ABSTRACT PROBLEM: Pre-eclampsia is a common obstetrical disorder of placental origin with both local and systemic anomalies, which affects 3-5% of pregnancies representing the leading cause of maternal, fetal and neonatal mortality. Altough it is manifested in the second half of pregnancy, pre-eclampsia is thought to be an implantation disorder. The current hypothesis regarding the etiology of pre-eclampsia is focused on inadequate trophoblast invasion and placentation presumably as a result of maladaptation of maternal immune responses locally. Later on, an excessive maternal inflammatory response develops systemically in response to the placental factors released by the oxidatively stressed and functional impared placenta. TIM family is a relatively newly described group of molecules with a conserved structure and important immunological functions. A growing body of evidence supports the critical role of different TIM molecules as modulators of the immune response in transplant tolerance. There is mounting evidence that TIM-3 is a potent regulator of both the adaptive and innate immune response. TIM-3 is expressed in a variety of immune cells, including Th1, Th17, NK cells, NKT cells, regulatory T cells, dendritic cells, monocytes, macrophages and mast cells. Identification of Galectin-9 (Gal-9) as a ligand for TIM-3 has established the Galectin-9/TIM-3 pathway as an important regulator of Th1 immunity and tolerance induction. Although data about the role of Galectin-9/TIM-3 pathway in the pathogenesis of human diseases is emerging, data about their role during human pregnancy and feto-maternal immunological relationship is scarce. The aim of our present study was to investigate the expression of Galectin-9 and TIM-3 molecules by peripheral blood mononuclear cells in healthy pregnancy and pre-eclampsia. METHODS: Pregnant women with early onset pre-eclampsia and classical symptoms (hypertonia, proteinuria and edema) were included in the study. Healthy pregnant women appropriatelymatched for gestational age formed the control group. Peripheral bloodmononuclear cells (PBMC) were separated fromheparinized venous blood on Ficoll-Paque gradient. Separated PBMC were used for staining and flow cytometric analysis. RESULTS: Investigating peripheral blood lymphocytes of women with pre-eclampsia, our results showed a decreased TIM-3 expression by CD8+ T and NK cells compared to healthy pregnant women. Although Gal-9 expression by CD8+ T and NK cells was significantly higher in patients with pre-eclampsia, we hypothesize that low TIM-3 expression allows cells to escape Gal-9 induced cell death leading to uninhibited expansion of pro-inflammatory Th1 and Th17 responses characteristics of the maternal syndrome of the disease. CONCLUSIONS: These data suggest that Gal-9/TIM-3 pathway could play an important role in the immunoregulation during pregnancy and the altered Galectin-9 and TIM-3 expression could result in an enhanced systemic inflammatory response including the activation of Th1 lymphocytes and type-1 bias in pre-eclampsia. Understanding the pathways and molecules responsible for regulation of TIM-3 and Gal-9 expression will greatly facilitate the ability to ultimately modulate this pathway for therapeutic benefit. Since Gal-9/TIM-3 pathway play an important role in the induction of immunological tolerance, activation of the pathway might represent a novel therapeutic strategy for the treatment of pathological conditions during pregnancy
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