The concept that pregnancy is associated with immune suppression has created a myth of pregnancy as a state of immunological weakness and, therefore, of increased susceptibility to infectious diseases. A challenging question is whether the maternal immune system is a friend or a foe of pregnancy. In this review, we discuss data associated to the role of the immune system during pregnancy. We propose a new paradigm in terms of the fetal-maternal immune interaction as well as the immunological response of the mother to micro-organism. Our challenge is to better understand the immunology of pregnancy in order to deliver the appropriate treatment to patients with pregnancy complications as well as to determine public policies for the protection of pregnant women during pandemics. Keywordsinflammation; pregnancy; TH1/TH2; macrophages; dendritic cellsThe idea that pregnancy is associated with immune suppression has created a myth of pregnancy as a state of immunological weakness and, therefore, of increased susceptibility to infectious diseases. A challenging question is whether the maternal immune system is a friend or a foe of pregnancy. In order to discuss this question we will first review some fundamental concepts associated with the immune system and pregnancy.A fundamental feature of the immune system is to protect the host from pathogens. This function depends upon the innate immune system's capacity to coordinate cell migration for surveillance and to recognize and respond to invading microorganisms. During normal pregnancy, the human decidua contains a high number of immune cells, such as macrophages, natural killer (NK) cells and, regulatory T cells (Treg) [1][2][3] [2,4,5]. B cells are absent from the adaptive immune system, but T lymphocytes constitute about 3-10% of the decidual immune cells [6]. During the first trimester, NK cells, dendritic cells, and macrophages infiltrate the decidua and accumulate around the invading trophoblast cells [7,8]. Interestingly, depletion of immune cells, instead of helping the pregnancy, terminates the pregnancy. Thus, deletion of macrophages, NK cells, or dendritic cells (DC) has deleterious effects on placental development, implantation, or decidual formation [9][10][11][12][13][14]. In elegant studies, it has been shown that in the absence of NK cells, trophoblast cells are not able to reach the endometrial vascularity leading to termination of the pregnancy [12]. These studies suggest that uNK cells are critical for trophoblast invasion in the uterus. Similarly, depletion of DCs prevented blastocyst implantation and decidual formation [15]. Indeed, this Consequently, the presence of immune cells at the implantation site is not associated with a response to the "foreign" fetus but is attracted to facilitate and protect the pregnancy. Therefore, the immune system at the implantation site is not suppressed-on the contrary it is active, functional, and is carefully controlled.Is the systemic immunity of the mother suppressed? Although we can find numerous studie...

Evidence suggests that an inflammatory profile of cytokines and chemokines persisting at a particular site would lead to the development of a chronic disease. Recent studies implicate bacterial infection as one possible link between inflammation and carcinogenesis; however, the crucial molecular pathways involved remain unknown. We hypothesized that one possible upstream signaling pathway leading to inflammation in carcinogenesis may be mediated by Toll-like receptors (TLR). We describe for the first time an adaptive mechanism acquired by ovarian cancer cells that allows them to promote a proinflammatory environment and develop chemoresistance. We propose that the TLR-4-MyD88 signaling pathway may be a risk factor for developing cancer and may represent a novel target for the development of biomodulators. Our work explains how bacterial products, such as lipopolysaccharide, can promote, directly from the tumor, the production of proinflammatory cytokines and the enhancement of tumor survival. In addition, we provide new evidence that links TLR-4 signaling, inflammation, and chemoresistance in ovarian cancer cells. (Cancer Res 2006; 66(7): 3859-68)

Intrauterine infections have been associated with pregnancy complications that are also linked with increased trophoblast apoptosis. TLRs are key components of the innate immune system which recognize conserved sequences on the surface of pathogens and trigger effector cell functions. We hypothesize that intrauterine infections may cause the excessive trophoblast cell apoptosis observed in abnormal pregnancies and that TLR may provide a mechanism of pathogenesis. In this study we describe the expression and function of TLR-2 and TLR-4 in first trimester trophoblast cells. Although ligation of TLR4 induced cytokine production by trophoblast cells, TLR-2 activation induced apoptosis. TLR-2 mediated apoptosis was dependent upon the Fas-associated death domain, the inactivation of the X-linked inhibitor of apoptosis, and the activation of caspases 8, 9, and 3. These results suggest that certain intrauterine infections may directly induce trophoblast cell death through TLR-2. Our findings provide a novel mechanism of pathogenesis for certain pregnancy complications in which there is engagement of the innate immune system.

Problem-Women with antiphospholipid antibodies (aPL) are at risk for recurrent miscarriage, preeclampsia and preterm labor. aPL target the placenta directly by binding to Beta 2 -Glycoprotein I (β 2 GPI) expressed on the surface of trophoblast cells. The objective of this study was to determine the effects of aPL on trophoblast function and the mechanisms involved.Method of study-First trimester trophoblast were treated with anti-β 2 GPI monoclonal antibodies and patient-derived aPL, after which cell survival and function was evaluated.Results-We report that anti-β 2 GPI antibodies trigger an inflammatory response in trophoblast, characterized by increased secretion of IL-8, MCP-1, GRO-α and IL-1β, and that this occurs in a TLR-4/MyD88-dependent manner. At high concentrations, these antibodies also induce caspasemediated cell death. This was attenuated upon disabling of the MyD88 pathway, suggesting that anti-β 2 GPI-induced inflammatory mediators compromise trophoblast survival by acting in an autocrine/ paracrine manner. Enhanced IL-8, GRO-α and IL-1β secretion also occured when trophoblast were incubated with antibodies from patients with antiphospholipid syndrome. Heparin, which acts as a pro-survival factor in human trophoblast, attenuated the anti-β 2 GPI antibody-mediated cell death, and also the pro-inflammatory response, but only at high concentrations.Conclusions-These findings demonstrate that aPL triggers a placental inflammatory response via the TLR-4/MyD88 pathway, which in turn compromises trophoblast survival. Thus, the TLR-4/ MyD88 pathway may provide a new therapeutic target to improve pregnancy outcome in antiphospholipid syndrome patients.

The function of the maternal immune system during implantation and throughout pregnancy is, therefore, an important area of investigation. This review will discuss the role of decidual macrophages in apoptotic cell clearance during pregnancy.