Pregnancy has long been associated with a non-inflammatory environment similar to and often thought of in terms of the allograft paradigm. This paradigm considers the fetus a semi-allograft that is not rejected by the maternal immune system (Medawar, 1948, 1961; Medawar et al., 1953). This hypothesis brought forth by Medawar’s assumptions that the placenta is an allograft because the placenta is expressing paternal proteins, therefore, the fetus should be rejected, lead researches to investigate the mechanism whereby the placenta and fetus are escaping the maternal immune system. In addition, there is a large presence of leukocytes and B cells present at the maternal-fetal interface and the only way to explain the acceptance of the semi-allograft fetus is by a maternal immune response that does not elicit rejection (Fest et al., 2007). Nearly 70% of decidual leukocytes are natural killer cells, 20-25% are macrophages, 1.7% are dendritic cells, approximately 3-10% are T cells, and B cells have been reported at low numbers (Abelius et al., 2015; Bulmer et al., 1988; Gardner and Luciw, 2008; Mor et al., 2017; Muzzio et al., 2014). However, today we know that the placenta is not just a transplanted organ. Rather there are mechanisms by which the maternal immune system does not respond against paternal antigens, the maternal immune system, and trophoblast cells are developing together to create a cooperative environment, all of which ultimately aids in the production of a successful pregnancy (Mor et al., 2011). Therefore, it has become to be accepted that the establishment of pregnancy is no longer thought of as being a non-inflammatory event rather it is a pro-inflammatory process.
Implantation and placentation are pro-inflammatory events. During these two stages the blastocyst initiating attachment to the luminal epithelium of the uterus and require the up-regulation of adhesive molecules, such as integrins for attachment. Upon attachment, the trophoblast will begin to invade into the luminal epithelium, which is species dependent (Arck and Hecher, 2013). The invasion process by the trophoblast is fairly destructive and damages the endometrial tissue. Following this process, the trophoblast will replace the endothelium lining and the vascular smooth muscle of the maternal blood vessels in order to provide an adequate supply of nutrients and oxygen (Dekel et al., 2014). These stages are immunologically similar to the processes that are observed during tissue injury and repair where different cytokines, chemokines, adhesion molecules, and growth factors are released (Dunn et al., 2003; Paria et al., 2002). The inflammation at the site of implantation is characterized by a high level of pro-inflammatory T helper-1 and cytokines, such as: interlukin-6 (IL-6), IL-8, IL-15, chemokine ligand 1, chemokine ligand 4, osteopontin, and tumor necrosis factor (TNF), granulocyte macrophage colony-stimulating factor (GM-CSF) (Mor et al., 2017). These inflammatory factors can be derived from both the infiltrating immune cells and the endometrial stromal cells (Norwitz et al., 2015). All of these factors are important for the inflammatory environment in order to move the stored adhesion molecules to the apical surface of the luminal epithelium, increase the affinity of the adhesion molecules (such as L-selectins) to make contact with the blastocyst for adhesion, and to reorganize the adhesion molecules to aid in blastocyst attachment (Mor et al., 2017).
There is also an abundance of uterine-specific natural killer cells, macrophages, and dendritic cells (Abrahams et al., 2004; Laskarin et al., 2007; Le Bouteiller and Piccinni, 2008). The uterine natural killer cells play an important role in regulating the invading trophoblast through the secretion of IL-8 and interferon-inducible protein-10 chemokines (Mor et al., 2011). In addition to regulating the invasion process, they are also potent secretors of angiogenic factors which stimulate vascular growth (Burke et al., 2010; Mor, 2008). There are heterogeneous populations of dendritic cells that aid in the initiation and coordination of the innate and adaptive immune responses (Laskarin et al., 2007, 2007; Scholz et al., 2008). There is a substantial amount of evidence to support that macrophages and dendritic cells play an essential role in determining the cytokine profile at the uterine-placental interface (Koga and Mor, 2008; Laskarin et al., 2007; Mor, 2008).
The natural killer cells present in the decidual are specialized natural killer cells. Meaning, they are less cytotoxic than the natural killer cells in the periphery. It is thought that the uterine natural killer cells are less cytotoxic because they were induced by IL-15 and TGF derived from the trophoblast cells (Hanna et al., 2006). The uterine natural killer cells have a specialized role in that they are important for the remodeling of the vasculature in the decidua and essential in the development of the placenta (Mor et al., 2017).
Similar to the natural killer cells, the monocytes that are recruited take on a unique M2-like macrophage phenotype. This phenotype is thought to be induced by a trophoblast factor called trophoblast-derived macrophage colony stimulating factor (M-CSF) and IL-10 (Aldo et al., 2014; Svensson-Arvelund et al., 2015). These specialized M2-like macrophages are essential for tissue remodeling because they aid in the removal of the degraded extracellular matrix, as well as in the removal of apoptotic cells (Abrahams et al., 2004; Houser et al., 2011; Repnik et al., 2008). In addition to their phagocytic mechanisms, these M2-like macrophages are able to secrete immunomodulatory cytokines, such as TGF and type I interferons (Houser et al., 2011).
The trophoblast cells of the placenta also play a role in immune regulation. During the process of implantation and early placentation the trophoblast is actively molding the immunological environment at the site of implantation. They do this by attracting immune cells and educating them at the site of implantation. The trophoblast cells are constantly producing cytokines, such as; CXCL12, CXCL8, transforming growth factor- (TGF) and CCL2. These chemokines secreted by the trophoblast are promoting the recruitment of monocytes, neutrophils, natural killer cells, T cells, and T regulatory cells (Ramhorst et al., 2012). In addition to secreting chemokines, the trophoblast cells also secret cytokines. The cytokines produced promote the differentiation of the recruited immune cells. This allows them to differentiate into cells that are important for the successful maintained of pregnancy (Manaster et al., 2008).
The trophoblast cells can sense and respond to their microenvironment in addition to their production of cytokines and chemokines. The trophoblast cells are able to do this through their expression of cell surface receptors that are able to recognize molecular patterns within the microenvironment. These cell surface receptors are toll-like receptors and NOD-like receptors. Both of these are able to recognize pathogen-associated molecular patterns (PAMPs) and DAMPs that are produced by dying cells (Abrahams et al., 2005; Costello et al., 2007; Janeway and Medzhitov, 2002). By having these receptors, the trophoblast cells are able to sense are respond to signals, as well as, attract and educate the immune cells properly. This allows the trophoblast cells a unique ability in how they aid in decidual differentiation, the migration and invasion of trophoblast cells, angiogenesis and remodeling of uterine spiral arteries, and the development of the placenta and fetus (Mor et al., 2017).
CD4 T regulatory are important in mediating fetal tolerance. It has been observed in mice and human studies that the frequency of T regulatory cells increases in the decidua as pregnancy progresses (Guleria et al., 2005; Mjösberg et al., 2010; Zhao et al., 2007). Regulatory T cells express the chemokine receptor 5 (CCR5), which has been associated with proinflammatory and anti-inflammatory effects of T cells (Kallikourdis et al., 2007). The CCR5 is expressed on mature or antigen-experienced effector T cells and is involved in homing of cells to the site of inflammation from secondary lymphoid organs. It seems likely that the fetal antigens are the cause for expansion of the CCR5- CD4 T regulatory cells (Kallikourdis et al., 2007). Potentially, aiding in the increase of T regulatory cells during pregnancy. Interestingly, this study also showed that pregnancy loss rates were lower in second pregnancies then first pregnancy, this may be due to the antigen specific memory of the T regulatory cells from the first pregnancy and allow for greater accumulation of these cells during the second pregnancy.
Over the years there has been an increase in the numbers of studies that support the idea that pregnancy occurs in an immune environment that is dynamic and responsive, not one that is suppressive. The trophoblast plays a significant role in initiating a receptive immune environment at the uterine-placental interface, which occurs through the production secretion of cytokines and chemokines, as well as, through the upregulation of cell surface receptors. In addition, invasion into the uterine luminal epithelium by the trophoblast is similar to the tissue damage and repair response seen in wound healing of the skin. This initiates a proinflammatory response, that again, becomes modified by the trophoblast cells. The original paradigm that pregnancy is ant-inflammatory process continues to be challenged and hopefully will soon be accepted as being a proinflammatory process.