American Journal of Reproductive Immunology

Citation Redman CWG, Sargent IL. Immunology of Pre‐eclampsia. Am J Reprod Immunol 2010

Pre‐eclampsia develops in stages, only the last being the clinical illness. This is generated by a non‐specific, systemic (vascular), inflammatory response, secondary to placental oxidative stress and not by reactivity to fetal alloantigens. However, maternal adaptation to fetal (paternal alloantigens) is crucial in the earlier stages. A pre‐conceptual phase involves maternal tolerization to paternal antigens by seminal plasma. After conception, regulatory T cells, interacting with indoleamine 2,3‐dioxygenase, together with decidual NK cell recognition of fetal HLA‐C on extravillous trophoblast may facilitate placental growth by immunoregulation. Complete failure of this mechanism would cause miscarriage, while partial failure would cause poor placentation and dysfunctional uteroplacental perfusion. The first pregnancy preponderance and partner specificity of pre‐eclampsia can be explained by this model. For the first time, the pathogenesis of pre‐eclampsia can be related to defined immune mechanisms that are appropriate to the fetomaternal frontier. Now, the challenge is to prove the detail.

The authors explore the hypothesis that tumor necrosis factor‐α (TNF‐α) and possibly other inflammatory cytokines are overproduced by the placenta in response to local ischemia/hypoxia contributing to increased plasma levels, and subsequent endothelial activation and dysfunction in the pregnancy disorder, preeclampsia. It is widely held that inadequate trophoblast invasion and physiologic remodeling of spiral arteries initiate placental ischemia/hypoxia in preeclampsia. Furthermore, focal areas of placental hypoxia have been implicated in the production of “toxic” factor(s) by the placenta, which circulate and cause maternal disease. Placental trophoblast cells and fetoplacental macrophages normally produce TNF‐α and in‐terleukin‐1 (IL‐1), which are capable of producing endothelial cell activation and dysfunction. Hypoxia has recently been reported to increase TNF‐α and IL‐1 production by term villous explants from the human placenta. Placental cells also express erythropoietin (EPO), which is the prototype molecule for transcriptional regulation by hypoxia in mammals. Interestingly, TNF‐α and IL‐1 have DNA sequences homologous or nearly homologous to the hypoxia‐responsive enhancer element of the EPO gene, thus providing a potential, but as of yet, untested molecular link between placental hypoxia and stimulation of cytokine production. Inflammatory cytokines overproduced by the placenta in response to hypoxia may then lead to increased plasma levels and endothelial activation and dysfunction in preeclampsia. The purpose of this short review is to critically evaluate the hypothesis that placental cytokines contribute to the pathogenesis of preeclampsia. Of note, the etiology of the disease presumably related to deficient trophoblast invasion is beyond the scope of this work.

PROBLEM: Circulating inflammatory cytokines have been implicated in the pathogenesis of preeclampsia. To test this hypothesis, we measured plasma levels of immunoreactive tumor necrosis factor (TNF)‐α and ‐β, interleukin (IL)−1α and ‐β, and IL‐6 and −10 in women with preeclampsia, in women with transient gestational hypertension, and throughout normal pregnancy.

METHOD OF STUDY: Enzyme‐linked immunosorbent assays were used and subjected to extensive validation studies.

RESULTS: The median concentration of plasma TNF‐α was increased by twofold in women with preeclampsia compared with that in normal third‐trimester pregnancy (P < 0.001) and in women with gestational hypertension (P < 0.04). The median concentration of plasma IL‐6 was increased by threefold in women with preeclampsia compared with that in normal third‐trimester pregnancy (P < 0.001) and increased twofold compared with that in women with gestational hypertension (P < 0.1). There were no significant differences observed in the levels of plasma IL‐1β and IL‐10 between the preeclamptic and other subject groups. The level of IL‐1β, but not the levels of IL‐10, TNF‐α, or IL‐6, was significantly changed during normal pregnancy compared with the nonpregnant condition manifesting an overall decline (P < 0.04). TNF‐β and IL‐1α were not detected in any samples, possibly because of the low sensitivity of these particular immunoassays.

CONCLUSION: Elevated levels of TNF‐α and IL‐6 may contribute to the putative endothelial dysfunction of preeclampsia.

PROBLEM:  To review the literature on the role of peritoneal cytokines in the pathogenesis and endometriosis‐related infertility.

METHODS OF STUDY:  A MEDLINE search was conducted by the key words of cytokine and endometriosis in the English publications, and references identified within the identified papers were also reviewed.

RESULTS:  Several cytokines including interleukin (IL)‐1, 6, 8, 10, tumor necrosis factor (TNF)‐α, and vascular endothelial growth factor (VEGF) were reported to be increased in the peritoneal fluid (PF) of women with endometriosis. Those cytokines may be involved in macrophage activation, inflammatory change and enhanced angiogenesis. However, some cytokines were less expressed such as IL‐2, and interferon (IFN)‐γ. They reflect the impaired T‐ and natural killer (NK)‐cell function. Endometriotic implants produce some factors, e.g. matrix metalloproteinases (MMPs), Bcl‐2, and affect their capacity to implant into the peritoneum.

CONCLUSION:  Peritoneal cytokines, which are produced by mesothelial cells, leukocytes and ectopic endometrial cells, interwork locally and systemically in women with endometriosis. More studies about the specific role and interactions of these cytokines are needed to improve the understanding of endometriosis and to develop novel therapies.

PROBLEM: Trophectoderm of ruminant conceptuses (embryo and associated membranes) secretes tau interferons (IFNẗ) as the pregnancy recognition signal. How does it act?

METHOD: Review of current data.

RESULTS: IFNt acts on uterine epithelium to suppress transcription of the genes for estrogen receptor and oxytocin receptor. This blocks development of the uterine luteolytic mechanism and, therefore, release of luteolytic pulses of prostaglandin F_2α, but it has no effect on expression of the progesterone receptor. Maintenance of progesterone secretion by the corpus luteum ensures establishment and maintenance of pregnancy. Secretion of IFNẗ on days 12–15 for sheep and days 14–17 for cows and goats is essential for pregnancy recognition.

CONCLUSION: We propose that IFNẗ affects endometrial gene expression by activating the Jak/Stat pathway, which results in formation of the ISGF3α transcription factor complex. ISGF3α binds to interferon‐stimulated response elements and activates transcription of interferon‐responsive genes such as interferon regulatory factor‐1 (IRF‐1) which, in turn, activates expression of the negative‐acting transcription factor IRF‐2. Pregnancy (or intrauterine injection of roIFNẗ) results in a transient increase in endometrial IRF‐1 expression followed 36–48 hr later by a sustained increase in IRF‐2. We propose that IRF‐2, or an IFNẗ‐induced negative regulatory factor like IRF‐2, suppresses expression of the estrogen receptor gene and directly or indirectly blocks expression of the gene for oxytocin receptor to abrogate the uterine luteolytic mechanism and ensure the establishment of pregnancy.

PROBLEM: Pregnancy affects the maternal immune system and the clinical course of maternal diseases. Here we report the changes in the detailed lymphocyte subsets of helper T cells, suppressor T cells, CD5⁺ B cells, T cell receptor (TCR) αβ‐positive T cells (Tαβ cells), TCRαβ‐negative T cell (Tγδ cells), and others during and after pregnancy through to one year postpartum, and discuss the significance of the changes.

METHOD: The absolute numbers of helper T cells, suppressor T cells, cytotoxic T cells, TCRαβ‐negative T cells (Tγδ cells), CD5^— B cells, CD5⁺ B cells, and NK cell subsets were examined by two‐color flow cytometry in peripheral blood from 51 healthy non‐pregnant women, 106 healthy pregnant women, and 148 healthy postpartum women.

RESULTS: In early pregnancy, the numbers of suppressor T cells and NK cells with strong cytotoxicity (NK⁺⁺⁺ cells) increased, and the number of cytotoxic T cells decreased. In late pregnancy, the helper T cell and NK⁺⁺⁺ cell numbers decreased. Tαβ, CD5^— B and CD5⁺ B cells decreased during pregnancy. After delivery, helper T cells and cytotoxic T cells increased from 1 to 4 months postpartum, and suppressor T cells increased at 7 months postpartum. TCRαβ‐negative T cells increased at 4 to 10 months postpartum. Both CD5^— and CD5⁺ B cells decreased further at 1 month postpartum, but CD5⁺ B cells increased markedly at 7 to 10 months postpartum.

CONCLUSIONS: These data indicate that 1) early increases of suppressor T cells and NK⁺⁺⁺ cells during pregnancy may be related to the mechanism to accept or reject the fetus in early pregnancy, respectively; 2) late decreases of helper T cells and NK⁺⁺⁺ cells may be related to the maintenance of pregnancy: 3) postpartum increases of helper T cells, cytotoxic T cells, TCRαβ‐negative T cells (Tγδ cells), and CD5⁺ B cells may be related to the postpartum aggravation of autoimmune diseases; and 4) the immunological effects of pregnancy remains until about 1 year after delivery.

Causes for pre‐implantation embryo loss, which can be as high as 50% or more of fertilized embryos, are multifactorial and largely undescribed. Studies in cattle using mastitis as a model indicate that one cause of early embryonic loss is infectious disease or activation of immune responses at sites outside the reproductive tract. Infection of the mammary gland in dairy cattle is associated with a reduction in pregnancy rate (proportion of inseminated cows that become pregnant) and an increase in the number of inseminations required to establish pregnancy. Also, intravenous challenge with bacterial peptidoglycan and polysaccharide at ∼days 3–5 after breeding reduced subsequent pregnancy rate in sheep that had been previously immunized against the same material. The mechanism by which extrauterine activation of immune and inflammatory responses leads to embryonic loss is not clear although cytokines probably play a crucial role. Effects could be exerted at the level of the hypothalamic–pituitary axis, ovary, reproductive tract or embryo. Interferon (IFN)‐α, for example, which can reduce pregnancy rate in cattle when injected around 13–19 days after breeding, increases body temperature, inhibits secretion of luteinizing hormone, and reduces circulating concentrations of progesterone. Other cytokines or products of cytokine activation could cause embryonic loss by causing hyperthermia (as elevated temperature blocks oocyte function and embryonic development), exerting toxic effects on the corpus luteum [for example, IFN‐γ, tumor necrosis factor‐α (TNF‐α) and prostaglandin F_2α], stimulating endometrial prostaglandin synthesis [TNF‐α and interleukin(IL)‐1β], reducing endometrial cell proliferation (IL‐1β), and interfering with oocyte maturation and embryonic development (TNF‐α, nitric oxide, and prostaglandin F_2α). Although largely neglected by reproductive immunologists, study of the involvement of the immune system in pre‐implantation embryonic loss is likely to lead to new methods for enhancing fertility.

PROBLEM: Integrins belong to a family of cell adhesion molecules that are present on virtually all cells. The temporal and spatial expression of these important proteins on the human endometrium suggests that certain integrins may participate in the cascade of molecular events leading to successful implantation.

METHODS: Using immunohistochemistry, we studied the expression of 12 different integrins in up to 600 samples of human endometrium throughout the menstrual cycle. Intensity and distribution of staining was determined using the semiquantitative HSCORE, with specific focus on the differences between glandular and luminal expression.

RESULTS: We noted that the glandular and luminal epithelium undergo independent alterations in integrin expression throughout the menstrual cycle. Specifically, glandular epithelium express certain integrins only during the window of implantation, while luminal epithelium down‐regulate certain integrins during this time. The expression of one integrin (the αvβ3 vitronectin receptor) on both luminal and glandular epithelium coincides with the time of embryo attachment; aberrant expression of this integrin is associated with infertility.

CONCLUSION: It appears that the endometrium is a unique tissue with regard to the number of integrins that undergo temporal and spatial changes during the menstrual cycle. These data may offer new directions for the development of a novel contraceptive approach targeted to the endometrium as well as a better understanding of occult causes of infertility in women.

PROBLEM: The demand for increased angiogenesis and microvascular permeability during cyclical changes in the endometrium and during placentation raises the possibility that aberrations in these events could lead to suboptimal reproductive performance. However, relatively little is presently known regarding the regulation of vascular growth and permeability in these tissues.

METHOD OF STUDY: This review of current literature focuses on the expression, regulation, and potential physiological effects of vascular endothelial growth factor (VEGF) within endometrial and placental tissue.

RESULTS: Spatial and temporal expression of VEGF as well as its restricted specificity, essential role in vasculogenesis/angiogenesis, and ability to induce vascular permeability makes VEGF an attractive regulator of vascular growth and permeability in the endometrium and placenta.

CONCLUSION: A better understanding of the production, regulation, and physiological responses of the vasculature to angiogenic growth factors may lead to new therapeutic strategies for reproductive disturbances secondary to vascular insufficiencies within the female reproductive tract.