Features of the functioning of immunological tolerance during pregnancy (literature review)
DOI:
https://doi.org/10.15574/PP.2023.93.76Keywords:
immunological tolerance, pro-inflammatory cytokines, anti-inflammatory cytokines, placental dysfunction, stages of implantation, angiogenic factors, anti-angiogenic factorsAbstract
Pregnancy is a special state in a woman’s life, which can definitely be considered an «immunological paradox», because the growth of a genetically «alien» fetus takes place in a woman’s body. Despite the direct contact between cells of fetal origin (syncytiotrophoblast) and cells of the maternal immune system, which are in excess in the decidual membrane of the uterus, rejection of the semi-allogeneic fetus does not occur. A state of permanent natural immunological tolerance, during which the body does not respond to certain antigens expressed by trophoblast cells, while maintaining the ability to respond immunologically to other immunogens is the opposite phenomenon of the immune response, it is acquired by the body during its development and is not genetically determined.
Purpose - to analyze the phasing of immunological changes in the mother’s body, which are aimed at the development and preservation of pregnancy, to specify their role in the correct flow of placental waves, prevention of the development of placental dysfunction and obstetric complications associated with it.
A review of modern medical literature on the processes of immunological changes during trophoblast invasion and placentation in early pregnancy is given. For a more detailed understanding, the influence of each link of the immune response in the process of developing immune tolerance was analyzed.
It has been established that for the development of a normal pregnancy there is a genetically programmed immune mechanism that ensures a decrease in the local and systemic immune response to the semi-alien implanted blastocyst, embryo and fetus. This is achieved through the step-by-step course of three phases of immunological shifts: the unfolded immune conflict; suppression of the immune response and intense immune conflict. The physiological course of gestation and the development of the placenta, in which the balance between the processes of neoangiogenesis and apoptosis is maintained, is ensured by adequate expression of HLA-G locus molecules by trophoblast cells, inhibition of Th1-type cytotoxic reactions against placenta cells by the mother's body. Analyzed changes in the cytokine balance, which shifts towards immunosuppressive cytokines, which suppress cellular immune reactions and stimulate the production of blocking antibodies, the quantitative composition of which can be considered decisive when carrying a genetically foreign fetus.
Consequently, a relative secondary cellular immunodeficiency is formed, which is mainly due to a deficiency of circulating T-helper/inducers, a decrease in the CD4/CD8 immunoregulatory index and suppression of the functional activity of the T-cell immune system. It has been proven that impaired immunological tolerance, trophoblast invasion and vascular remodelling processes controlled by the maternal immune system at the local and systemic levels lead to early reproductive losses, premature birth, placental dysfunction, and are associated with fetal growth retardation syndrome, pre-eclampsia and other complications.
No conflict of interests was declared by the authors.
References
Abrahams VM, Kim YM, Straszewski SL, Romero R, Mor G. (2004). Macrophages and apoptotic cell clearance during pregnancy. American journal of reproductive immunology (New York, N.Y.: 1989). 51 (4): 275-282. https://doi.org/10.1111/j.1600-0897.2004.00156.x; PMid:15212680
Alijotas-Reig J, Llurba E, Gris JM. (2014). Potentiating maternal immune tolerance in pregnancy: a new challenging role for regulatory T cells. Placenta. 35 (4): 241-248. https://doi.org/10.1016/j.placenta.2014.02.004; PMid:24581729
Ashton SV, Whitley GS, Dash PR, Wareing M, Crocker IP, Baker PN, Cartwright JE. (2005). Uterine spiral artery remodeling involves endothelial apoptosis induced by extravillous trophoblasts through Fas/FasL interactions. Arteriosclerosis, thrombosis, and vascular biology. 25 (1): 102-108. https://doi.org/10.1161/01.ATV.0000148547.70187.89; PMid:15499040 PMCid:PMC4228192
Bulmer JN, Lash GE. (2019). Uterine natural killer cells: Time for a re-appraisal? F1000Research. 8: F1000. Faculty Rev-999. https://doi.org/10.12688/f1000research.19132.1; PMid:31316752 PMCid:PMC6611138
Calleja-Agius J, Jauniaux E, Muttukrishna S. (2012). Placental villous expression of TNFα and IL-10 and effect of oxygen tension in euploid early pregnancy failure. American journal of reproductive immunology (New York, N.Y.: 1989). 67 (6): 515-525. https://doi.org/10.1111/j.1600-0897.2012.01104.x; PMid:22243719
Dosiou C, Giudice LC. (2005). Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives. Endocrine reviews. 26 (1): 44-62. https://doi.org/10.1210/er.2003-0021; PMid:15689572
Drannik GN. (2010). Klinicheskaya immunologiya i alergologiya: posobie dlya studentov, vrachey-internov, immunologov, allergologov, vrachey lechebnogo profilya vseh spetsIalnostey (4-te vid.). OOO «Poligraf plyus».
Faas MM, de Vos P. (2017). Uterine NK cells and macrophages in pregnancy. Placenta. 56: 44-52. https://doi.org/10.1016/j.placenta.2017.03.001; PMid:28284455
Faas MM, De Vos P. (2018). Innate immune cells in the placental bed in healthy pregnancy and preeclampsia. Placenta. 69: 125-133. https://doi.org/10.1016/j.placenta.2018.04.012; PMid:29748088
Faas MM, Spaans F, De Vos P. (2014). Monocytes and macrophages in pregnancy and pre-eclampsia. Frontiers in immunology. 5: 298. https://doi.org/10.3389/fimmu.2014.00298; PMid:25071761 PMCid:PMC4074993
Fournel S, Aguerre-Girr M, Huc X, Lenfant F, Alam A, Toubert A, Bensussan A, Le Bouteiller P. (2000). Cutting edge: soluble HLA-G1 triggers CD95/CD95 ligand-mediated apoptosis in activated CD8+ cells by interacting with CD8. Journal of immunology (Baltimore, Md. : 1950). 164 (12): 6100-104. https://doi.org/10.4049/jimmunol.164.12.6100; PMid:10843658
Gamliel M, Goldman-Wohl D, Isaacson B, Gur C, Stein N, Yamin R et al. (2018). Trained Memory of Human Uterine NK Cells Enhances Their Function in Subsequent Pregnancies. Immunity. 48 (5): 951-962.e5. https://doi.org/10.1016/j.immuni.2018.03.030; PMid:29768178
Gardner L, Moffett A. (2003). Dendritic cells in the human decidua. Biology of reproduction. 69 (4): 1438-1446. https://doi.org/10.1095/biolreprod.103.017574; PMid:12826583
Haistruk NA, Mazchenko OO, Nadiezhdin MV. (2012). Suchasni aspekty diahnostyky ta terapii dystresu ploda i rannikh sudynnykh porushen u vahitnykh. Zdorove zhenshchyny. 74: 98-101.
Haldar M, Murphy KM. (2014). Origin, development, and homeostasis of tissue-resident macrophages. Immunological reviews. 262 (1): 25-35. https://doi.org/10.1111/imr.12215; PMid:25319325 PMCid:PMC4203404
Hunt JS, Petroff MG, McIntire RH, Ober C. (2005). HLA-G and immune tolerance in pregnancy. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 19 (7): 681-693. https://doi.org/10.1096/fj.04-2078rev; PMid:15857883
Huppertz B, Kingdom JC. (2004). Apoptosis in the trophoblast - role of apoptosis in placental morphogenesis. Journal of the Society for Gynecologic Investigation. 11 (6): 353-362. https://doi.org/10.1016/j.jsgi.2004.06.002; PMid:15350247
Hviid TV. (2006). HLA-G in human reproduction: aspects of genetics, function and pregnancy complications. Human reproduction update. 12 (3): 209-232. https://doi.org/10.1093/humupd/dmi048; PMid:16280356
Italiani P, Boraschi D. (2014). From Monocytes to M1/M2 Macrophages: Phenotypical vs. Functional Differentiation. Frontiers in immunology. 5: 514. https://doi.org/10.3389/fimmu.2014.00514; PMid:25368618 PMCid:PMC4201108
Jetten N, Verbruggen S, Gijbels MJ, Post MJ, De Winther MP, Donners MM. (2014). Anti-inflammatory M2, but not pro-inflammatory M1 macrophages promote angiogenesis in vivo. Angiogenesis. 17 (1): 109-118. https://doi.org/10.1007/s10456-013-9381-6; PMid:24013945
Kämmerer U, Eggert AO, Kapp M, McLellan AD, Geijtenbeek TB, Dietl J, van Kooyk Y, Kämpgen E. (2003). Unique appearance of proliferating antigen-presenting cells expressing DC-SIGN (CD209) in the decidua of early human pregnancy. The American journal of pathology. 162 (3): 887-896. https://doi.org/10.1016/S0002-9440(10)63884-9; PMid:12598322
Kämmerer U, Schoppet M, McLellan AD, Kapp M, Huppertz HI, Kämpgen E, Dietl J. (2000). Human decidua contains potent immunostimulatory CD83(+) dendritic cells. The American journal of pathology. 157(1): 159-169. https://doi.org/10.1016/S0002-9440(10)64527-0; PMid:10880386
Kanai T, Fujii T, Kozuma S, Miki A, Yamashita T, Hyodo H, Unno N, Yoshida S, Taketani Y. (2003). A subclass of soluble HLA-G1 modulates the release of cytokines from mononuclear cells present in the decidua additively to membrane-bound HLA-G1. Journal of reproductive immunology. 60 (2): 85-96. https://doi.org/10.1016/S0165-0378(03)00096-2; PMid:14638437
Kazimirko NK, Akimova EE, Zavatskiy VYu, Polyakov AS, Tatarenko DP. (2014). Immunologiya fiziologicheskoy beremennosti. Molodiy vcheniy. 3: 132-138.
Kuznetsova LV, Babadzhan VD, Kharchenko NV et al. (2013). Imunolohiia. L.V. Kuznetsova, V.D. Babadzhan, N. V. Kharchenko, Ed. TOV «Merkiuri Podillia».
Lanier LL. (2005). NK cell recognition. Annual review of immunology. 23: 225-274. https://doi.org/10.1146/annurev.immunol.23.021704.115526; PMid:15771571
Le Bouteiller P, Fons P, Herault JP, Bono F, Chabot S, Cartwright JE, Bensussan A. (2007). Soluble HLA-G and control of angiogenesis. Journal of reproductive immunology. 76 (1-2): 17-22. https://doi.org/10.1016/j.jri.2007.03.007; PMid:17467060
Lyamina SV, Malyishev IYu. (2014). Polyarizatsiya makrofagov v sovremennoy kontseptsii formirovaniya immunnogo otveta. Fundamentalnyie issledovaniya. 10-5: 930-935.
Manaster I, Mandelboim O. (2010). The unique properties of uterine NK cells. American journal of reproductive immunology (New York, N.Y. 1989). 63 (6): 434-444. https://doi.org/10.1111/j.1600-0897.2009.00794.x; PMid:20055791
Martínez-García EA, Sánchez-Hernández PE, Chavez-Robles B, Nuñez-Atahualpa L, Martín-Márquez BT, Arana-Argaez VE et al. (2011). The distribution of CD56(dim) CD16+ and CD56(bright) CD16- cells are associated with prolactin levels during pregnancy and menstrual cycle in healthy women. American journal of reproductive immunology (New York, N.Y.: 1989). 65 (4): 433-437. https://doi.org/10.1111/j.1600-0897.2010.00916.x; PMid:20825378
McIntire RH, Morales PJ, Petroff MG, Colonna M, Hunt JS. (2004). Recombinant HLA-G5 and -G6 drive U937 myelomonocytic cell production of TGF-beta1. Journal of leukocyte biology. 76 (6): 1220-1228. https://doi.org/10.1189/jlb.0604337; PMid:15459235
Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S et al. (2014). Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 41 (1): 14-20. https://doi.org/10.1016/j.immuni.2014.06.008; PMid:25035950 PMCid:PMC4123412
Rajagopalan S, Bryceson YT, Kuppusamy SP, Geraghty DE, van der Meer A, Joosten I, Long EO. (2006). Activation of NK cells by an endocytosed receptor for soluble HLA-G. PLoS biology. 4 (1): e9. https://doi.org/10.1371/journal.pbio.0040009; PMid:16366734 PMCid:PMC1318474
Sanguansermsri D, Pongcharoen S. (2008). Pregnancy immunology: decidual immune cells. Asian Pacific journal of allergy and immunology. 26 (2-3): 171-181.
Santoni A, Carlino C, Stabile H, Gismondi A. (2008). Mechanisms underlying recruitment and accumulation of decidual NK cells in uterus during pregnancy. American journal of reproductive immunology (New York, N.Y.: 1989). 59 (5): 417-424. https://doi.org/10.1111/j.1600-0897.2008.00598.x; PMid:18405312
Scherbakov VI, Pozdnyakov IM, Shirinskaya AV, Volkov MV. (2020). Rol provospalitelnyih tsitokinov v patogeneze prezhdevremennyih rodov i preeklampsii. Rossiiskii Vestnik Akushera-Ginekologa. 20: 2. https://doi.org/10.17116/rosakush20202002115
Shivhare SB, Bulmer JN, Innes BA, Hapangama DK, Lash GE. (2015). Menstrual cycle distribution of uterine natural killer cells is altered in heavy menstrual bleeding. Journal of reproductive immunology. 112: 88-94. https://doi.org/10.1016/j.jri.2015.09.001; PMid:26398782
Sykes L, MacIntyre DA, Teoh TG, Bennett PR. (2014). Anti-inflammatory prostaglandins for the prevention of preterm labour. Reproduction. 148 (2): R29-R40. https://doi.org/10.1530/REP-13-0587; PMid:24890751
Tan K, Duquette M, Liu JH, Dong Y, Zhang R, Joachimiak A, Lawler J, Wang JH. (2002). Crystal structure of the TSP-1 type 1 repeats: a novel layered fold and its biological implication. The Journal of cell biology. 159 (2): 373-382. https://doi.org/10.1083/jcb.200206062; PMid:12391027 PMCid:PMC2173040
Tang AW, Alfirevic Z, Turner MA, Drury JA, Small R, Quenby S. (2013). A feasibility trial of screening women with idiopathic recurrent miscarriage for high uterine natural killer cell density and randomizing to prednisolone or placebo when pregnant. Human reproduction (Oxford, England). 28 (7): 1743-1752. https://doi.org/10.1093/humrep/det117; PMid:23585559
Vacca P, Moretta L, Moretta A, Mingari MC. (2011). Origin, phenotype and function of human natural killer cells in pregnancy. Trends in immunology. 32 (11): 517-523. https://doi.org/10.1016/j.it.2011.06.013; PMid:21889405
Van Kooyk Y, Geijtenbeek TB. (2003). DC-SIGN: escape mechanism for pathogens. Nature reviews. Immunology. 3 (9): 697-709. https://doi.org/10.1038/nri1182; PMid:12949494
Van Sinderen M, Menkhorst E, Winship A, Cuman C, Dimitriadis E. (2013). Preimplantation human blastocyst-endometrial interactions: the role of inflammatory mediators. American journal of reproductive immunology (New York, N.Y.: 1989). 69 (5): 427-440. https://doi.org/10.1111/aji.12038; PMid:23176081
Ventskivska IB, Aksonova AV, Lahoda NM. (2016). Morfolohichni osoblyvosti platsenty pry preeklampsii za danymy histokhimii. Zdorove zhenshchyni. 6: 73-76.
Warning JC, McCracken SA, Morris JM. (2011). A balancing act: mechanisms by which the fetus avoids rejection by the maternal immune system. Reproduction (Cambridge, England). 141 (6): 715-724. https://doi.org/10.1530/REP-10-0360; PMid:21389077
Yie SM, Li LH, Li YM, Librach C. (2004). HLA-G protein concentrations in maternal serum and placental tissue are decreased in preeclampsia. American journal of obstetrics and gynecology. 191 (2): 525-529. https://doi.org/10.1016/j.ajog.2004.01.033; PMid:15343231
Yuldashev AYu, Komilov MS. (2015). Tsitokino-endokrinnyiy profil organizma pri fiziologicheskoy i preryivayuscheysya beremennosti i morfologicheskie osobennosti platsentyi. Mezhdunarodnyiy zhurnal prikladnyih i fundamentalnyih issledovaniy. 3-1: 25-28.
Yushchenko MI, Duka YuM. (2022). Modern view on the etiology and pathogenesis of preeclampsia as the main cause of perinatal losses. Ukrainian Journal Health of Woman. 4 (161): 58-68. https://doi.org/10.15574/HW.2022.161.58
Ziganshina MM, Krechetova LV, Vanko LV, Nikolaeva MA, Khodzhaeva ZS, Sukhikh GT. (2013). Time course of the cytokine profiles during the early period of normal pregnancy and in patients with a history of habitual miscarriage. Bulletin of experimental biology and medicine. 154 (3): 385-387. https://doi.org/10.1007/s10517-013-1956-0; PMid:23484206
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