NK CELL ACTIVITY IN OBSTETRICS

NATURAL KILLER CELL AND PREGNANCY PROCESS

1. The relationship between mother and embryo, the role of NK cells

Surely many of us have ever asked ourselves: In normal people, why can the mother’s body accept and support fetal development without excretion by the natural mechanism ?The way our immune system responds to protect the body, destroy foreign substances that come in from outside (bacteria, viruses) or appear in the body (like in cancer). The question is because as we know, the nature of pregnancy is a semi-harmonized transplant process because half of the genome is inherited from the father [1]. The full answer (so far) may be analyzed in another context, where we will talk about the role of NK cells in the coexistence and maintenance of fetal development (immune tolerance). The essence of the formation of the relationship between the mother’s body and the fetus is the process of restructuring the uterine lining in which the invasion of trophoblast leaves into the uterine lining with the strict control of Immune cells, especially uterine NK (uNK) cells, secreting factors that directly affect embryonic growth and development, influencing the formation of twisted vessels to supply the embryonic nutrients to the mother body [1,2,3].

Interaction between foliar cells and uNK cells helps uNK cells continue to secrete a series of cytokines including activating and inhibiting factors for normal embryo development such as (TNF-a; IFN- g; GM-CSF; and macrophage inhibitory factor – MIF) [4,5,6]. In particular, a number of recent studies show that NK also secretes two active ingredients, pleiotrophin and osteoglycin (called growth factor GPFs), which help promote the development of the embryo. An increasing or insufficience of these both can stop the embryo from developing [7].
On the other hand, the lining of the uterus has many changes, restructuring of the cornea, vessels … and normally, the same processes take place with the participation and strong activation of the cells that cause The inflammatory process (Th17), however, does not occur because the tumor cells are here to control and inhibit Th17 cells [8], and so the fetus can develop, avoiding interference & clear inflammation of other immune cells such as leukocytes, macrophages.
In the uterus, the secretory activity of IFN-gma (IFN-g) secreted by NK cells is to activate dCD14 cells, which secrete cytokines L-kynurenin and TGF-beta, which activate the cell. Tregs cells (CD25bright FOXP3), which are responsible for regulating immune responses, inhibiting proliferation and activating cells that can harm embryos [9].
Another important mechanism, perhaps the most important for embryos to survive and develop, is that embryonic leaf cells reduce expression of molecular structure class I MHC (also known as Ia: HLA – A, B, C), helping embryos to avoid the identification and destruction of toxic T cells (TCD8). If we just stop here, according to the normal mechanism when reducing the expression of MHC class I, embryonic leaf cells will be identified and killed by NK cells. However, the natural mechanism is that the embryonic leaf cells strongly express the class MHC structures (HLA-G), HLA-G has the ability to inhibit the toxic ability of NK cells [10,11,12]. So far, there have been studies evaluating the association between the amount of HLA-G present in foster leaf cells and the mother, and the reduction of HLA-G expression in plasma associated with an increasing risk of miscarriage [13, 14].

2. High value of NK activity affects fetal development?

As can be understood, the fetus is still an organization that is “strange” to the mother’s body but a “natural” survival mechanism that helps it avoid the attack of toxic T cells (TCD8) is due to reduced leaf cell expression of HLA-A, B, C molecular structures, on the other hand avoiding the detection and attack of NK natural killer cells due to increasing expression of HLA-G. And, when low HLA-G is associated with miscarriage, does the NK activity beyond the control of HLA-G on foliar leaf cells lead to embryo disadvantage? Obviously, the nature of HLA-G decreases and the NK activity increases in the matter of damaging the embryos of the same nature (for example, in a battle either our army is too weak or the enemy is too strong, it is difficult for our army to avoid the failure)!
There are also studies suggesting that uNK only has a secretory function and is not capable of direct toxicity but that it is only under normal conditions, when there is no appearance or the import does not detect the “strange” elements. Bulmer and colleagues’ research showed that in contrast to the CD56bright cells in peripheral blood (mainly responsible for cytokine secretion), the CD56bright in the uterus in addition to secretory function also contains a large number of toxic enzymes called perforin. and Granzyme in cells [15,4].
Another hypothesis of an increase in NK density and activity that adversely affects embryos, coming from one of the main functions of NK cells here is to help restructure the blood vessels in the mucosa. When NK activity is increased, angiogenesis is rapid, pressure and volume of blood flow from mother to embryo stage of strong nesting can cause “stress” leading to miscarriage due to oxidation. Excessive cell stress (excessive oxidative stress) [4].

3. Studies on the fac that “High value of NK activity affects fetal development”

So far, there have been many research studies proving the relationship between the increase in NK activity and consecutive miscarriage [1,4,16-21].
So, is there any way to effectively treat this problem? The answer is yes and in many ways, complicated and expensive treatments such as high-dose intravenous immunoglobulin (IVIg) or as common as corticosteroids or Intralipid… are shown to be effective [21- 28]. However, and importantly, it is your doctor who decides whether you need to check this activity and how to treat it because there can be many causes of infertility and not everyone need to do, you should not automatically do tests or automatically buy treatment drugs without advice, indications, monitoring from your doctor. As far as we know, there are many obstetricians who think of many infertility cases that have immune abnormalities (Excluding immunological abnormalities due to NK, according to published studies, leading the cause of consecutive miscarriage are respectively hormonal disorders, autoimmune diseases, abnormalities in resolution uterine surgery and genetic abnormalities. And the remaining 50% of consecutive miscarriages are of unknown cause [20]).
In this context, many patients have received immunosuppressive treatment and there have been cases with good results, but we need here a tool (NK activity test) for the correct diagnosis and treatment to control the activity before and after treatment, because if patients are not treated properly, abnormal activity will lead to the risk of other diseases later. For there is also a lot of interest in and understanding of this field, in order to avoid confusion, please objectively analyze some of the testing methods currently hoping to help you find the information you need. We would like to analyze only the principles and values of these test.
– NK quantitative assay: This test uses the flow cytometry analysis system to count the number of NK cells (or other cells) present in the analyzed population. This test is used to count NK mainly for hematological diagnosis and treatment, the quantity of NK does not reflect whether NK cell function is functioning normally or not. It can be likened to counting the number of imports as a “military roll call” while the import activity as a measure of the “operational capability” of that army. Therefore, in many cases, the number does not reflect the true ability to function, which can lead to omission of the cause or interference, so some previous studies on the number are not related to consecutive miscarriage. Also mentioned in some recent forums. Remember, the quantitative test if performed in this case is only a supportive (but not a substitute) test for the test to assess NK activity.
– Testing and evaluating direct toxicity of NK by culture method with cancer cell line K562, this method evaluates the ability to kill cancer cells of NK cells by their ability to cause toxicity, the result is the number of cancer cells destroyed by NK. No assessment of cytokine secretory ability, immunomodulation of NK cells (the main function of NK in utero).
– NK ACTIVITY TESTING (NKA) is a therapy to assess the overall ability of NK cells to be stimulated and cultured in a specialized environment (activating and inhibiting factors). produces similar components in the blood, in the womb when NK cells encounter). Quantify the activity of NK cells to know the true “ability” of these cells in the body.
– NK test in uterine mucosa by biopsy and immunohistochemistry, this is also a method to assess the number and morphology of the cell, this method requires biopsy endoscopy, currently in Vietnam there is no basis to implement this method.
Above we analyze some of the roles of NK cells with the special embryonic development process early in pregnancy and provide for those who are interested in the scientific basis of this problem. Of course, in science somewhere it’s inevitable that results, controversial perspectives, even controversies still exist even when the results are proven, are looking forward to discussion and Contributing ideas of scientists, colleagues, and even women who have not been fortunate enough to be mothers so that each unexplained issue will be clarified gradually.

References:

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