.Е. Бактериальный вагиноз и аэробный вагинит как основные нарушения баланса вагинальной микрофлоры: особенности диагностики и терапии. Акушерство и гинекология. 2017; 5: 24–31. DOI: 10.18565/aig.2017.5.24-31
[Savicheva A.M., Tapil'skaia N.I., Shipitsyna E.V., Vorob'eva N.E. Bakterial'nyi vaginoz i aerobnyi vaginit kak osnovnye narusheniia balansa vaginal'noi mikroflory: osobennosti diagnostiki i terapii. Akusherstvo i ginekologiia. 2017; 5: 24–31. DOI: 10.18565/aig.2017.5.24-31 (in Russian).]
14. Прошин С.Н., Глушаков Р.И., Шабанов П.Д. и др. Значение экспрессии TLR-рецепторов для выбора фармакологической коррекции патологии шейки матки и эндометрия. Клет. трансплантология и тканевая инженерия. 2011; 6 (1): 91–7.
[Proshin S.N., Glushakov R.I., Shabanov P.D. et al. Znachenie ekspressii TLR-retseptorov dlia vybora farmakologicheskoi korrektsii patologii sheiki matki i endometriia. Klet. transplantologiia i tkanevaia inzheneriia. 2011; 6 (1): 91–7 (in Russian).]
15. Bryant C, Fitzgerald KA. Molecular mechanisms involved in inflammasome activation. Trends Cell Biol 2009; 19 (9): 455–64. DOI: 10.1016/j.tcb.2009.06.002
16. Lee J, Chuang T-H, Redecke V et al. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. PNAS USA 2003; 100 (11): 6646–51. DOI: 10.1073/pnas.0631696100
17. Bahia W, Soltani I, Haddad A et al. Links between SNPs in TLR-2 and TLR-4 and idiopathic recurrent pregnancy loss. Br J Biomed Sci 2020; 77 (2): 64–8. DOI: 10.1080/09674845.2019.1687151
18. Herbst-Kralovetz MM, Quayle AJ, Ficarra M et al. Quantification and comparison of Toll-like receptor expression and responsiveness in primary and immortalized human female lower genital tract epithelia. Am J Reprod Immunol 2008; 59 (3): 212–24. DOI: 10.1111/j.1600-0897.2007.00566.x
19. Pioli PA, Amiel E, Schaefer TM et al. Differential expression of Toll-like receptors 2 and 4 in tissues of the human female reproductive tract. Infect Immun 2004; 72 (10): 5799–806. DOI: 10.1128/IAI.72.10.5799-5806.2004
20. Hirata T, Osuga Y, Hamasaki K et al. Expression of Toll-like receptors 2, 3, 4, and 9 genes in the human endometrium during the menstrual cycle. J Reprod Immunol 2007; 72 (1–2): 53–60. DOI: 10.1016/j.jri.2006.11.004
21. Lin Z, Xu J, Jin X et al. Modulation of expression of Toll-like receptors in the human endometrium. Am J Reprod Immunol 2009; 61 (5): 338–45. DOI: 10.1111/j.1600-0897.2009.00700.x
22. Aflatoonian R, Tuckerman E, Elliott SL et al. Menstrual cycle-dependent changes of Toll-like receptors in endometrium. Hum Reprod 2007; 22 (2): 586–93. DOI: 10.1093/humrep/del388
23. Ulevitch RJ. Immunology: toll gates for pathogen selection. Nature 1999; 401 (6755): 755–6. DOI: 10.1038/44490
24. Andersen JM, Ak-khairy D, Ingalls RR. Innate immunity at the mucosal surface: role of Toll-like receptor 3 and Toll-like receptor 9 in cervical epithelial cell responses to microbial pathogens. Biol Reprod 2006; 74 (5): 824–31. DOI: 10.1095/biolreprod.105.048629
25. Harwani SC, Lurain NS, Zariffard MR, Spear GT. Differential inhibition of human cytomegalovirus (HCMV) by Toll-like receptor ligands by interferon-beta in human foreskin fibroblasts and cervical tissue. Virol J 2007; 4: Article 133. DOI: 10.1186/1743-422X-4-133
26. Askra S, Kalla M, Delecluse H-J et al. Toll-like receptor agonist synergistically increase proliferation and activation of B cells by Epstein–Barr virus. J Virology 2010; 84 (7): 3612–23. DOI: 10.1128/JVI.01400-09
27. Nagai Y, Akashi S, Nagafuku M et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immun 2002; 3 (7): 667–72. DOI: 10.1038/ni809
________________________________________________
1. Zaba B, Gregson S. Measuring the impact of HIV on fertility in Africa. AIDS 1998; 12 (Suppl. 1): 41–50. PubMed PMID: 9677188.
2. Favot I, Ngalula J, Mgalla Z et al. HIV infection and sexual behaviour among women with infertility in Tanzania: a hospital-based study. Int J Epidemiol 1997; 26 (2): 414–9. DOI: 10.1093/ije/26.2.414
3 Massad LS, Springer G, Jacobson L et al. Pregnancy rates and predictors of conception, miscarriage and abortion in US women with HIV. AIDS 2004; 18 (2): 281–6. DOI: 10.1097/00002030-200401230-00018
4. Chirgwin KD, Feldman J, Muneyyirci-Delale O et al. Menstrual function in human immunodeficiency virus-infected women without acquired immunodeficiency syndrome. J Acquir Immune Defic Syndr Hum Retrovirol 1996; (5): 489–94. DOI: 10.1097/00042560-199608150-00008
5. Cejtin HE, Kalinowski A, Bacchetti P et al. Effects of human immunodeficiency virus on protracted amenorrhea and ovarian dysfunction. Obstet Gynecol 2006; 108 (6): 1423–31. DOI: 10.1097/01.AOG.0000245442.29969.5c
6. Clark RA, Mulligan K, Stamenovic E et al. Frequency of anovulation and early menopause among women enrolled in selected adult AIDS clinical trials group studies. J Infect Dis 2001; 184 (10): 1325–7. DOI: 10.1086/323999
7. Seifer DB, Golub ET, Lambert-Messerlian G et al. Biologic markers of ovarian reserve and reproductive aging: application in a cohort study of HIV infection in women. Fertil Steril 2007; 88 (6): 1645–52. DOI: 10.1016/j.fertnstert.2007.01.122
8. Coll O, Lopez M, Vidal R et al. Fertility assessment in non-infertile HIV-infected women and their partners. Reprod Biomed Online 2007; 14 (4): 488–94. DOI: 10.1016/s1472-6483(10)60897-8
9. Gilbert RO. Symposium review: Mechanisms of disruption of fertility by infectious diseases of the reproductive tract. J Dairy Sci 2019; 102 (4): 3754–65. DOI: 10.3168/jds.2018-15602
10. Tapil'skaia N.I. Rol' immunnoi sistemy v patogeneze nevynashivaniia beremennosti. Predposylki dlia farmakologicheskoi korrektsii. Obzory po klinicheskoi farmakologii i lekarstvennoi terapii. 2002; 1 (2): 15–26 (in Russian).
11. Tapil'skaia N.I., Savicheva A.M., Ryzhkova O.S., Sinitsyna O.V. Effektivnost' preparata ViruterR v lechenii khronicheskogo endometrita. Med. alfavit. 2016; 1 (7): 10–4 (in Russian).
12. Proshin S.N., Glushakov R.I., Semenova I.V. et al. Kliniko-immunologicheskie kriterii effektivnosti nukleospermata natriia v lechenii khronicheskogo endometrita u patsientok s besplodiem i papillomavirusnoi infektsiei. Eksper. i kiln. farmakologiia. 2013; 76 (3): 27–30. DOI: 10.30906/0869-2092-2013-76-3-27-30 (in Russian).
13. Savicheva A.M., Tapil'skaia N.I., Shipitsyna E.V., Vorob'eva N.E. Bakterial'nyi vaginoz i aerobnyi vaginit kak osnovnye narusheniia balansa vaginal'noi mikroflory: osobennosti diagnostiki i terapii. Akusherstvo i ginekologiia. 2017; 5: 24–31. DOI: 10.18565/aig.2017.5.24-31 (in Russian).
14. Proshin S.N., Glushakov R.I., Shabanov P.D. et al. Znachenie ekspressii TLR-retseptorov dlia vybora farmakologicheskoi korrektsii patologii sheiki matki i endometriia. Klet. transplantologiia i tkanevaia inzheneriia. 2011; 6 (1): 91–7 (in Russian).
15. Bryant C, Fitzgerald KA. Molecular mechanisms involved in inflammasome activation. Trends Cell Biol 2009; 19 (9): 455–64. DOI: 10.1016/j.tcb.2009.06.002
16. Lee J, Chuang T-H, Redecke V et al. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. PNAS USA 2003; 100 (11): 6646–51. DOI: 10.1073/pnas.0631696100
17. Bahia W, Soltani I, Haddad A et al. Links between SNPs in TLR-2 and TLR-4 and idiopathic recurrent pregnancy loss. Br J Biomed Sci 2020; 77 (2): 64–8. DOI: 10.1080/09674845.2019.1687151
18. Herbst-Kralovetz MM, Quayle AJ, Ficarra M et al. Quantification and comparison of Toll-like receptor expression and responsiveness in primary and immortalized human female lower genital tract epithelia. Am J Reprod Immunol 2008; 59 (3): 212–24. DOI: 10.1111/j.1600-0897.2007.00566.x
19. Pioli PA, Amiel E, Schaefer TM et al. Differential expression of Toll-like receptors 2 and 4 in tissues of the human female reproductive tract. Infect Immun 2004; 72 (10): 5799–806. DOI: 10.1128/IAI.72.10.5799-5806.2004
20. Hirata T, Osuga Y, Hamasaki K et al. Expression of Toll-like receptors 2, 3, 4, and 9 genes in the human endometrium during the menstrual cycle. J Reprod Immunol 2007; 72 (1–2): 53–60. DOI: 10.1016/j.jri.2006.11.004
21. Lin Z, Xu J, Jin X et al. Modulation of expression of Toll-like receptors in the human endometrium. Am J Reprod Immunol 2009; 61 (5): 338–45. DOI: 10.1111/j.1600-0897.2009.00700.x
22. Aflatoonian R, Tuckerman E, Elliott SL et al. Menstrual cycle-dependent changes of Toll-like receptors in endometrium. Hum Reprod 2007; 22 (2): 586–93. DOI: 10.1093/humrep/del388
23. Ulevitch RJ. Immunology: toll gates for pathogen selection. Nature 1999; 401 (6755): 755–6. DOI: 10.1038/44490
24. Andersen JM, Ak-khairy D, Ingalls RR. Innate immunity at the mucosal surface: role of Toll-like receptor 3 and Toll-like receptor 9 in cervical epithelial cell responses to microbial pathogens. Biol Reprod 2006; 74 (5): 824–31. DOI: 10.1095/biolreprod.105.048629
25. Harwani SC, Lurain NS, Zariffard MR, Spear GT. Differential inhibition of human cytomegalovirus (HCMV) by Toll-like receptor ligands by interferon-beta in human foreskin fibroblasts and cervical tissue. Virol J 2007; 4: Article 133. DOI: 10.1186/1743-422X-4-133
26. Askra S, Kalla M, Delecluse H-J et al. Toll-like receptor agonist synergistically increase proliferation and activation of B cells by Epstein–Barr virus. J Virology 2010; 84 (7): 3612–23. DOI: 10.1128/JVI.01400-09
27. Nagai Y, Akashi S, Nagafuku M et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immun 2002; 3 (7): 667–72. DOI: 10.1038/ni809
1 ФГБОУ ВО «Санкт-Петербургский государственный педиатрический медицинский университет» Минздрава России, Санкт-Петербург, Россия;
2 ФГБНУ «Научно-исследовательский институт акушерства, гинекологии и репродуктологии им. Д.О. Отта», Санкт-Петербург, Россия;
3 ФГБВОУ ВО «Военно-медицинская академия им. С.М. Кирова» Минобороны России, Санкт-Петербург, Россия;
4 ФГБОУ ВО «Санкт-Петербургский государственный университет», Санкт-Петербург, Россия
*ririna-1979@yandex.ru
________________________________________________
Irina N. Vorobtsova*1, Natalya I. Tapilskaya1,2, Elena S. Orlova3, Nikolay N. Rukhlyada1, Sergei N. Proshin4, Ruslan I. Glushakov1,3
1 Saint Petersburg State Pediatric Medical University, Saint Petersburg, Russia;
2 Ott Research Institute of Obstetrics, Gynecology and Reproductology, Saint Petersburg, Russia;
3 Kirov Military Medical Academy, Saint Petersburg, Russia;
4 Saint Petersburg State University, Saint Petersburg, Russia
*ririna-1979@yandex.ru