Ana Mathew

Introduction: Preeclampsia (PE) is the leading hypertensive disorder of pregnancy affecting approximately 5-10% of pregnant mothers. ^1-3 Despite its prevalence, the exact mechanism causing PE remains elusive.³ In previous experimental models of PE, there has been evidence of deficiencies in regulatory T cell (Treg) counts leading to excessive inflammation and increased cytokine levels.^4,5,6  These studies have identified a reduction of Treg cells in the peripheral and cord blood of mothers with PE compared to the control group.^4,5 A potential explanation for the Treg depletion is abnormal lymphangiogenesis. In particular, activation of Tregs to obtain immune tolerance requires adequate antigen presentation through the lymphatic system.⁷ Therefore, these studies provide a potential mechanism explaining the hypertension, proteinuria, and edema that are pathognomonic for PE. Methods: Entire uterus from normal pregnant mice was used to identify the presence of lymphatic vessels at the maternal-fetal interface.⁸ Placental and fetal membranes were obtained from pregnant women with severe PE and gestational age-matched controls.⁷ Immunohistochemistry for LYVE1 was used to localize the distribution of lymphatic vessels and CD4, CD25, and FOXP3 for Tregs.⁸ Results: Interestingly, in both human and mouse tissues, LYVE1-positive vessels were present in the uterine wall and localized on the human decidua.⁸ Tubular lymphatics were abundant in the control decidua but significantly reduced in severe PE.⁷ These results were the first to demonstrate that the distribution of lymphatics at the maternal-fetal interface differs between normal and severe preeclamptic pregnancies. Compared to the controls, the number and ratio of CD4+ CD25+FOXP3+ cells were decreased in the decidua of severe PE.⁶ Treg-cell depletion in mice resulted in elevated serum proinflammatory cytokines.⁷ TNF (tumor necrosis factor) was increased by 400%, IFN-γ (interferon) by 135%, and IL-6 by 230% compared with Foxp3 control mice.⁷ Linear regression analysis identified a positive correlation between increased lymphatic vessel density and Treg numbers.⁸ Conclusions: Since the etiology of preeclampsia is unknown, the reduction of Treg cells due to abnormal lymphangiogenesis provides a potential mechanism in which clinical effects are manifested. The studies support the hypothesis that PE patients have lower levels of Treg cells that could be attributed to a disruption in lymphatic development. These results provide a conceptual base for further targeted studies investigating adoptive Treg transfer studies or other therapies to increase Tregs in vivo and suggest that this pathway may be targeted to improve preeclampsia outcomes.⁹

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