Journal of Neonatology & Clinical Pediatrics Category: Clinical Type: Review Article
Immunological Aspects of Pregnancy: A Literature Review
- Ana Karina Marques Salge1*, Karina Machado Siqueira2, Thaíla Correa Castral3, Janaína Valadares Guimarães3, André Adriano Rocha4, Renata Calciolari Rossi E Silva5, Douglas Reis Abdalla6, Eumenia Costa Da Cunha Castro7
- 1 School Of Nursing School, Goiás Federal University, UFG Rua 227 Qd 68, S/N - Setor Leste Universitário, CEP: 74605-080, Goiânia, Goiás, Brazil
- 2 School Of Nursing School, , Goiás Federal University, Goiânia, Goiás, Brazil
- 3 School Of Nursing School, Goiás Federal University, Goiânia, Goiás, Brazil
- 4 Department Of Immunology, Federal University Of The Triângulo Mineiro University, Uberaba, Minas Gerais, Brazil
- 5 Department Of Pathology, Oeste Paulista University, Presidente Prudente, São Paulo, Brazil
- 6 Department Of Immunology, Talentos Humanos University, Uberaba, Minas Gerais, Brazil
- 7 Department Of Pathology And Immunology, Pediatric Pathology, Texas Children’s Hospital, Baylor College Of Medicine, Texas, United States
*Corresponding Author:Ana Karina Marques Salge
School Of Nursing School, Goiás Federal University, UFG Rua 227 Qd 68, S/N - Setor Leste Universitário, CEP: 74605-080, Goiânia, Goiás, Brazil
Tel:+55 (62) 32096280,
Fax:+55 (62) 32096282
Received Date: Aug 24, 2016 Accepted Date: Mar 06, 2017 Published Date: Mar 21, 2017
IMMUNOLOGICAL ASPECTS OF PREGNANCY
The immunological relationship between the mother and the fetus is a bi-directional communication determined on the one hand by fetal antigen presentation and on the other hand by recognition of and reaction to these antigens by the maternal immune system .
There is evidence now that immunological recognition of pregnancy is important for the maintenance of gestation, and that inadequate recognition of fetal antigens might result in failed pregnancy .
Two main theories have been proposed to explain the phenomenon of pregnancy. One theory emphasizes the role of immunosuppressive reactions to protect the fetus. A second one, the “immune tropism theory”, works on the importance of the maternal immune response to paternal antigens present in the conceptus .
In 1953 it was formulated the hypothesis that the embryo can be considered as a semi-allogeneic graft and thus is vulnerable to rejection and immune tolerance. The mechanisms of adaptive immune response during pregnancy that allows successful placental graft have been investigated since then though not yet fully understood .
Today it is known the maternal immune system recognizes the embryo without triggering a response against its presence and development in the intrauterine environment. However, understanding the immunological mechanisms involved in the non-rejection of the placenta by the maternal immune system has been challenging. The placenta, for its embryonic origin, has both maternal and paternal genetic material and can potentially express paternal antigens, which are genetically foreign to the mother and therefore could induce an immune reaction that leads to rejection in a manner similar to that of other grafted tissues .
Similar to a neo plastic growth, early pregnancy is strongly characterized by intense cell proliferation (embryo and placenta ion). However, during pregnancy, the maternal immune system does not set of factions to block this proliferation, as would be expected in pathological conditions such as in tumors. There is an environment that favors conceptus development to a state of maturity where the fetus is capable of supporting extra uterine life .
This phenomenon, so-called “immune tolerance”, is initiated with the implantation of the conceptus. The main tissue exposed to the maternal immune system consists of trophoblasts, and the maternal-embryonic interface is created. In addition to a differentiated expression of HLA molecules that can identify what is “self” and “non-self” in the human body, these cells have a unique potential of response to local cytokines .
A pregnancy-specific immune status can be evidenced by the fact that certain diseases of autoimmune origin may aggravate or improve during pregnancy depending on the immune response pattern of the underlying disease. Thus, autoimmune diseases typically due to exacerbated inflammatory responses improve with gestational homeostasis while those characterized by the action of auto antibodies are significantly aggravated .
Like in any other inflammatory immune processes, during pregnancy, the uteroplacental unit initiates and modulates a harmonic interaction between the maternal vascular endothelium, local immune competent cells, and antigenic determinants on the surface of trophoblasts to actively regulate cell adhesion, activation, and migration through changes in local cytokines .
As pregnancy progresses anew vascular system that can efficiently provide oxygen and nutrients to the embryo develops. This “new” vascular system (placentation) is created when the trophoblasts cells invade the endometrial wall and reach uterine spiral arteries. Cytotrophoblast cells penetrate into the decidua and destroy the muscular layer of these vessels transforming them into high-capacitance/low resistance vessels. During the process of vascular invasion, the cytotrophoblasts differentiate from an originally epithelial phenotype to an endothelial phenotype covering the endovascular layer of spiral arteries .
Placentation allows the uterine artery to grow as pregnancy progresses, preventing shortage of blood flow to the fetal-placental unit. Fetal gene products as well as specific differentiation antigens are exposed locally to maternal immune competent cells .
In early stages of implantation of the ovum, when the human body acknowledges the presence of a “semi-allogeneic graft” - the trophoblast, an immune inflammatory response is set up, similar to that in the early of graft rejection. Mononuclear cell columns derived from trophoblasts are formed and invade the uterine decidua and its blood vessels to provide anchorage and blood supply to the developing fetus. Thus, trophoblast antigen presenting at the maternal-fetal interface seems to be an important component of the maternal immune response during pregnancy [1,4].
FACTORS INVOLVED WITH THE IMMUNE RESPONSE DURING PREGNANCY
Several genes are likely regulators of human implantation including Decay Accelerating Factor (DAF), Indoleamine 2,3 Dioxygenase (IDO), IL-15, IL-15Rα, Interferon Regulatory Factor-1 (IRF-1), lymphotoxin, Natural Killer (NK) Associated Transcript2 (NKAT2) and NKG5. The functions of these genes are quite diverse including promotion of NK cell proliferation, chemotaxis, inhibition of NK cell cytolytic activity, inhibition of cell growth (T-cells and pathogens), and inhibition of the classical complement pathway. These diverse functions are likely designed to prepare the endometrium for implantation and particularly to adapt the maternal immune system so that it can accommodate the fetus, an immunological “stranger” . Normal human pregnancy is characterized by low peripheral NK activity, and increased NK activity seems to play a role in spontaneous abortions of unknown etiology. The dynamics of the appearance of uterine NK cells suggest that one of the functions of these cells is control of placentation .
Ovulation, mating, and fertilization produce inflammatory immune changes at the mucosal surfaces of the female reproductive tract with direct effects on the blastocyst implantation in the uterus. The very exposure to sperm and its elements produces an immunosuppressive effect on the mucosal surfaces of the female reproductive tract .
Steroid hormones produced during ovulation also contribute to this effect. They modulate the activity of Antigen-Presenting Cells (APC) - originated from both myeloid and lymphoid lineage - that are directly involved with the immune responses [9,10].
Progesterone is the female hormone that has the most distinctive activity on the maternal immune system and maternal-fetal interface. Progesterone can suppress the effectors function of T cells and modulate calcium ion and potassium channels of cell membranes with a direct effect on gene expression in these cells .
The most important immunoregulatory effect of progesterone is probably its action on T lymphocytes that possess gamma/delta (γδ) T Cell Receptors (TCR). Following allogeneic stimulation by fatally derived antigens; this subset of pregnancy T lymphocytes develops progesterone receptors. At high progesterone concentrations, these lymphocytes produce an immunomodulatory protein, Progesterone-Induced Blocking Factor (PIBF), a mediator that, through changes in cytokine balance, inhibits NK activity and exerts an antiabortive effect in mice [3,12].
It is thus possible that, under certain circumstances, the semi-allogeneic fetus is not able to induce progesterone receptor expression in γδ T cells so that progesterone supplementation is not strong enough to elicit an appropriate alloimmune response and to maintain pregnancy . A successful pregnancy requires the maternal immune system to recognize and tolerate the semiallogeneic fetus, and allow for normal invasion of trophoblasts. Pregnancy complications are considered to be associated with dysfunctional maternal-fetal crosstalk .
Syncytiotrophoblast cells are responsible for nutrition of the embryo and production of ?-HCG and progesterone. These cells are originated from the cytotrophoblasts and recover almost all fetal surfaces and do not express HLA molecules. On the other hand, villous, extra villous, endovascular, and interstitial cytotrophoblasts cells express small amounts of HLA class I molecules. Extra villous cytotrophoblast cells express a specific HLA class I molecule, so-called HLA-G. HLA-Gexpressionis restricted to placental andthymic epithelial cells .
Decidual leukocytes are composed of a prominent cell population including NK cells, macrophages and T cells. These cells are responsible for alerting the maternal immune system for the presence of alloantigens throughout the entire pregnancy .
The decidua and its components function as a specialized immune tissue with several different functions including an essential role in implantation and maintenance of pregnancy. Decidual leukocytes may act directly and indirectly by expressing receptors that potentially mediate the recognition of fetal trophoblasts, trophoblastic invasion, and production of cytokines that regulate and modulate the maternal immune response and vascular function [7,8].
An orchestrated evolutionary maternal adaption toward tolerance of the semiallogeneic fetus is required to ensure decidualization and early embryo development . The mother does not reject the embryo as it develops in an isolated semi permeable environment. Thus, the maternal immune response is modulated and recognizes the fetus, which allows for the development of a successful pregnancy (Figure 1).
EPIGENETIC CONTROL OF IMMUNE RESPONSE IN PREGNANCY
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Citation:Salge AKM, Siqueira KM, Castral TC, Guimarães JV, Rocha AA, et al. (2017) Immunological aspects of pregnancy: a literature review. J Neonatol Clin Pediatr 4: 016.
Copyright: © 2017 Ana Karina Marques Salge, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.