mimmunМедицинская иммунологияMedical Immunology (Russia)1563-06252313-741XSPb RAACI10.15789/1563-0625-2019-4-603-616mimmun-1738Research ArticleОБЗОРЫREVIEWSРОЛЬ ГЛИКОДЕЛИНА В РЕГУЛЯЦИИ ИММУННОЙ СИСТЕМЫ В КОНТЕКСТЕ РАЗВИВАЮЩЕЙСЯ БЕРЕМЕННОСТИTHE ROLE OF GLYCODELIN IN THE REGULATION OF THE IMMUNE SYSTEM IN THE CONTEXT OF DEVELOPING PREGNANCYhttps://orcid.org/0000-0001-5784-6224БочковаМ. С.BochkovaM. S.

к.б.н., научный сотрудник лаборатории экологической иммунологии 

PhD (Biology), Research Associate, Laboratory of Ecological Immunology

Perm

krasnykh-m@mail.ruhttps://orcid.org/0000-0002-6474-1487ЗаморинаС. А.ZamorinaS. A.

д.б.н., ведущий научный сотрудник лаборатории экологической иммунологии; профессор кафедры микробиологии и иммунологии биологического факультета

 

PhD, MD (Biology), Leading Research Associate, Laboratory of Ecological Immunology; Professor, Department of Microbiology and Immunology, Faculty of Biology

Perm

mantissa7@mail.ruhttps://orcid.org/0000-0003-4581-1969ТимгановаВ. П.TimganovaV. P.

к.б.н., младший научный сотрудник лаборатории экологической иммунологии 

PhD (Biology), Junior Research Associate, Laboratory of Ecological Immunology

Perm

timganovavp@gmail.comhttps://orcid.org/0000-0002-1707-4423ХрамцовП. В.KhramtsovP. V.

к.б.н., младший научный сотрудник лаборатории экологической иммунологии; доцент кафедры микробиологии и иммунологии биологического факультета 

PhD (Biology), Junior Research Associate, Laboratory of Ecological Immunology; Associate Professor, Department of Microbiology andImmunology, Faculty of Biology

Perm

khramtsovpavel@yandex.ruРаевМ. Б.RayevM. B.

д.б.н., ведущий научный сотрудник лаборатории экологической иммунологии; профессор кафедры микробиологии и иммунологии биологического факультета 

614081, Россия, г. Пермь, ул. Голева, 13

Тел.: 8 (342) 280-77-94Факс: 8 (342) 280-92-11

MD (Biology), Leading Research Associate, Laboratory of Ecological Immunology; Professor, Department of Microbiology andImmunology, Faculty of Biology

Perm

mraev@iegm.ruИнститут экологии и генетики микроорганизмов Уральского отделения Российской академии наукРоссияInstitute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of Sciences, Branch of Perm Federal Research Center, Ural Branch, Russian Academy of SciencesRussian FederationИнститут экологии и генетики микроорганизмов Уральского отделения Российской академии наук, ФГБОУ ВПО «Пермский государственный национальный исследовательский университет»РоссияInstitute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of Sciences, Branch of Perm Federal Research Center, Ural Branch, Russian Academy of Sciences, Perm State UniversityRussian FederationИнститут экологии и генетики микроорганизмов Уральского отделения Российской академии наук, ФГБОУ ВПО «Пермский государственный национальный исследовательский университет»РоссияInstitute of Ecology and Genetics of Microorganisms, Ural Branch, Russian Academy of Sciences, Branch of Perm Federal Research Center, Ural Branch, Russian Academy of Sciences, Perm State UniversityRussian Federation201912032019214препринт603616Copyright © Бочкова М.С., Заморина С.А., Тимганова В.П., Храмцов П.В., Раев М.Б., 20192019Бочкова М.С., Заморина С.А., Тимганова В.П., Храмцов П.В., Раев М.Б.Bochkova M.S., Zamorina S.A., Timganova V.P., Khramtsov P.V., Rayev M.B.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/1738

В обзоре представлены данные о роли гликоделина А (GdA, РР14, α2-PEG, EР15, PEP, AUP, PAEP) в регуляции функций иммунной системы в контексте формирования иммунной толерантности во время беременности.

Гликоделин был впервые выделен и идентифицирован в 1976 году Петруниным Д.Д. и Татариновым Ю.С. с коллегами как новый антиген плаценты, который был назван хорионическим α2-микроглобулином. С тех пор получено огромное количество научных данных о структуре, свойствах и биологических эффектах этого гликопротеина. Этот белок имеет четыре дифференциально гликозилированные изоформы, а именно, GdA, GdF, GdC и GdS, которые секретируются в различных частях репродуктивного тракта.

Наиболее изученная изоформа, гликоделин А (GdA), секретируется децидуальным железистым эпителием, и в процессе беременности накапливается в амниотической жидкости и материнской сыворотке. Уровень GdA служит признаком фертильной функции эндометрия. GdA обладает разнонапраленными биологическими эффектами, в частности, модулирует эндокринную функцию и дифференцировку клеток трофобласта.

Роль GdA в регуляции иммунной системы заключается в ингибировании пролиферации Т- и В-лимфоцитов, подавлении цитотоксичности NK-клеток, индукции апоптоза активированных CD4+ клеток, моноцитов и NK-клеток, угнетении активности цитотоксических Т-лимфоцитов и подавление функциональной активности макрофагов и дендритных клеток. Помимо этого, GdA повышает уровень регуляторных T-лимфоцитов, сдвигает баланс Th1/Th2 в сторону Th2 и индуцирует толерантный фенотип в дендритных клетках.

Иммуномодулирующая активность GdA зависит от степени его гликозилирования, которая, в свою очередь, связана со способом получения препарата. Поэтому в обзоре проанализированы особенности иммуномодулирующего действия нативного и рекомбинантного типов гликоделина на клетки иммунной системы.

Тем не менее, суммарные эффекты GdA на клетки иммунной системы позволяют рассматривать его как один из основных факторов, формирующих иммунную толерантность организма матери к развивающемуся эмбриону. Важно также отметить, что клинические исследования выявили корреляцию между низким уровнем циркулирующего GdA с повторяющимися спонтанными абортами, что подтверждает важность этого белка в фетопротекции.

В целом, очевидно, что GdA имеет перспективы применения в биомедицине в качестве фармакологического препарата для лечения аутоиммунных заболеваний, посттрансплантационных осложнений и «перепрограммирования» аутореактивных клонов Т-лимфоцитов in vitro для дальнейшей клеточной иммунотерапии.

The review presents data on the role of glycodelin A (GdA, PP14, α2-PEG, EP15, PEP, AUP, PAEP) in regulating the functions of the immune system in the context of the formation of feto-maternal immune tolerance during pregnancy.

Glycodelin was first isolated and identified in 1976 by D.D. Petrunin. and Tatarinov Yu.S. with colleagues as a new placenta antigen, which was named chorionic α2-microglobulin. Since then, a huge amount of scientific data has been obtained on the structure, properties, and biological effects of this glycoprotein. This protein has four differentially glycosylated isoforms, namely GdA, GdF, GdC, and GdS, which are secreted in different parts of the reproductive system.

The most studied isoform, glycodelin A (GdA), is secreted by the decidual glandular epithelium and accumulates in the amniotic fluid and maternal serum during pregnancy. GdA level is a sign of endometrial fertile function. GdA has diverse biological effects, in particular, it modulates endocrine function and differentiation of trophoblast cells.

The role of GdA in the regulation of the immune system is to inhibit the proliferation of T and B lymphocytes, suppress the cytotoxicity of NK cells, induce apoptosis of activated CD4+ cells, monocytes and NK cells, inhibit the activity of cytotoxic T lymphocytes and suppress the functional activity of macrophages and dendritic cells. In addition, GdA increases the level of regulatory T cells, regulates the Th1/Th2 balance towards Th2, and induces a tolerant phenotype of dendritic cells.

The immunomodulating activity of GdA depends on the degree of its glycosylation, which, in turn, is associated with the preparation obtaining method. Therefore, the review analyzed the features of the immunomodulating effects of the native and recombinant types of glycodelin on the immune system cells.

However, the cumulative effects of GdA on the cells of the immune system make it possible to consider it as one of the main factors shaping the feto-maternal immune tolerance during pregnancy. It is also important to note that clinical studies have revealed a correlation between low levels of circulating GdA and repetitive spontaneous abortions that confirms the importance of this protein in fetoprotection.

In general, it is obvious that GdA has the potential as a medicinal preparation for autoimmune deseases treatment, post-transplant complications and in vitro “reprogramming” of autoreactive T-cell clones for further cellular immunotherapy.

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