Immunoregulatory potential of pregnancy-specific β1-glycoprotein

V P Timganova,P V Khramtsov,M S Bochkova,M B Rayev,S A Zamorina

doi:10.15789/1563-0625-ipo-2170

Abstract

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.

Highlights

The embryo, which carries half of the “foreign” to the mother’s body molecules, must cause a response from her immune system
Over the past five years, we have demonstrated the effects of a native human PSG preparation, obtained according to the author’s method, on the expression of IDO by antigen-presenting cells, T regulatory lymphocytes, Th17 cells, T cells of immune memory, as well as the regulation of the cytokine profile of these cells
PSG can increase the level of Tregs as well as their activity in vitro. If these effects of PSG are extrapolated in vivo, Tregs, in turn, suppress proliferation, activation, and effector functions of a wide range of immunocompetent cells, including CD4+, CD8+ lymphocytes, NK, NKT, B cells, and antigen-presenting cell (APC) [45]

Summary

Обзоры Reviews

Тимганова В.П.1, Бочкова М.С.1, Храмцов П.В.1, 2, Раев М.Б.1, 2, Заморина С.А.1, 2. В частности, одним из факторов, обеспечивающим иммунную толерантность при беременности, являются белки, ассоциированные с беременностью. Что PSG достоверно увеличивал уровень адаптивных Treg in vitro, а также экспрессию этими клетками CTLA-4 и GITR и продукцию IL-10. Что в отношении активности индоламин-2,3-диоксигеназы (IDO) на уровне периферических моноцитов реализуется стимулирующий эффект PSG. В отношении Th17клеток 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, TNFα). На уровне Т-клеток иммунной памяти PSG подавлял экспрессию CD25 и продукцию IL-2 этими клетками, одновременно снижая экспрессию генов Gfi, hnRNPLL, препятствуя таким образом формированию «зрелой» изоформы СD45R0. Что на уровне Т-хелперов PSG препятствовал конверсии наивных Т-клеток в терминально-дифференцированную эффекторную субпопуляцию Т-хелперов.

Роль PSG в иммунорегуляции Role of PSG in immunoregulation

Introduction

The role of PSG in the regulation of Treg differentiation

Findings

Conclusion