• Ешқандай Нәтиже Табылған Жоқ


4. Immunological and molecular genetic aspects of the pathogenesis of spontaneous preterm birth

To date, the development of the inflammatory process in the absence of an infectious agent of spontaneous preterm birth remains incompletely understood. A significant increase in proinflammatory cytokines in amniotic fluid,

uterus, placenta, umbilical cord blood and fetus indicates the initiation of an inflammatory response during spontaneous preterm birth [1, 15, 23, 59].

That is why a large number of scientists are currently paying a lot of attention to the study of the immunological and molecular genetic aspects of the pathogenesis of spontaneous preterm birth it has been proved that the state of the immune system during pregnancy determines its outcome.

For example, an increase in the level of proinflammatory cytokines in the pregnant woman's plasma precedes pregnancy termination [10]. Pregnancy is a very complex process in which a fetus containing paternal antigens is partly a foreign body to the woman's body. It is the mother-placenta-fetus system that contributes to the creation of a unique immunological situation that contributes to prolonged pregnancy. During pregnancy, syncytiotrophoblast, which forms the outer layer of placental villi and is exposed to maternal blood, but does not express class 1 HLA-antigens on its surface and is 'not visible' to the maternal immune system [21]; a number of changes also occur in the trophoblast, such as the production of active substances that activate and stimulate apoptosis of maternal T- lymphocytes (e.g. protein B7H1, IDO) [21, 50, 24]; Trophoblast cells produce regulatory proteins for the complement system (CD46, CD55, CD59) and this helps to protect fetal tissue from cytotoxic maternal antibodies [21, 42]; in utero: a large number of decidual macrophages with anti-inflammatory activity (M2 phenotype) appear, which in turn secrete immunosuppressive factors, reducing inflammatory responses in the mother-placenta-fetal system.

This immunological process is seen not only in preterm birth, but also in pre-eclampsia and placental insufficiency.

Progesterone also has a direct effect on the production of anti-inflammatory cytokines in placental cells (e.g. IL-10);

it also helps to suppress the maternal immune response and changes the balance of Th1\Th2-helpers towards the anti-inflammatory state of Th2 and blocks TNF-α synthesis [21, 74].

It should be noted that all these changes are predominantly local in nature and there is no generalised maternal immunosuppression during pregnancy [21]. Many immunologists agree that pregnancy is an anti-inflammatory state. However, when the balance, for one reason or another, shifts to the pro-inflammatory side, there is an increase in the production and concentration of cytokines in the uteroplacental complex, then spontaneous miscarriages and other pregnancy complications occur [6]. For example, increased IL-6, IL-1β and TNF-α in plasma, cervico-vaginal secretion and amniotic fluid are associated with a high risk of premature births [38, 11].

The study of the immunological factor in the development of preterm birth has a long history.

Researchers have studied the balance of pro-inflammatory cytokines and anti-inflammatory cytokines in different biological media and in different combinations. Each of the studies has shown the crucial importance in the processes of fetal implantation, placental preparation and pregnancy outcome of certain components of immunity [38, 11]. For example, F. Hertelendy et al. (2002) determined that IL-1β and TNF-α stimulate the release of arachidonic acid and increase the production of prostaglandins in the

myometrium, these processes are similar to the action of oxytocin [40], and a little later J. Dowd et al. (2005) found a significant increase in IL-8 concentration in cervical mucus in women whose pregnancies ended subsequently in preterm birth, R. Romero et al. (2007) found that the increased levels of proinflammatory cytokines (IL-1, IL-6, IL8, TNF-α) in amniotic fluid are directly proportional to the risk of developing preterm birth, and they also found increased concentrations of proinflammatory cytokines in the lungs, intestine, liver and brain of the fetus [63; 34]. Of recent studies in this direction, a significantly increased concentration of IL-1β, IL-6, IL-8, TNF-α, IL-17A, interferon- γ-induced protein-10 in blood, amniotic fluid or cervical- vaginal lavage samples from patients with spontaneous premature birth compared to normal birth was found by J.M.

Fettweis et al. (2019).

We would like to elaborate further on the role of tumour necrosis factor (TNF-α) TNF-α during pregnancy. According to the literature, a certain level of TNF-α is necessary for the normal development of pregnancy, as in early gestation it interacts with receptors expressed on the surface of the trophoblast, thereby protecting it from the action of maternal cytotoxic lymphocyte clones.

In the serum of healthy pregnant women, tumour necrosis factor is almost undetectable, but if an infective agent of viral or bacterial nature enters the body, TNF-α concentrations increase tenfold. It is known that high concentrations of this cytokine can increase inflammation and trigger apoptosis of trophoblast cells, thus causing serious complications such as placental detachment and premature delivery [22, 79].

Overproduction of TNF-α can adversely affect the development of pregnancy. A study by V.M. Sidelnikova (2010) found a significant increase in TNF-α levels in the blood of women in the 3rd trimester with threatened fetus compared with a normal pregnancy [15]. There are also studies proving that TNF-α can induce amnion epithelial cell death and hence lead to premature antenatal expulsion of amniotic fluid. Among other things, proinflammatory cytokines are important in the pathogenesis of preterm birth, which in turn cause leukocyte and endothelial cell activation and complement, which correspond to the acute phase of inflammation.

Speaking of proinflammatory cytokines, one cannot but mention anti-inflammatory cytokines, the increased content of which during pregnancy provides maternal immunosuppression in relation to the forming feto-placental complex [1, 68, 20, 28], and can also form highly active oxygen and nitrogen metabolites, enhance differentiation into cytotoxic Тh2 cells, activate macrophages, induce proliferation of NK cells [65]. This eventually suppresses the proinflammatory link and ensures the progression of pregnancy to term.

Summarizing the above described mechanisms, there is no doubt about the role of cytokines in the genesis of preterm birth at present.

In the presence of an infectious agent, the mechanism of increased production of proinflammatory cytokines in the uteroplacental complex is quite clear; this cannot be said for preterm birth of a non-infectious genesis, in which the production of proinflammatory cytokines is also increased.

One version of this mechanism may be a genetic predisposition as a result of their gene polymorphism [6].

Given that cytokines are polypeptides, their synthesis begins with gene transcription. Currently, there is evidence of a large variation in the polymorphisms of cytokine genes.

One of the most studied and significant SNP polymorphisms is the Leiden mutation. This mutation is represented by the substitution of the guanine nucleotide for the adenine nucleotide at position 1691 in chromosome 1 CGA→CAA and as a result, glutamine is synthesised instead of arginine in factor V, which leads to thrombophilia.

It is now known that different polymorphisms have been identified for each pro- and anti-inflammatory cytokine [60].

The major gene polymorphisms of a number of cytokine polymorphisms TNF-α -308G/A (rs1800629) -238G/A (rs361525) -863C/A (rs1800630) IL-6 -174G/C - 572G/C - 597G/A -634C/G IL-1β -511C/T (rs16944) 3953 C/T (rs1143634) 3954 C/T (rs1143644) -31 (rs1143627) IL-1Ra VNTR (intron 2) IL-4 VNTR (intron 3) -589 C/T So, the TNF- α -308G/A polymorphism results in a substitution of the guanine (G) nucleotide for adenine (A) in the regulatory region of the gene. Thus there are people in the population with a normal GG genotype as well as heterozygotes (GA) and homozygotes (AA) with a pathological genotype. Pro- and anti-inflammatory cytokine gene polymorphisms have been shown to play a role in many diseases of inflammatory etiology. For example, such diseases as rheumatoid arthritis and chronic periodontitis [43] occur more frequently in patients with TNF-α gene polymorphism. Whereas the presence of TNF-α -308G/A variant increases the risk of developing metabolic syndrome, type 1 diabetes, bronchial asthma, psoriasis, oncological diseases, including cervical cancer in carriers of oncogenic human papilloma virus (HPV). This genotype variant can also be considered as a marker of the efficacy of hormonal therapy for diseases such as Crohn's disease and ulcerative colitis and rheumatoid arthritis (49).

For women with preterm birth, polymorphisms of different cytokine genes are also quite common. For example, a study by E. Moura et al. (2011) found that different polymorphisms of the TNF-α gene are associated with a high percentage of preterm birth, and in a meta- analysis by J. Cui et al. (2015) found an association between IL-1Ra gene polymorphisms and an increased incidence of preterm birth in their carriers [3, 55, 29]. It is also now known that the IL-4 VNTR gene polymorphism (intron 3), particularly the presence of the 2R allele, increases the risk of early termination of pregnancy (6).

However, despite the current knowledge on this issue, there is still interest in identifying different combinations of gene polymorphisms of several cytokines at once and their direct impact on the frequency and duration of pregnancy termination. It is possible that multiple cytokine gene polymorphisms may be combined in one woman and that these combinations may lead to increased production of pro-inflammatory cytokines during pregnancy and hence to the realization of preterm birth.

A brief mention of the role of toll-like receptors in the pathogenesis of preterm birth was made above.

A little history of this type of receptor: they were discovered in 1985 by the German biologist Christian Nüsslein-Follhard, and years later Jules Hoffmann was awarded the Nobel Prize in 2011 for the discovery of their gene. TLRs were first discovered in Drosophila Toll, from which they were given their name. They are innate immunity

receptors and are found in large numbers on various cells of the immune system (monocytes, dendritic cells, leukocytes, etc.), as well as on many other cells of the body (fibroblasts, endothelium, epithelium, cardiomyocytes, etc.).

They are all similar in chemical structure and are represented by type I transmembrane glycoproteins.

Currently, about 13 types of TLRs have been studied in humans, but their properties have not been adequately studied. TLRs have been found to have a specific relationship with the main groups of pathogens with which multicellular organisms - bacteria, viruses, fungi, and protozoa - are in contact [44]. We would like to point out that TLRs recognize not only exogenous structures, but also endogenous molecules that are released or produced during tissue damage and inflammation - damage- associated molecular fragments (DAMPs). These include heat shock proteins, fibronectin, fatty acids, haem, mitochondrial DNA, ATP, uric acid, heparin sulphate and others [44]. These components, once released, interact with toll-like receptors, resulting in the release of cytokines. This inflammatory process is termed "sterile inflammation" due to the lack of identification of the infectious agent [12, 53]. The mechanism of toll-like receptor functioning begins with the recognition of ligands by toll-like receptors, then an activation signal is generated and pro-inflammatory cytokines (TNF-α, interleukins) begin to be produced and the inflammatory process is realized. Different TLRs ligands, interact with their specific receptors and thereby contribute to the production of different cytokines. For this reason, depending on which combination of toll-like receptors is specific to the cell type of a particular tissue, the immune response will differ according to the characteristics of the tissue.


Having studied a large number of literature sources, it is evident that the problem of preterm birth is not losing its relevance at present. This can be seen from the statistics that show a fairly high percentage of preterm births in different countries with different levels of socio-economic development [76, 16, 13]. The consequences of early preterm birth affect all areas of national development and cause huge economic losses due to the huge monetary costs of nursing preterm babies and the treatment of chronic diseases that inevitably develop in these newborns in the near future. In addition, preterm birth tends to recur and the literature suggests that about 2.5 million preterm births worldwide are carried out each year. This is why there are a huge number of different programmes and methodologies around the world aimed at reducing preterm birth. In spite of this, there has been no downward trend in the incidence of preterm birth worldwide over the last 20 years, according to WHO data. This is most likely due to delayed preventive measures aimed at treating the complaints rather than the pathogenetic links.

Understanding the pathogenetic mechanisms of preterm birth is therefore a particularly important topic for research at this time. Indeed, in 2015, the WHO led recommendations "On measures to improve the outcomes of preterm birth" were adopted to stimulate research into the causes and pathogenetic links of preterm birth, as well as to improve methods for the prevention of preterm birth and reduce the complications associated with it [77]. It has long been known that the inflammatory process is the main

cause of the development of preterm birth, as various variations of pro- and anti-inflammatory cytokines are detected in the uteroplacental complex during preterm birth [35, 34]. The interaction of immune complexes on cyclooxygenases (COX-1 and COX-2) results in the activation of prostaglandins, particularly E and F2α, leading to cervical maturation, uterine contractions and the realization of preterm labour. All these mechanisms, where bacterial and viral ligands activate toll-like receptors, resulting in increased production of pro-inflammatory cytokines and triggering the above described mechanism, are well studied and understood.

However, the nature of the occurrence of high concentrations of proinflammatory cytokines in the absence of an infectious factor remains unclear. And since about half of all preterm births are spontaneous, it is the pathogenesis of these spontaneous preterm births that is of great interest to researchers worldwide. Most likely, the realization of spontaneous preterm birth occurs by the same pathogenetic mechanism, through the activation of toll-like receptors. However, in the absence of an infectious agent it is unclear what can activate TLRs. The following hypothesis for the pathogenesis of preterm birth has been proposed by various researchers. One of the trigger mechanisms for spontaneous PR is premature death of placental cells. As a result of their early death, various cellular fragments (DAMPs) are released, which act as a ligand for toll-like receptors. An increased pro-inflammatory cytokine production in the uterine-placental complex may also be due to a genetically determined propensity for increased production due to cytokine gene polymorphism.

Based on the results of the literature review, a certain structure of pathogenetic mechanisms was formed:

➢ one of the significant pathogenetic mechanisms of spontaneous preterm birth is increased production of pro- inflammatory cytokines and is associated with cytokine gene polymorphisms, and their combination most often leads to very early and early preterm birth;

➢ a trigger mechanism for the activation of premature spontaneous labour is premature placental cell death. Dead placenta cell fragments (DAMPs) are ligands of toll-like receptors whose expression is also increased in spontaneous preterm labour. As a result of their activation, and because of the presence of proinflammatory cytokine gene polymorphisms, there is an increased production of the latter in the utero-placental complex - a process of 'sterile' inflammation is realized;

➢ a comprehensive assessment of the key pathogenetic mechanisms of spontaneous preterm birth is required to develop pathogenetically sound algorithms for antenatal preparation, prevention and management of pregnancy in women at risk of preterm birth.

Conclusions: The analysis of the sources once again demonstrates the polyetiology of the problem. It is clear that preterm birth continues to be an issue for a long time due to the lack of a complete understanding of the pathogenetic mechanisms.

Authors' contribution - All authors contributed equally to the writing of this article.

Сonflict of interest - No conflicts of interest have been declared. This material has not been previously submitted for publication in other publications and is not under consideration by other publishers.

Funding - There was no third-party funding or medical representatives for this work.


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