mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-IPO-2170mimmun-2170Research ArticleОБЗОРЫREVIEWSИммунорегуляторный потенциал трофобластического β1-гликопротеинаImmunoregulatory potential of pregnancy-specific β1-glycoproteinhttps://orcid.org/0000-0003-4581-1969ТимгановаВ. П.TimganovaV. P.

Валерия Павловна Тимганова — кандидат биологических наук, научный сотрудник лаборатории экологической иммунологии.

Пермь

Timganova V.P., PhD (Biology), Research Associate, Laboratory of Ecological Immunology.

Perm

timganovavp@gmail.comhttps://orcid.org/0000-0001-5784-6224БочковаМ. С.BochkovaM. S.

Мария Станиславовна Бочкова — кандидат биологических наук, научный сотрудник лаборатории экологической иммунологии.

Пермь

Bochkova M.S., PhD (Biology), Research Associate, Laboratory of Ecological Immunology.

Perm

krasnykh-m@mail.ruhttps://orcid.org/0000-0002-1707-4423РаевМ. Б.RayevM. B.

Михаил Борисович Раев — доктор биологических наук, ведущий научный сотрудник лаборатории экологической иммунологии Институт экологии и генетики микроорганизмов Уральского отделения РАН; профессор кафедры микробиологии и иммунологии ПГНИУ.

Пермь

Rayev M.B., PhD, MD (Biology), Leading Research Associate, Laboratory of Ecological Immunology, Institute of Ecology and Genetics of Microorganisms; Professor, Department of Microbiology and Immunology, PSU.

Perm

khramtsovpavel@yandex.ruhttps://orcid.org/0000-0001-6882-4928ХрамцовП. В.KhramtsovP. V.

Павел Викторович Храмцов — кандидат биологических наук, младший научный сотрудник лаборатории экологической иммунологии, Институт экологии и генетики микроорганизмов Уральского отделения РАН; доцент кафедры микробиологии и иммунологии ПГНИУ.

Пермь

Khramtsov P.V, PhD (Biology), Junior Research Associate, Laboratory of Ecological Immunology, Institute of Ecology and Genetics of Microorganisms; Associate Professor, Department of Microbiology and Immunology, PSU.

Perm

mraev@iegm.ruЗаморинаС. А.ZamorinaS. A.

Светлана Анатольевна Заморина — доктор биологических наук, ведущий научный сотрудник лаборатории экологической иммунологии, Институт экологии и генетики микроорганизмов Уральского отделения РАН; профессор кафедры микробиологии и иммунологии ПГНИУ.

614081, Пермь, ул. Голева, 13. Тел.: 8(342) 280-77-94. Факс: 8 (342) 280-92-11

Zamorina S.A., PhD, MD (Biology), Leading Research Associate, Laboratory of Ecological Immunology, Institute of Ecology and Genetics of Microorganisms; Professor, Department of Microbiology and Immunology, PSU.

614081, Perm, Golev str., 13. Phone: 7(342) 280-77-94. Fax: 7 (342) 280-92-11

mantissa7@mail.ruИнститут экологии и генетики микроорганизмов, Уральское отделение Российской академии наукРоссияInstitute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of SciencesRussian FederationИнститут экологии и генетики микроорганизмов, Уральское отделение Российской академии наук; ФГБОУВО Пермский государственный национальный исследовательский университетРоссияInstitute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of Sciences; Perm State UniversityRussian Federation202120062021233455468Copyright © Тимганова В.П., Бочкова М.С., Раев М.Б., Храмцов П.В., Заморина С.А., 20212021Тимганова В.П., Бочкова М.С., Раев М.Б., Храмцов П.В., Заморина С.А.Timganova V.P., Bochkova M.S., Rayev M.B., Khramtsov P.V., Zamorina S.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.mimmun.ru/mimmun/article/view/2170

Эмбрион, являясь наполовину «чужеродным» в антигенном отношении организмом, должен вызывать ответную реакцию иммунной системы матери. Однако в процессе эволюции сформировались механизмы, обеспечивающие успешное развитие беременности. В частности, одним из факторов, обеспечивающим иммунную толерантность при беременности, являются белки, ассоциированные с беременностью. Трофобластический β 1-гликопротеин (PSG, PSG1; SP1; PS G1) является доминантным фетоплацентарным белком, который продуцируется клетками цито- и синцитиотро-фобласта и обладает иммуносупрессивными свойствами. Наш авторский коллектив владеет собственной запатентованной методикой получения нативного препарата PSG человека из сыворотки крови беременных женщин, который представляет собой смесь PSG1, PSG3, PSG7, PSG9, а также их изоформ и прекурсоров. В данном обзоре представлен анализ собственных результатов за период с 2015 по 2020 г. Изучали иммунорегуляторный эффект полученного препарата PSG в концентрациях, сопоставимыми с беременностью (1, 10, 100 мкг/мл), объектами исследования служили клетки периферической крови, полученные от небеременных женщин. Было установлено, что PSG достоверно увеличивал уровень адаптивных Treg in vitro, а также экспрессию этими клетками CTLA-4 и GITR и продукцию IL-10. Показано, что в отношении активности индоламин-2,3-диоксигеназы (IDO) на уровне периферических моноцитов реализуется стимулирующий эффект PSG. В отношении Th17-клеток было продемонстрировано, что PSG способен подавлять дифференцировку и пролиферацию этих клеток, а также продукцию ими ключевых провоспалительных цитокинов (IL-8, IL-10, IL-17, IFNγ, MCP-1, TNF α). На уровне Т-клеток иммунной памяти PSG подавлял экспрессию CD25 и продукцию IL-2 этими клетками, одновременно снижая экспрессию генов Gfi1, hnRNPLL, препятствуя таким образом формированию «зрелой» изоформы СD45R0. Было показано, что на уровне Т-хелперов PSG препятствовал конверсии наивных Т-клеток в терминально-дифференцированную эффекторную субпопуляцию Т-хелперов. При анализе влияния PSG на цитокиновый профиль иммунокомпетентных клеток было установлено, что белок преимущественно подавляет продукцию Th1-цитокинов исследуемыми типами клеток и разнонаправленно регулирует продукцию Th2 -цитокинов. Полученные результаты согласуются с общим вектором иммуносупрессии в период беременности. Таким образом, PSG является одним из факторов, не позволяющим сформироваться и реализоваться иммунному ответу на фетоплацентарные антигены.

The embryo, being half an antigenically “foreign” organism, should elicit a maternal immune response. During evolution, however, the mechanisms ensuring successful development of pregnancy have been formed. In particular, among factors providing immune tolerance during pregnancy are some proteins associated with pregnancy. The pregnancy-specific β 1-glycoprotein (PSG, PSG1; SP1; PSβG1) is a dominant fetoplacental protein produced by cyto- and syncytiotrophoblast cells, and it exhibits immunosuppressive properties. Our team of authors possesses a patented method for obtaining native human PSG preparation from blood serum of pregnant women, a mixture of PSG1, PSG3, PSG7, PSG9, and their isoforms and precursors. This review presents an analysis of our results for the period from 2015 to 2020. We studied the immunoregu-latory effects of the obtained PSG preparation at concentrations comparable to those observed in pregnancy (1, 10, 100 |ag/mL). The study was performed with peripheral blood cells obtained from non-pregnant women. It was found that PSG significantly increased the percentage of adaptive Tregs in vitro, as well as expression of CTLA-4, GITR, and production of IL-10 by these cells. It has been shown that PSG has a stimulating effect upon indoleamine-2,3-dioxygenase (IDO) activity of peripheral blood monocytes. For Th17 cells, we have demonstrated that PSG can suppress differentiation and proliferation of these cells, along with reduced production of critical proinflammatory cytokines (IL-8, IL-10, IL-17, IFNγ, MCP-1, TNF α). As for the memory T cells, PSG suppressed CD25 expression and IL-2 production by them, along with simultaneous decreased expression of Gfi1, hnRNPLL genes, thus preventing the formation of the “mature” CD45R0 isoform. PSG has been shown to inhibit naive T cells’ conversion to the terminally differentiated effector subpopulation of helper T cells. When analyzing PSG effects upon cytokine profile of immunocompetent cells, it was found that the protein predominantly suppresses the Th1 cytokine production by the studied cell types, and regulates the Th2 cytokine production in divergent manner. The results obtained are consistent with general concept of immunosuppression during pregnancy. Thus, PSG could be one of the factors preventing formation and implementation of immune response to placental antigens.

трофобластический β 1-гликопротеиниммуномодулирующие эффектыиммунокомпетентные клеткииммунная толерантность при беременностиpregnancy-specific β 1-glycoproteinimmunomodulatory effectsimmunocompetent cellsfetomaternal immune toleranceReferencesBallesteros A., Mentink-Kane M.M., Warren J., Kaplan G., Dveksler G. Induction and activation of latent transforming growth factor-pi are carried out by two distinct domains of pregnancy-pecific glycoprotein 1 (PSG1). J. Biol. Chem., 2015, Vol. 290, pp. 4422-4431.Ballesteros A., Mentink-Kane M.M., Warren J., Kaplan G., Dveksler G. Induction and activation of latent transforming growth factor-pi are carried out by two distinct domains of pregnancy-pecific glycoprotein 1 (PSG1). J. Biol. Chem., 2015, Vol. 290, pp. 4422-4431.Blois S.M., Sulkowski G., Tirado-Gonzalez I., Warren J., Freitag N., Klapp B., Rifkin D., Fuss I., Strober W., Dveksler G. Pregnancy-specific glycoprotein 1 (PSG1) activates TGF-P and prevents dextran sodium sulfate (DSS)-induced colitis in mice. Mucosal Immunol., 2014, Vol. 7, pp. 348-358.Blois S.M., Sulkowski G., Tirado-Gonzalez I., Warren J., Freitag N., Klapp B., Rifkin D., Fuss I., Strober W., Dveksler G. Pregnancy-specific glycoprotein 1 (PSG1) activates TGF-P and prevents dextran sodium sulfate (DSS)-induced colitis in mice. Mucosal Immunol., 2014, Vol. 7, pp. 348-358.Bohn H. Detection and characterization of pregnancy proteins in the human placenta and their quantitative immunochemical determination in sera from pregnant women. Arch. Gynakol., 1971, Vol. 210, pp. 440-457. (In German)Bohn H. Detection and characterization of pregnancy proteins in the human placenta and their quantitative immunochemical determination in sera from pregnant women. Arch. Gynakol., 1971, Vol. 210, pp. 440-457. (In German)Braun D., Longman R.S., Albert M.L. A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation. Blood, 2005, Vol. 106, pp. 2375-2381.Braun D., Longman R.S., Albert M.L. A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation. Blood, 2005, Vol. 106, pp. 2375-2381.Butte J.M., Lee J.S., Jesneck J. CD28 costimulation regulates genome-wide effects on alternative splicing. PLoS One, 2012, Vol. 7, no. 6, e40032. doi: 10.1371/journal.pone.0040032.Butte J.M., Lee J.S., Jesneck J. CD28 costimulation regulates genome-wide effects on alternative splicing. PLoS One, 2012, Vol. 7, no. 6, e40032. doi: 10.1371/journal.pone.0040032.Coskun M., Salem M., Pedersen J., Nielsen O.H. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol. Res., 2013, Vol. 76, pp. 1-8.Coskun M., Salem M., Pedersen J., Nielsen O.H. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol. Res., 2013, Vol. 76, pp. 1-8.Doherty L.F., Kwon H.E., Taylor H.S. Regulation of tryptophan 2,3-dioxygenase by HOXA10 enhances embryo viability through serotonin signaling. Am. J. Physiol. Endocrinol. Metab., 2011, Vol. 300, pp. 86-93.Doherty L.F., Kwon H.E., Taylor H.S. Regulation of tryptophan 2,3-dioxygenase by HOXA10 enhances embryo viability through serotonin signaling. Am. J. Physiol. Endocrinol. Metab., 2011, Vol. 300, pp. 86-93.Dong M., Ding G., Zhou J., Wang H., Zhao Y., Huang H. The effect of trophoblasts on T lymphocytes: possible regulatory effector molecules--a proteomic analysis. Cell Physiol. Biochem., 2008, Vol. 21, pp. 463-472.Dong M., Ding G., Zhou J., Wang H., Zhao Y., Huang H. The effect of trophoblasts on T lymphocytes: possible regulatory effector molecules--a proteomic analysis. Cell Physiol. Biochem., 2008, Vol. 21, pp. 463-472.Durr S., Kindler V Implication of indolamine-2,3-dioxygenase in the tolerance toward fetuses, tumors and allografts. J. Leukoc. Biol., 2013, Vol. 93, pp. 681-687.Durr S., Kindler V Implication of indolamine-2,3-dioxygenase in the tolerance toward fetuses, tumors and allografts. J. Leukoc. Biol., 2013, Vol. 93, pp. 681-687.Fallarino F., Grohmann U., Vacca C., Bianchi R., Orabona C., Spreca A., Fioretti M.C., Puccetti P. T cell apoptosis by tryptophan catabolism. Cell. Death Differ., 2002, Vol. 9, no. 10, pp. 1069-1077.Fallarino F., Grohmann U., Vacca C., Bianchi R., Orabona C., Spreca A., Fioretti M.C., Puccetti P. T cell apoptosis by tryptophan catabolism. Cell. Death Differ., 2002, Vol. 9, no. 10, pp. 1069-1077.Falcon C.R., Martinez F.F., Carranza F., Cervi L., Motran C.C. In vivo expression of recombinant pregnancy-specific glycoprotein 1a inhibits the symptoms of collagen-induced arthritis. Am. J. Reprod. Immunol., 2014, Vol. 72, pp. 527-533.Falcon C.R., Martinez F.F., Carranza F., Cervi L., Motran C.C. In vivo expression of recombinant pregnancy-specific glycoprotein 1a inhibits the symptoms of collagen-induced arthritis. Am. J. Reprod. Immunol., 2014, Vol. 72, pp. 527-533.Farber D.L., Yudanin N.A., Restifo N.P. Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol., 2014, Vol. 14, pp. 24-35.Farber D.L., Yudanin N.A., Restifo N.P. Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol., 2014, Vol. 14, pp. 24-35.Grudzinskas J.G., Gordon Y.B., Menabawey M., Lee J.N., Wadsworth J., Chard T. Identification of high-risk pregnancy by the routine measurement of pregnancy-specific beta 1-glycoprotein. Am. J. Obstet. Gynecol., 1983, Vol. 147, pp. 10-12.Grudzinskas J.G., Gordon Y.B., Menabawey M., Lee J.N., Wadsworth J., Chard T. Identification of high-risk pregnancy by the routine measurement of pregnancy-specific beta 1-glycoprotein. Am. J. Obstet. Gynecol., 1983, Vol. 147, pp. 10-12.Ha C.T., Waterhouse R., Wessells J., Wu J.A., Dveksler G.S. Binding of pregnancy-specific glycoprotein 17 to CD9 on macrophages induces secretion of IL-10, IL-6, PGE2, and TGF-beta1. J. Leukoc. Biol., 2005, Vol. 77, pp. 948-957.Ha C.T., Waterhouse R., Wessells J., Wu J.A., Dveksler G.S. Binding of pregnancy-specific glycoprotein 17 to CD9 on macrophages induces secretion of IL-10, IL-6, PGE2, and TGF-beta1. J. Leukoc. Biol., 2005, Vol. 77, pp. 948-957.Hertz J.B., Schultz-Larsen P. Human placental lactogen, pregnancy-specific 1 glycoproteins and alpha-fetoprotein in serum in threatened abortion. Int. J. Gynaecol. Obstet., 1983, Vol. 21, pp. 111-117.Hertz J.B., Schultz-Larsen P. Human placental lactogen, pregnancy-specific 1 glycoproteins and alpha-fetoprotein in serum in threatened abortion. Int. J. Gynaecol. Obstet., 1983, Vol. 21, pp. 111-117.Heyd F., ten Dam G., M5r5y T. Auxiliary splice factor U2AF26 and transcription factor Gfi1 cooperate directly in regulating CD45 alternative splicing. Nat. Immunol., 2006, Vol. 7, no. 8, pp. 859-867.Heyd F., ten Dam G., M5r5y T. Auxiliary splice factor U2AF26 and transcription factor Gfi1 cooperate directly in regulating CD45 alternative splicing. Nat. Immunol., 2006, Vol. 7, no. 8, pp. 859-867.Jones K., Ballesteros A., Mentink-Kane M., Warren J., Rattila S., Malech H., Kang E., Dveksler G. PSG9 stimulates increase in FoxP3+ regulatory T-cells through the TGF-P 1 pathway. PLoS One, 2016, Vol. 11, no. 7, e0158050. doi: 10.1371/journal.pone.0158050.Jones K., Ballesteros A., Mentink-Kane M., Warren J., Rattila S., Malech H., Kang E., Dveksler G. PSG9 stimulates increase in FoxP3+ regulatory T-cells through the TGF-P 1 pathway. PLoS One, 2016, Vol. 11, no. 7, e0158050. doi: 10.1371/journal.pone.0158050.Jones K., Bryant S., Luo J., Kiesler P., Koontz S., Warren J., Malech H., Kang E., Dveksler G. Recombinant pregnancy-specific glycoprotein 1 has a protective role in a murine model of acute graft-versus-host disease. Biol. Blood Marrow Transplant., 2019, Vol. 25, pp. 193-203.Jones K., Bryant S., Luo J., Kiesler P., Koontz S., Warren J., Malech H., Kang E., Dveksler G. Recombinant pregnancy-specific glycoprotein 1 has a protective role in a murine model of acute graft-versus-host disease. Biol. Blood Marrow Transplant., 2019, Vol. 25, pp. 193-203.Kammerer R., Zimmermann W. Coevolution of activating and inhibitory receptors within mammalian carcinoembryonic antigen families. BMC Biol., 2010, Vol. 12, pp. 4-12.Kammerer R., Zimmermann W. Coevolution of activating and inhibitory receptors within mammalian carcinoembryonic antigen families. BMC Biol., 2010, Vol. 12, pp. 4-12.Kieffer T.E., Faas M.M., Scherjon S.A., Prins J.R. Pregnancy persistently affects memory T cell populations. J. Reprod. Immunol., 2016, Vol. 119, pp. 1-8.Kieffer T.E., Faas M.M., Scherjon S.A., Prins J.R. Pregnancy persistently affects memory T cell populations. J. Reprod. Immunol., 2016, Vol. 119, pp. 1-8.Kieffer T.E., Laskewitz A., Scherjon S.A., Faas M.M., Prins J.R. Memory T Cells in Pregnancy. Front. Immunol, 2019, Vol. 10, 625. doi: 10.3389/fimmu.2019.00625.Kieffer T.E., Laskewitz A., Scherjon S.A., Faas M.M., Prins J.R. Memory T Cells in Pregnancy. Front. Immunol, 2019, Vol. 10, 625. doi: 10.3389/fimmu.2019.00625.King N., Thomas S. Molecules in focus: indoleamine 2,3-dioxygenase. Int. J. Biochem. Cell. Biol., 2007, Vol. 39, pp. 2167-2172.King N., Thomas S. Molecules in focus: indoleamine 2,3-dioxygenase. Int. J. Biochem. Cell. Biol., 2007, Vol. 39, pp. 2167-2172.Kudryashova A.V., Sotnikova N.Yu., Panov I.A., Kadyrova L.V. Differentiation of memory cells in the t-helper population in uncomplicated pregnancy and preeclampsia. Journal of Obstetrics and Women’s Diseases, 2013, Vol. 62, pp. 110-115. (In Russ.)Kudryashova A.V., Sotnikova N.Yu., Panov I.A., Kadyrova L.V. Differentiation of memory cells in the t-helper population in uncomplicated pregnancy and preeclampsia. Journal of Obstetrics and Women’s Diseases, 2013, Vol. 62, pp. 110-115. (In Russ.)Kudryavtsev I.V T cells: major populations and stages of differentiation. Russian Journal of Immunology, 2014, Vol. 8, no. 4, pp. 947-964. (In Russ.)Kudryavtsev I.V T cells: major populations and stages of differentiation. Russian Journal of Immunology, 2014, Vol. 8, no. 4, pp. 947-964. (In Russ.)La Rocca C., Carbone G.F., Longobardi S., Matarese G. The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol. Lett., 2014, Vol. 162, no. 1, Pt A, pp. 41-48.La Rocca C., Carbone G.F., Longobardi S., Matarese G. The immunology of pregnancy: regulatory T cells control maternal immune tolerance toward the fetus. Immunol. Lett., 2014, Vol. 162, no. 1, Pt A, pp. 41-48.Lin T.M., Halbert S.P., Spellacy W.N. Measurement of pregnancy associated plasma proteins during human gestation. J. Clin. Invest., 1974, Vol. 54, no. 3, pp. 576-582.Lin T.M., Halbert S.P., Spellacy W.N. Measurement of pregnancy associated plasma proteins during human gestation. J. Clin. Invest., 1974, Vol. 54, no. 3, pp. 576-582.Litvinova L.S., Gutsol A.A., Sohonevich N.A., Kofanova K.A., Khaziahmatova O.G., Shupletsova V.V., Kaygorodova E.V., Goncharov A.G. The main surface markers of the functional activity of T-lymphocytes. Medical Immunology (Russia), 2014, Vol. 6, no. 1, pp. 7-26. (In Russ.) doi: 10.15789/1563-0625-2014-1-7-26.Litvinova L.S., Gutsol A.A., Sohonevich N.A., Kofanova K.A., Khaziahmatova O.G., Shupletsova V.V., Kaygorodova E.V., Goncharov A.G. The main surface markers of the functional activity of T-lymphocytes. Medical Immunology (Russia), 2014, Vol. 6, no. 1, pp. 7-26. (In Russ.) doi: 10.15789/1563-0625-2014-1-7-26.MacDonald D.H., Scott J.M., Gemmell R.S., Mack D.S. A prospective study of three biochemical fetoplacental tests: serum human placental lactogen, pregnancy-specific beta 1 glycoproteins, and urinary estrogens, and their relationship to placental sufficiency. Am. J. Obstet. Gynecol., 1983, Vol. 147, pp. 430-436.MacDonald D.H., Scott J.M., Gemmell R.S., Mack D.S. A prospective study of three biochemical fetoplacental tests: serum human placental lactogen, pregnancy-specific beta 1 glycoproteins, and urinary estrogens, and their relationship to placental sufficiency. Am. J. Obstet. Gynecol., 1983, Vol. 147, pp. 430-436.Martinez F.F., Cervi L., Knubel C.P., Panzetta-Dutari G.M., Motran C.C. The role of pregnancy-specific glycoprotein 1a (PSG1a) in regulating the innate and adaptive immune response. Am. J. Reprod. Immunol, 2013, Vol. 69, pp. 383-394.Martinez F.F., Cervi L., Knubel C.P., Panzetta-Dutari G.M., Motran C.C. The role of pregnancy-specific glycoprotein 1a (PSG1a) in regulating the innate and adaptive immune response. Am. J. Reprod. Immunol, 2013, Vol. 69, pp. 383-394.Martinez F.F., Knubel C.P., Sanchez M.C. Pregnancy-specific glycoprotein 1a activates dendritic cells to provide signals for Th17-, Th2-, and Treg-cell polarization. Eur. J. Immunol., 2013, Vol. 42, pp. 1573-1584.Martinez F.F., Knubel C.P., Sanchez M.C. Pregnancy-specific glycoprotein 1a activates dendritic cells to provide signals for Th17-, Th2-, and Treg-cell polarization. Eur. J. Immunol., 2013, Vol. 42, pp. 1573-1584.McLellan A.S., Zimmermann W., Moore T. Conservation of pregnancy-specific glycoprotein (PSG) N domains following dependent expansions of the gene families in rodents and primates. BMC Evol. Biol., 2005, Vol. 5, pp. 39-57.McLellan A.S., Zimmermann W., Moore T. Conservation of pregnancy-specific glycoprotein (PSG) N domains following dependent expansions of the gene families in rodents and primates. BMC Evol. Biol., 2005, Vol. 5, pp. 39-57.McNeill L., Salmond R.J., Cooper J.C., Carret C.K., Cassady-Cain R.L., Roche-Molina M., Tandon P, Holmes N., Alexander D.R. The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses. Immunity, 2007, Vol. 27, no. 3, pp. 425-437.McNeill L., Salmond R.J., Cooper J.C., Carret C.K., Cassady-Cain R.L., Roche-Molina M., Tandon P, Holmes N., Alexander D.R. The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses. Immunity, 2007, Vol. 27, no. 3, pp. 425-437.Miwa N., Hayakawa S., Miyazaki S., Myojo S., Sasaki Y., Sakai M., Takikawa O., Saito S. IDO expression on decidual and peripheral blood dendritic cells and monocytes/macrophages after treatment with CTLA-4 or interferon-gamma increase in normal pregnancy but decrease in spontaneous abortion. Mol. Hum. Reprod., 2005, Vol. 12, pp. 865-870.Miwa N., Hayakawa S., Miyazaki S., Myojo S., Sasaki Y., Sakai M., Takikawa O., Saito S. IDO expression on decidual and peripheral blood dendritic cells and monocytes/macrophages after treatment with CTLA-4 or interferon-gamma increase in normal pregnancy but decrease in spontaneous abortion. Mol. Hum. Reprod., 2005, Vol. 12, pp. 865-870.Moldogazieva N.T., Mokhosoev I.M., Terentiev A.A. Pregnancy-Specific P1-Glycoproteins: combined biomarker roles, structure/function relationships and implications for drug design. Curr. Med. Chem., 2016, Vol. 23, pp. 245-267.Moldogazieva N.T., Mokhosoev I.M., Terentiev A.A. Pregnancy-Specific P1-Glycoproteins: combined biomarker roles, structure/function relationships and implications for drug design. Curr. Med. Chem., 2016, Vol. 23, pp. 245-267.Moore T., Dveksler G. Pregnancy-specific glycoproteins: complex gene families regulating maternal-fetal interactions. Int. J. Dev. Biol., 2014, Vol. 58, pp. 273-280.Moore T., Dveksler G. Pregnancy-specific glycoproteins: complex gene families regulating maternal-fetal interactions. Int. J. Dev. Biol., 2014, Vol. 58, pp. 273-280.Motran C.C., Diaz F.L., Gruppi A., Slavin D., Chatton B., Bocco J.L. Human pregnancy-specific glycoprotein 1a (PSG1a) induces alternative activation in human and mouse monocytes and suppresses the accessory cell-dependent T cell proliferation. J. Leukoc. Biol., 2002, Vol. 72, pp. 512-521.Motran C.C., Diaz F.L., Gruppi A., Slavin D., Chatton B., Bocco J.L. Human pregnancy-specific glycoprotein 1a (PSG1a) induces alternative activation in human and mouse monocytes and suppresses the accessory cell-dependent T cell proliferation. J. Leukoc. Biol., 2002, Vol. 72, pp. 512-521.Paiva P, Hannan N.J., Hincks C., Meehan K.L., Pruysers E., Dimitriadis E., Salamonsen L.A. Human chorionic gonadotrophin regulates FGF2 and other cytokines produced by human endometrial epithelial cells, providing a mechanism for enhancing endometrial receptivity. Hum. Reprod., 2011, Vol. 26, pp.1153-1162.Paiva P, Hannan N.J., Hincks C., Meehan K.L., Pruysers E., Dimitriadis E., Salamonsen L.A. Human chorionic gonadotrophin regulates FGF2 and other cytokines produced by human endometrial epithelial cells, providing a mechanism for enhancing endometrial receptivity. Hum. Reprod., 2011, Vol. 26, pp.1153-1162.Peterson A.R. Regulatory T-Cells: diverse phenotypes integral to immune homeostasis and suppression. Toxicol. Pathol., 2012, Vol. 40, no. 2, pp. 186-204.Peterson A.R. Regulatory T-Cells: diverse phenotypes integral to immune homeostasis and suppression. Toxicol. Pathol., 2012, Vol. 40, no. 2, pp. 186-204.Posiseeva L.V., Nazarov S.B., Tatarinov Yu.S. Trophoblast-specific beta-glycoprotein in obstetrics and gynecology. Ivanovo: Ivanovo Publishing, 2004. 240 p. (In Russ.)Posiseeva L.V., Nazarov S.B., Tatarinov Yu.S. Trophoblast-specific beta-glycoprotein in obstetrics and gynecology. Ivanovo: Ivanovo Publishing, 2004. 240 p. (In Russ.)Rayev M.B., Litvinova L.S., Yurova K.A., Dunets N.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Zamorina S.A. Role of the pregnancy-specific glycoprotein in regulation of the cytokine and chemokine profiles of intact mononuclear cells. Proceedings of the Academy of Sciences, 2017, Vol. 475, pp. 180-182. (In Russ.)Rayev M.B., Litvinova L.S., Yurova K.A., Dunets N.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Zamorina S.A. Role of the pregnancy-specific glycoprotein in regulation of the cytokine and chemokine profiles of intact mononuclear cells. Proceedings of the Academy of Sciences, 2017, Vol. 475, pp. 180-182. (In Russ.)Rayev M.B. A method for the isolation and purification of trophoblastic beta-1-glycoprotein. Patent of the Russian Federation No. 2367449, published on September 20, 2009, Bulletin No. 26. (In Russ.)Rayev M.B. A method for the isolation and purification of trophoblastic beta-1-glycoprotein. Patent of the Russian Federation No. 2367449, published on September 20, 2009, Bulletin No. 26. (In Russ.)Rayev M.B., Litvinova L.S., Yurova K.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Zamorina S.A. The role of pregnancy-specific glycoprotein in regulation of molecular genetic differentiation mechanisms of immune memory T cells. Medical Immunology (Russia), 2019, Vol. 21, pp. 49-58. (In Russ.) doi: 10.15789/1563-0625-2019-1-49-58.Rayev M.B., Litvinova L.S., Yurova K.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Zamorina S.A. The role of pregnancy-specific glycoprotein in regulation of molecular genetic differentiation mechanisms of immune memory T cells. Medical Immunology (Russia), 2019, Vol. 21, pp. 49-58. (In Russ.) doi: 10.15789/1563-0625-2019-1-49-58.Saito S., Nakashima A., Shima T., Ito M. Thl/Th2/Thl7 and regulatory T-cell paradigm in pregnancy. Am. J. Reprod. Immunol., 2010, Vol. 601, pp. 601-610.Saito S., Nakashima A., Shima T., Ito M. Thl/Th2/Thl7 and regulatory T-cell paradigm in pregnancy. Am. J. Reprod. Immunol., 2010, Vol. 601, pp. 601-610.Sallusto F., Geginat J., Lanzavecchia A.. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol., 2004, Vol. 22, pp. 745-763.Sallusto F., Geginat J., Lanzavecchia A.. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu. Rev. Immunol., 2004, Vol. 22, pp. 745-763.Shevach E.M. Foxp3+ T Regulatory Cells: still many unanswered questions-a perspective after 20 years of study. Front. Immunol., 2018, Vol. 9, 1048. doi: l0.3389/fimmu.20l8.0l048.Shevach E.M. Foxp3+ T Regulatory Cells: still many unanswered questions-a perspective after 20 years of study. Front. Immunol., 2018, Vol. 9, 1048. doi: l0.3389/fimmu.20l8.0l048.Shumacher A., Heinze K., Witte J., Poloski E., Linzke N., Woidacki K., Zenclussen A.C. Human chorionic gonadotropin as a central regulator of pregnancy immune tolerance. J. Immunol., 2013, Vol. 190, pp. 2650-2658.Shumacher A., Heinze K., Witte J., Poloski E., Linzke N., Woidacki K., Zenclussen A.C. Human chorionic gonadotropin as a central regulator of pregnancy immune tolerance. J. Immunol., 2013, Vol. 190, pp. 2650-2658.Snyder S.K., Wessner D.H., Wessells J.L., Waterhouse R.M., Wahl L.M., Zimmermann W., Dveksler G.S. Pregnancy-specific glycoproteins function as immunomodulators by inducing secretion of IL-10, IL-6 and TGF-betal by human monocytes. Am. J. Reprod Immunol., 2001, Vol. 45, pp. 205-216.Snyder S.K., Wessner D.H., Wessells J.L., Waterhouse R.M., Wahl L.M., Zimmermann W., Dveksler G.S. Pregnancy-specific glycoproteins function as immunomodulators by inducing secretion of IL-10, IL-6 and TGF-betal by human monocytes. Am. J. Reprod Immunol., 2001, Vol. 45, pp. 205-216.Sotnikova N.Yu. Formation of the phenomenon of immunological memory in the dynamics of the gestational process. Russian Journal of Immunology, 2010, Vol. 4 (13), no. 4. pp. 321-326. (In Russ.)Sotnikova N.Yu. Formation of the phenomenon of immunological memory in the dynamics of the gestational process. Russian Journal of Immunology, 2010, Vol. 4 (13), no. 4. pp. 321-326. (In Russ.)Tatarinov Yu.S. Trophoblast-specific betal-glycoprotein as a marker for pregnancy and malignancies. Gynecol. Obstet. Invest., 1978, Vol. 9, pp. 65-97.Tatarinov Yu.S. Trophoblast-specific betal-glycoprotein as a marker for pregnancy and malignancies. Gynecol. Obstet. Invest., 1978, Vol. 9, pp. 65-97.Tatarinov Yu.S., Masyukevich V.N. Immunochemical identification of new pl-globulin in the blood serum of pregnant wome. Bulletin of Experimental Biology and Medicine, 1970, Vol. 69, no. 6, pp. 66-69. (In Russ.)Tatarinov Yu.S., Masyukevich V.N. Immunochemical identification of new pl-globulin in the blood serum of pregnant wome. Bulletin of Experimental Biology and Medicine, 1970, Vol. 69, no. 6, pp. 66-69. (In Russ.)Temur M., Serpim G., Tuzluoglu S., Ta$g5z F.N., §ahin E., Ustunyurt E. Comparison of serum human pregnancy-specific beta-1-glycoprotein l levels in pregnant women with or without preeclampsia. J. Obstet. Gynaecol., 2020. Vol. 8, pp. 1074-1078.Temur M., Serpim G., Tuzluoglu S., Ta$g5z F.N., §ahin E., Ustunyurt E. Comparison of serum human pregnancy-specific beta-1-glycoprotein l levels in pregnant women with or without preeclampsia. J. Obstet. Gynaecol., 2020. Vol. 8, pp. 1074-1078.Terentyev A.A., Moldogazieva N.T., Komarov O.S. Study of human trophoblastic beta globulin - some results and perspectives. International Journal of Applied and Basic Research, 2009, no. 6, pp. 30-33. (In Russ.)Terentyev A.A., Moldogazieva N.T., Komarov O.S. Study of human trophoblastic beta globulin - some results and perspectives. International Journal of Applied and Basic Research, 2009, no. 6, pp. 30-33. (In Russ.)Timganova V., Bochkova M., Khramtsov P., Kochurova S., Rayev M., Zamorina S. Effects of Pregnancy-specific P-l-glycoprotein on the helper T Cell response. Arch. Biol. Sci., 2019, Vol. 71, pp. 369-378.Timganova V., Bochkova M., Khramtsov P., Kochurova S., Rayev M., Zamorina S. Effects of Pregnancy-specific P-l-glycoprotein on the helper T Cell response. Arch. Biol. Sci., 2019, Vol. 71, pp. 369-378.Timganova V., Zamorina S., Litvinova L., Todosenko N., Bochkova M., Khramtsov P., Rayev M. The effects of human pregnancy-specific pl-glycoprotein preparation on Thl7 polarization of CD4+ Cells and their cytokine profile. BMC Immunology, 2020, Vol. 21, 56. doi: l0.ll86/sl2865-020-00385-6.Timganova V., Zamorina S., Litvinova L., Todosenko N., Bochkova M., Khramtsov P., Rayev M. The effects of human pregnancy-specific pl-glycoprotein preparation on Thl7 polarization of CD4+ Cells and their cytokine profile. BMC Immunology, 2020, Vol. 21, 56. doi: l0.ll86/sl2865-020-00385-6.Topp J.D., Jackson J., Melton A.A., Lynch K.W. A cell-based screen for splicing regulators identifies hnRNP LL as a distinct signal-induced repressor of CD45 variable exon 4. RNA, 2008, Vol. 14, pp. 2038-2049.Topp J.D., Jackson J., Melton A.A., Lynch K.W. A cell-based screen for splicing regulators identifies hnRNP LL as a distinct signal-induced repressor of CD45 variable exon 4. RNA, 2008, Vol. 14, pp. 2038-2049.Warren J., Im M., Ballesteros A., Ha C., Moore T., Lambert F., Lucas S., Hinz B., Dveksler G. Activation of latent transforming growth factor-pl, a conserved function for pregnancy-specific beta l-glycoproteins. Mol. Hum. Reprod., 2018, Vol. 24, pp. 602-612.Warren J., Im M., Ballesteros A., Ha C., Moore T., Lambert F., Lucas S., Hinz B., Dveksler G. Activation of latent transforming growth factor-pl, a conserved function for pregnancy-specific beta l-glycoproteins. Mol. Hum. Reprod., 2018, Vol. 24, pp. 602-612.Wegmann T., Lin H., Guilbert L., Mosmann T.R. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol. Today, 1993, Vol. 14, pp. 353-356.Wegmann T., Lin H., Guilbert L., Mosmann T.R. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol. Today, 1993, Vol. 14, pp. 353-356.Whitcomb B.W., Schisterman E.F., Klebanoff M.A., Baumgarten M., Rhoton-Vlasak A., Luo X.C., Chegini N. Circulating chemokine levels and miscarriage. Am. J. Epidemiol., 2007, Vol. 166, pp. 323-331.Whitcomb B.W., Schisterman E.F., Klebanoff M.A., Baumgarten M., Rhoton-Vlasak A., Luo X.C., Chegini N. Circulating chemokine levels and miscarriage. Am. J. Epidemiol., 2007, Vol. 166, pp. 323-331.Wu J.A., Johnson B.L., Chen Y., Ha C., Dveksler G. Murine pregnancy-specific glycoprotein 23 induces the proangiogenic factors transforming-growth factor beta l and vascular endothelial growth factor in cell types involved in vascular remodeling in pregnancy. Biol. Reprod., 2008, Vol. 79, pp. 1054-1061.Wu J.A., Johnson B.L., Chen Y., Ha C., Dveksler G. Murine pregnancy-specific glycoprotein 23 induces the proangiogenic factors transforming-growth factor beta l and vascular endothelial growth factor in cell types involved in vascular remodeling in pregnancy. Biol. Reprod., 2008, Vol. 79, pp. 1054-1061.Wu J., Xie A., Chen W. Cytokine regulation of immune tolerance. Burns Trauma, 2014, Vol. 2, pp. 11-17.Wu J., Xie A., Chen W. Cytokine regulation of immune tolerance. Burns Trauma, 2014, Vol. 2, pp. 11-17.Wu Z., Yates A.L., Hoyne G.F., Goodnow C.C. Consequences of increased CD45RA and RC isoforms for TCR signaling and peripheral T cell deficiency resulting from heterogeneous nuclear ribonucleoprotein L-like mutation. J. Immunol., 2010, Vol. 185, pp. 231-238.Wu Z., Yates A.L., Hoyne G.F., Goodnow C.C. Consequences of increased CD45RA and RC isoforms for TCR signaling and peripheral T cell deficiency resulting from heterogeneous nuclear ribonucleoprotein L-like mutation. J. Immunol., 2010, Vol. 185, pp. 231-238.Wulff C., Weigand M., Kreienberg R., Fraser H.M. Angiogenesis during primate placentation in health and disease. Reproduction, 2003, Vol. 126, pp. 569-577.Wulff C., Weigand M., Kreienberg R., Fraser H.M. Angiogenesis during primate placentation in health and disease. Reproduction, 2003, Vol. 126, pp. 569-577.Zamorina S.A., Litvinova L.S., Yurova K.A., Dunets N.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Rayev M.B. The effect of pregnancy-specific pl-glycoprotein l on the transcription factor FOXP3 expression by immunocompetent cells. Proceedings of the Academy of Sciences, 2016, Vol. 470, no. 1, pp. 361-363. (In Russ.)Zamorina S.A., Litvinova L.S., Yurova K.A., Dunets N.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Rayev M.B. The effect of pregnancy-specific pl-glycoprotein l on the transcription factor FOXP3 expression by immunocompetent cells. Proceedings of the Academy of Sciences, 2016, Vol. 470, no. 1, pp. 361-363. (In Russ.)Zamorina S.A., Litvinova L.S., Yurova K.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Rayev M.B. Effect of pregnancy-specific pl-glycoprotein on chemokine profile of cultured T-helper and mononuclear cells. Russian Journal of Immunology, 2019, Vol. 22, no. 2-1, pp. 257-259. (In Russ.)Zamorina S.A., Litvinova L.S., Yurova K.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Rayev M.B. Effect of pregnancy-specific pl-glycoprotein on chemokine profile of cultured T-helper and mononuclear cells. Russian Journal of Immunology, 2019, Vol. 22, no. 2-1, pp. 257-259. (In Russ.)Zamorina S.A., Litvinova L.S., Yurova K.A., Dunets N.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Raev M.B. The role of trophoblastic pl-glycoprotein in the regulation of TGF-pl mRNA expression by immunocompetent cells. Russian Journal of Immunology, 2016, Vol. 10, no. 19, no. 2 (1), pp. 104-106. (In Russ.)Zamorina S.A., Litvinova L.S., Yurova K.A., Dunets N.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Raev M.B. The role of trophoblastic pl-glycoprotein in the regulation of TGF-pl mRNA expression by immunocompetent cells. Russian Journal of Immunology, 2016, Vol. 10, no. 19, no. 2 (1), pp. 104-106. (In Russ.)Zamorina S.A., Litvinova L.S., Yurova K.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Raev M.B. The role of pregnancy-specific pl-glycoprotein in regulation of the production of key cytokines determining Thl/Th2 balance. Russian Journal of Immunology, 2017, Vol. 11, pp. 129-131. (In Russ.)Zamorina S.A., Litvinova L.S., Yurova K.A., Khaziakhmatova O.G., Timganova V.P., Bochkova M.S., Khramtsov P.V., Raev M.B. The role of pregnancy-specific pl-glycoprotein in regulation of the production of key cytokines determining Thl/Th2 balance. Russian Journal of Immunology, 2017, Vol. 11, pp. 129-131. (In Russ.)Zamorina S.A., Rayev M.B. Immunomodulating effects of human pregnancy-specific pl-glycoprotein. Human Physiology, 2015, Vol. 41, no. 1, pp. 98-103. (In Russ).Zamorina S.A., Rayev M.B. Immunomodulating effects of human pregnancy-specific pl-glycoprotein. Human Physiology, 2015, Vol. 41, no. 1, pp. 98-103. (In Russ).Zamorina S.A., Rayev M.B. Role of human pregnancy-specific pi-glycoprotein in the regulation of immunological tolerance-associated factors. Proceedings of the Academy of Sciences, 2015, Vol. 460, pp. 61-63. (In Russ.)Zamorina S.A., Rayev M.B. Role of human pregnancy-specific pi-glycoprotein in the regulation of immunological tolerance-associated factors. Proceedings of the Academy of Sciences, 2015, Vol. 460, pp. 61-63. (In Russ.)Zamorina S.A., Rayev M.B. Human trophoblastic pi-glycoprotein as a differentiation factor of minor regulatory T-lymphocyte subsets (TREG, TH17). The involvement of CD9. Biochemistry (Moscow) Supplement. Series A: Membrane and Cell Biology, 2016. Vol. 10, pp. 319-327. (In Russ.)Zamorina S.A., Rayev M.B. Human trophoblastic pi-glycoprotein as a differentiation factor of minor regulatory T-lymphocyte subsets (TREG, TH17). The involvement of CD9. Biochemistry (Moscow) Supplement. Series A: Membrane and Cell Biology, 2016. Vol. 10, pp. 319-327. (In Russ.)Zamorina S.A., Timganova V.P., Bochkova M.S., Raev M.B., Khramtsov P.V. Effect of pregnancy-specific pi-glycoprotein on indoleamine-2,3-dioxygenase activity in human monocytes. Proceedings of the Academy of Sciences, 2016, Vol. 469, pp. 206-208. (In Russ.)Zamorina S.A., Timganova V.P., Bochkova M.S., Raev M.B., Khramtsov P.V. Effect of pregnancy-specific pi-glycoprotein on indoleamine-2,3-dioxygenase activity in human monocytes. Proceedings of the Academy of Sciences, 2016, Vol. 469, pp. 206-208. (In Russ.)

The authors declare that there are no conflicts of interest present.