Can murine uterine natural killer cells give insights into the pathogenesis of preeclampsia?

These studies aimed to advance understanding of the functions of pregnancy- associated uterine lymphocytes of the natural killer (NK) cell lineage. The approach was morphometric analysis of implantation sites from timed pregna ncies in genetically modified mice deficient in NK cells or in signaling as sociated with their major product, the cytokine interferon-gamma. In four d ifferent strains of pregnant, NK cell-deficient mice, the major decidual ar terioles failed to undergo modifications to their smooth-muscle coats and d isplayed endothelial cell damage. Decidua lacked normal cell density. This pathology was observed by the end of the first trimester, before placental differentiation. By midgestation in these strains, placentas were smaller t han in control strains. In normal mice, many uterine NK cells are perivascu lar in location and appear to be activated because they are the major sourc es of interferon-gamma and of the interferon-gamma-regulated enzyme inducib le nitric oxide synthase. During pregnancy in mice genetically ablated for interferon-gamma, the interferon-gamma receptor chain-alpha or the transcri ption factor interferon regulatory factor-1, uterine NK cells differentiate but appear to be abnormal both morphologically and functionally. In these three strains, failure of pregnancy-induced vascular modifications and over t necrosis of decidua occur. Thus, in mice, lymphocytes of the NK cell line age make specialized contributions to pregnancy-associated modification of the uterine vasculature and to maintenance of decidua. These contributions are achieved through interferon-gamma-mediated gene regulation and appear t o enhance subsequent placental growth. Human CD56 bright decidual lymphocyt es may have analogous functions. If so, changes in numbers or levels of act ivity of human uterine NK cells or mutations in genes regulated by uterine interferon-gamma could contribute to initiation of preeclampsia. Copyright (C) 2000 by the Society for Gynecologic Investigations.