EXPRESSION, REGULATION AND RELEASE OF HUMAN PLACENTAL ANTIGENS: IMPLICATIONS FOR THE MATERNAL IMMUNE RESPONSE TO THE FETUS

Abstract

Pregnancy represents a unique immunological arrangement where the maternal immune system must tolerate and support the genetically foreign fetus. The mechanisms by which maternal tolerance to the fetus is achieved and the consequences if this balance is disrupted are not completely understood. In this work, we have shown for the first time that the placenta expresses at least six known human minor histocompatibility antigens (mHAgs), including three autosomal antigens, HA-1, BCL2A1 and KIAA0020, and three Y-chromosome-encoded antigens, DDX3Y, RPS4Y1 and KDM5D. In addition, we have shown that expression of at least one of these antigens, HA-1, is decreased in term as compared to first trimester placentas (P<0.01), is regulated by oxygen and is significantly higher in pre-eclamptic placentas as compared to controls (P=0.015). We also examined the protein content of exosomes released from the outermost layer of the placenta (trophoblast-derived exosomes) using mass spectrometry and found that, in addition to several exosome markers, trophoblast-derived exosomes contain the immune molecule HLA-DR, which is not expressed on the surface of the trophoblast. We then treated dendritic cells with trophoblast-derived exosomes either in the presence or absence of the immunostimulatory molecule, LPS. Dendritic cells treated with exosomes alone showed significant increases in IL-8 (P=0.05), VCAM-1 (P=0.01) and CD80 (P=0.05) mRNAs whereas dendritic cells treated with LPS + exosomes showed a significant decrease in CCL7 (P=0.03) and CD40LG (P=0.002) when compared to controls. In conclusion, we have found that the placenta expresses at least six mHAgs, that expression of at least one of these mHAgs, HA-1, is regulated by oxygen and is increased in placentas from women with pre-eclampsia, and that that exosomes released from placental trophoblast cells contain at least one known fetal antigen, HLA-DR, and can alter dendritic cell phenotype. Taken together, these findings indicate that the placenta expresses and releases antigenic materials into the maternal blood stream and may affect maternal immune responses to the fetus during pregnancy. These findings may have important implications for the maintenance of a healthy pregnancy, numerous pregnancy complications and many other diseases involving immune responses to foreign and self-antigens.