Abstract
Pregnancy is an immunological paradox whereby maternal immunity accepts a genetically unique fetus (or fetuses), while maintaining protective innate and adaptive responses to infectious pathogens. This close contact between the genetically diverse mother and fetus requires numerous mechanisms of immune tolerance initiated by trophoblast cell signals. However, in a placental condition known as villitis of unknown etiology (VUE), there appears to be a breakdown in this tolerance allowing maternal cytotoxic T-cells to traffic into the placenta to destroy fetal villi. VUE is associated with several gestational complications and an increased risk of recurrence in a subsequent pregnancy, making it a significant obstetrical diagnosis. The cause of VUE remains unclear, but dysfunctional signaling through immune checkpoint pathways, which have a critical role in blunting immune responses, may play an important role. Therefore, using placental tissue from normal pregnancy (n=8), VUE (n=8) and cytomegalovirus (CMV) infected placentae (n=4), we aimed to identify differences in programmed cell death 1 (PD-1), programmed death ligand-1 (PD-L1), LAG3 and CTLA4 expression between these etiologies by immunohistochemistry (IHC). Results demonstrated significantly lower expression of PD-L1 on trophoblast cells from VUE placentae compared to control and CMV infection. Additionally, we observed significantly higher counts of PD-1+ (>100 cells/image) and LAG3+ (0-120 cells/image) cells infiltrating into the villi during VUE compared to infection and control. Minimal CTLA4 staining was observed in all placentae, with only a few Hofbauer cells staining positive. Together, this suggests that a loss of tolerance through immune checkpoint signaling may be an important mechanism leading to the activation and trafficking of maternal cells into fetal villi during VUE. Further mechanistic studies are warranted to understand possible allograft rejection more clearly and in developing effective strategies to prevent this condition from occurring in utero.
Highlights
Chronic villitis is a placental condition characterized by inflammation and lymphohistiocytic infiltration into the chorionic villi with or without necrosis, and is categorized into either infectious villitis or non-infectious villitis, known as villitis of unknown etiology (VUE) [1]
VUE, a diagnosis characterized by the infiltration of maternal CD8+ T-cells into villous tissue of the placenta without infectious cause, is hypothesized to be the result of an immune rejection response targeted against the haploidentical fetus during pregnancy
Our results demonstrate that VUE leads to downregulation of programmed death ligand-1 (PD-L1) and upregulation of receptors programmed cell death 1 (PD-1) and lymphocyte activation gene protein 3 (LAG3) on infiltrating cells
Summary
Chronic villitis is a placental condition characterized by inflammation and lymphohistiocytic infiltration into the chorionic villi with or without necrosis, and is categorized into either infectious villitis or non-infectious villitis, known as villitis of unknown etiology (VUE) [1]. While villitis due to infectious etiologies are rare (1-4/1000 pregnancies), 6.6-33.8% of pregnancies are diagnosed with VUE following a term delivery [2,3,4]. The diagnosis of VUE requires exclusion of infectious etiologies and is hypothesized to be an anti-fetal allograft response [6, 7]. The cellular composition of VUE predominantly includes T-cells and macrophages with minor B-cell involvement [8, 9]. Immunohistochemical staining and in situ hybridization demonstrate maternal origin of T-cells and both maternal and fetal origin of macrophages, further supporting a breakdown in maternal-fetal tolerance [10, 11]
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