Placental-Uterine Immunological Crosstalk

Contents

1. Introduction

2. The Uterus
2.1 Anatomy and Alteration in the Cycle
2.2 Special Make-up during Embryonic Nidation

3. The Placenta
3.1 From Fertilization to Nidation
3.2 Implantation and Placentation
3.3 Function
3.3.1 Nutrition
3.3.2 The Placenta as a Hormonal Organ
3.3.3 Barrier between Fetal and Maternal Circulation

4. Immunological Uterine-Placental Crosstalk
4.1 Immunologic Reaction to Foreign, Allogeneic Tissue
4.2 Maternal Cells Involved in Direct Interactions
4.3 NK Cell Receptor Interactions
4.3.1 CD94/NKG2
4.3.2 KIR (killer cell Ig-like receptor)
4.3.3 ILT (Ig-like transcript)

5. Major Histocompatibility Complex (MHC) Expression on Placental Cells
5.1 Human Leukocyte Antigens (HLAs)
5.2 Characteristics of Classical and Non-classical MHC Class I Molecules
5.3 Subgroups of Trophoblast HLA Class I Antigens
5.3.2 HLA-C
5.3.1 HLA-E

6. Special role of HLA-G
6.1 Unique HLA-G Features
6.2 HLA-G Interactions with Maternal Cells
6.2.1 T Cell Interactions
6.2.2 B Cell Interactions
6.2.3 Monocyte Interactions

7. Discussion and Conclusion

8. References

Abbreviations

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Table 1: List of abbreviations.

1. Introduction

Approximate 100 million years ago an important evolutionary event occurred, the diversification of the stem of eutherian (placental) mammals.[3,4] In this transition from oviparity to viviparity, the mammalian success mainly depended on the simultaneous forming of a transient and omnipotent organ: The placenta.[5,6]

Viviparity gave rise to new advantages like the embryonic development in a safe inter-maternal environment as well as an advanced system in nutrient and waste-product exchange, compared to yolk-sac nutrition.[7]

For the intense placental-uterine fusion with a warranty of effectual anastomosis concerning the necessary embryonic supply, a fine-tuned and high coordinated trophoblast cell invasion of the uterine tissues and the uterine spiral arterial walls is required.[6,8] This event of placentation and thus the infiltration of extra villous trophoblasts (EVT) in the decidua, the maternal uterine membrane, equals the concept of transplantation.[9] The placenta is, as well as the embryo, a semi-allograft, possessing antigens from both, maternal and paternal origin. The anticipation for the penetration of genetic differing material is the immediate initiation of a broad immune response, which is not true in case of the placenta. So an immunological unique placental-uterine crosstalk is established in the uterine side of EVT exposure. Humans have haemochorial placentae, marked by extensive invasion of trophoblasts, which define the boundary between mother and fetus. These cells have unique patterns of gene expression and develop independently from embryonic tissue.[7]

The main issue of this paper is the question how the placenta, in particular placental trophoblast cells, prevent a maternal allograft immune rejection by modulating the immune response in the uterine side of implantation.

The attempt is done to give insights about special immunological interactions at the placental-uterine side of implantation that makes the fascinating event of pregnancy possible.

Of main interest are interactions between trophoblast human leukocyte antigens (HLAs), natural killer (NK) cells as well as T lymphocytes, in questions of state of the art literature. Although a broad introduction is given to the development of the embryo until nidation; how the uterus is made up during implantation and the mechanisms of placentation.

2. The Uterus

The uterus can be seen as the major female reproduction organ, the side where the embryo and fetus sojourns during the time of pregnancy.

2.1 Anatomy and Alteration in the Cycle

The endometrium, the outermost part of the epithelial layer of the uterus, pulls apart and reconstructs every 28 days in the normal menstrual cycle in women of child-bearing age.

The cycle begins with a proliferative phase in terms of refashioning of the endometrium, whereas a 9 day period antecedent ovulation marks strongly growths in size of the epithelial layer which gets richly vascularized as well as strongly infiltrated by NT( cells. The moment of ovulation is followed by a 14-day secretory phase, in which NT( cells proliferate and differentiate to create a site best attractive for embryonic implantation.[3] The short period of time where implantation is possible due to unique, hormone affected endometrial modulation is called the implantation window. It is regulated by the cyclic secretion of 17!-estradiol and progesterone, responsible for the regulation of growth factors, cytokines and adhesion molecules that alter the endometrial surface to open the implantation window by creating the best possible epithelial environment for placental trophoblast ingrowths. The window is closed after several days by amongst others fibronectin.[8] Also, if no fertilization and implantation takes place, NT( cells die and the five-day period of menstruation, the flaking of the endometrial layer, occurs.[3]

2.2 Special Make-up during Embryonic Nidation

The ´decidual reaction` is a cellular and vascular change occurring to the endometrium in response to embryonic implantation.[8] For an adequate oxygen and nutrition supply of the embryo the endometrium has to remodel into the decidua, a much-changed tissue highly nerved by blood vessels.[3] This process is initiated perpetual the opening of the implantation window during the menstruation cycle whereas decidualisation accumulates glycogen and lipids in epithelial cells causing their typical enlargement and pail-staining appearance. The exact function of the decidua stays vague but it can be adopt that besides the facilitation of implantation it plays a main role in restraining and controlling the massive trophoblast invasion.[8]

3. The Placenta

The placenta forms an organ between embryo/fetus and the uterus of the mother during pregnancy, ensuring adequate exchange of oxygen, nutrients and waste products and is responsible for remodeling processes of the uterine immune cell population and the maternal uterine arteries.[6,8]

3.1 From Fertilization to Nidation

Fertilization takes place in the ampulla of the oviduct, a region close to the ovary, by penetration of the spermatozoa through the zona pellicula of the ovulated oocyte: The zygote is formed with a diploid complement of chromosomes.

In the next 24 hours the zygote is pushed by cilia of the oviduct down in direction of the uterus and undergoes mitotic cell division known as cleavage, whereas new daughter cells, the blastomeres, are formed. By day 4 the embryo consists of 32 cells and is called morula. (Figure 2) Blastomeres in the center of the morula give rise to the inner cell mass, whereas cells of the periphery develop into the outer cell mass. The inner cell mass will further transfer into the embryo proper called the embryoblast. The outer cell mass, by primary forming the source of the chorion, the embryonic portion of the placenta, is called trophoblast (trophectoderm). The morula begins to absorb fluid, which shapes a cavity called the blastocyst cavity.

The trophoblast cells are now arranged in a thin outer cell layer around the blastocyst cavity and the embryoblast forms a compact mass at one side of the cavity, the embryonic pole, and is called the blastocyst.

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Figure 2: Development of a human embryo; from feritlization to implantation. [ 10 ]

The zona pellicula, which surrounds the blastocyst, prevents the embryo form adhering to the oviduct walls. Between day 3 and 4, the morula reaches the uterus and the blastocyst gets tightly bound to the uterine lining, by hatching from the zona pellicula. After that initial binding process, several adhesion systems ensure and coordinate a successful binding to the uterine wall.[11,12] After the zona pellicula is lost and the binding took place, the blastocyst sinks beneath the endometrial surface.[8]

3.2 Implantation and Placentation

The route of placentation begins after the blastocyst has implanted into the uterine epithelium and the process of differentiation into inter-, and extra-embryonic tissue is achieved.[13] Immediately after attachment, rapid proliferation of the trophoblast cell layer of the blastocyst takes place and differentiates into an inner cytotrophoblastic layer and an outer multinucleated syncytiotrophoblastic mass.[8]

At day 13 to 14 of pregnancy cytotrophoblast cells penetrate through the outer embryonic shell, which is composed of syncytiotrophoblasts, begin the invasion of the uterine stroma and give rise to the cell line of extravillous cytotrophoblasts and villous cytotrophoblast. (Figure 3)[8,13]

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Figure 3: Growth of placental villi. A: Ingrowths of cytotrophoblasts into the syncitiotrophoblast cell layer leads to formation of primary villi. B: Secondary villi are formed by mesnchyme migration. C: Remodeling of maternal spiral arteries occurred and tertiary villi are formed. [ 13 ]

Former function in two ways: locating and surrounding of the spiral arteries (uterine arterial circulation) and the mediation of an adaptive maternal response to the implantation of the embryo. This happens due to endocrine communication, inducing the onset of a successful pregnancy.

EVTs that proliferate inside the decidual spiral arteries are named ´endovascular trophoblasts` and primary prevent maternal blood-flow into the developing intervillous space until the placental disc has formed. Afterwards they replace the muscularized wall of the spiral arteries to ensure a sufficient blood flow to the intervillous space, which is, additively stimulated by angiogenic and vasodilator signals.[3,6,8,13]

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Figure 4: Placentation in a normal pregnancy. [ 7 ]

Maternal blood vessels create large, flaccid ducts to comply the great demand of blood from the fetus, especially from the developing fetal brain that consumes nearly 60% of nutritional needs in the third trimester, which explains the extra deep infiltration in humans.[3,6,7]

Another subpopulation of extravillous trophoblasts, the interstitial trophoblasts, transform into multinucleated placental bed giant cells and migrate deep into the decidua. Villous cytotrophoblast do not migrate but give rise to the choronic villi by fusing with the outer shell, the syncytiotrophoblast, and by forming the villous core, which is later on (third week of gestation) filled by mesenchyme.[8] Feto-placental blood vessels are formed in the extra-embryonic mesenchyme, by vasculogenesis of embryonic mesoderm. This tissue penetrates the more proximal layer of cytotrophoblast, giving rise to the ´tertiary choronic villi`, the forerunners of the gas-exchanging choronic villi. Later on latter will form the mature villous tree that is covered by the ´vasculo-syncytial membrane` (syncytiotrophoblast), proximal to the umbilical arteries as a border between maternal and fetal blood.[13,14] It is important to distinguish between the floating villi that are suspended within the intervillous space and the anchoring villi, attached to the maternal decidua.[14] Serious clinical conditions arise if trophoblasts invasion not proceed far enough or when the transformation of maternal vessels is incomplete. The result is an inadequate blood flow later on in pregnancy, the primary defect in Pre-eclampsia and intrauterine growth retardation (IUGR).[6]

3.3 Function

The placenta shows a fascinating ability to differentiate in a short period of time from the trophectoderm into a full-fledged multifunctional organ.[5] It has to ensure adequate nutrition of the developing embryo and fetus, to take over parts of hormonal pregnancy control and forms a unique immunological barrier between the maternal and fetal circulation.

3.3.1 Nutrition

The placenta is a haemochorial villous organ, creating direct contact between maternal blood and placental trophoblasts at the site where oxygen, nutrition and waste-product exchange takes place.[8] During the process of placentation a close contact between the interface of the maternal and fetal circulatory systems must be established to ensure this exchange in a sufficient manner. Herein a very important fact is that no direct contact of blood evolves between uterine blood vessels and fetal blood.[14] For the continuous supply of the developing fetus, maternal blood needs efficient access to the layer of multinucleated syncytiotrophoblast, which is made possible by the remodeling of maternal spiral arteries in the uterus by invasive mononucleated trophoblasts (discussed earlier).[5]

The placenta ensures transport of oxygen, water, carbohydrates, lipids, vitamins, minerals and other nutrients to the fetus, while removing carbon dioxide and other waste products.[8]

3.3.2 The Placenta as a Hormonal Organ

The placenta is a temporally hormonal organ, secreting hormones and cytokines, indispensable for the normal maturation and protection of the developing fetus, amongst others progesterone, estrogens (like oestrone, oestradiol and oestriol), human chorionic gonadotrophin (hCG), as well as many cytokines and chemokines.[5,8] Progesterone is very important for the inhibition of uterine contractions, whereas estrogens act as growth hormones on maternal reproductive organs like breast, uterus, cervix and vagina.[8] The glucoprotein hormone hCG is produced and secreted at high amounts by the syncytiotrophoblasts and is positively regulated by the gonadotropin releasing hormone (GnRH). It is responsible for the fusion of cytotrophoblasts and the differentiation of villous trophoblasts.[5,8]

Progesterone and prostaglandins are also immunosuppressants, reducing maternal immune reactions. Trophoblasts produce amongst others the chemokines CXCL12 and the stromal cell factor-1, which are able to attract immune cells of the innate immune system and are in that way responsible for a shift from acquired to innate immunity in the uterus, important for successful implantation of the conceptus.[2]

3.3.3 Barrier between Fetal and Maternal Circulation

The placenta as an intermediary organ between fetus and maternal tissue assures the complete separation of both circulation systems, to prevent a maternal immunological reaction against, and rejection of, the fetus as a semi-allograft. Besides this the placenta is a barrier not only for xenobiotics but also for a brought rage of bacteria and viruses, found in maternal blood. Important is that this function is related to a lot but not all substances and microorganisms.[8]

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