Immunology of Normal Pregnancy and Preeclampsia and the Role of Placental Non-Classical HLA and Decidual NK Cells

Pregnancy is considered a unique immunological process in which contact between the maternal innate immune system and the placental allograft results in maternal tolerance to paternally derived antigens. A growing body of research indicates that interactions between non-classical placental Human Leukocyte Antigen (NCHLA) and receptors on decidual Natural Killer (dNK) cells from early implantation are crucial to this process. Preeclampsia (PE), one of the leading causes of maternal and fetal morbidity and mortality, is also considered an autoimmune process. Currently, there is no treatment for PE except delivery. Most adverse outcomes derive from delayed diagnosis, while newer preventative therapies significantly improve outcomes. An early predictor of PE would enable universal screening, detect and treat high-risk populations earlier, and improve outcomes. Recently, we discovered that high placental HLA-E and G expression occurs during early normal pregnancies, and that placental NCHLA expression differs in PE. Others described the HLA-E/G complex, a potent immunosuppressor of dNK. Interestingly, dNK cells were found to have memory-like properties in binding to HLA-G and HLA-E. The theory proposed is that the HLA-G complex plays a major role in the etiology of PE. In this narrative review, we examine the relevant literature and present our recent findings and those of others that suggest a screening model for PE.