Placental Biology and Maternal-Fetal Interaction

John P. Atkinson, MD, is the Samuel B. Grant Professor of Medicine in the Department of Medicine, professor of molecular microbiology and chief of the Division of Rheumatology. He is also a member of the National Academy of Sciences. His research focuses on the complement system, which represents an integral part of the innate and adaptive immune response and thus defends the host against microbes. It recognizes pathogens and mediates inflammation and instructs adaptive immunity by releasing small peptides that activate cells and by attaching large fragments to a target. The latter serve as opsonins to promote immune adherence and phagocytosis and antigen processing and to educate the adaptive immune system. Many human diseases are mediated by autoantibodies that form complement-activating immune complexes that can damage cells and tissues if not properly regulated and disposed of. A more recently recognized function of the complement system is its interaction with altered self such as apoptotic and necrotic cells. Further, debris such as oxidized lipids (atherosclerosis), amyloid proteins (Alzheimer’s), lipofuscin pigments (age-related macular degeneration) and urate crystals (gout) may accumulate to cause much morbidity and mortality. Polymorphisms and heterozygous mutations in complement regulatory genes predispose humans to these conditions, which feature chronic inflammation.

To facilitate clinical-pathologic correlations, Atkinson’s laboratory has focused on characterizing a multigene family of receptor and regulatory proteins that regulate complement activation and serve as receptors for complement-coated antigens. Their structure-function relationships, cell signaling, disease associations and pathogen interactions are under investigation. Multiple pathogens, including viruses (measles, pox, adeno and flavi), bacteria (Neisseria, Streptococcus, E. coli) and parasites (malaria), abuse these proteins by employing them as a receptor for cellular attachment or as a regulator to protect themselves from complement attack. These complement regulatory proteins are also in clinical trials as therapeutic agents to thwart undesirable complement activation such as in autoimmune diseases.

D. Michael Nelson, MD, PhD, is the Virginia S. Lang Professor of Obstetrics and Gynecology and vice chair of the Department of Obstetrics and Gynecology. His long-term research interests focus on how the human placenta contributes to normal and abnormal pregnancy development. The trophoblast layer of human placental villi interfaces the mother and fetus, transporting nutrients to the baby and secreting multiple protein and steroid products that are important for the maintenance of pregnancy. Differentiation of the trophoblast layer is a tightly regulated process that proceeds on a continuum from a proliferative, undifferentiated, mononucleated cytotrophoblast to a terminally differentiated syncytiotrophoblast. Under-perfusion, villous hypoxia, and enhanced fibrin deposition are characteristic of placentas from pregnancies complicated by fetal growth restriction and preeclampsia. His lab studies the molecular and cellular mechanisms that regulate normal trophoblast differentiation and the altered differentiation and enhanced apoptosis that occur in response to hypoxia. He uses primary cultures of human trophoblast to investigate the roles of peroxisome proliferator-activated receptor-gamma (PPAR-g) and prostaglandins to mediate the effects of exogenous stimuli, including hypoxia, homocysteine and fibrin matrix, on trophoblast biology. His lab dissects signaling pathways involving the Bcl-2 proteins and caspases in our studies of apoptosis. His lab also studies the steps in apoptosis that are unique in the syncytiotrophoblast and that contrast this syncytium with a cell containing only one nucleus, the cytotrophoblast. Findings in vitro are then examined in placentas of women with pregnancy pathologies to determine if the mechanisms involved with differentiation and apoptosis in vitro apply to the in vivo state.

Wayne M. Yokoyama, MD, is the Sam J. Levin and Audrey Loew Levin Professor in the Department of Medicine and is professor of pathology and immunology. He is a member of the National Academy of Sciences and a Howard Hughes Medical Institute Investigator. His laboratory studies various aspects of the innate immune system in the context of murine cytomegalovirus (MCMV) and cowpox virus (CPXV) infections, as well as tumors. The innate immune system defends the host from pathogens and tumors while the adaptive immune system is being mustered. By providing early detection and control, it can also shape the T and B cell response. Natural killer (NK) cells are a major constituent of the innate immune system. Yokoyama is particularly interested in NK cell receptors that recognize ligands on their infected or tumor cell targets. Over the years, he has identified and characterized NK cell inhibitory receptors that recognize major histocompatibility complex class I molecules on the target cell. These inhibitory receptors block the function of NK cell activation receptors that recognize other target cell surface ligands, including molecules encoded by viruses. Together, these receptors dictate whether or not the NK cell will kill normal or diseased cells, not only because of ligand recognition but also due to other effects on NK cell function, i.e., tolerance, which includes a recently described process termed “licensing.”

In addition to their role in host defense, NK cells accumulate at the maternal-fetal interface and are thought to play a critical role during pregnancy. The close proximity of uterine NK (uNK) cells to fetal trophoblast cells of the placenta would seemingly lead to catastrophic consequences, as the trophoblast cells are semi-allogeneic. A fundamental enigma of pregnancy is that the fetal cells constitute an allograft but, in normal pregnancies, they are in effect not perceived as foreign and are not rejected by the maternal immune system. Although the mechanisms involved in achieving NK cell tolerance are becoming increasingly well-defined, further clarification is required, given the clinical implications of this work in the areas of infection, transplantation, cancer and pregnancy. In recent work, Yokoyama has investigated the mechanisms of NK cell tolerance and how it may apply to uNK cells at the maternal-fetal interface.

SUMMARY

John P. Atkinson, MD, chief, Division of Rheumatology, and D. Michael Nelson, MD, PhD, vice chair of the Department of Obstetrics and Gynecology, have recently developed a collaboration targeting the complement cascade in pregnancy complications and placental dysfunction. This collaboration stemmed from recent publications that indicate the complement cascade plays a key role not only in normal pregnancy but also in pregnancy maladies. Wayne M. Yokoyama, MD, is a world leader in the area of immunobiology and is currently working on projects with junior members of the Department of Obstetrics and Gynecology. The backgrounds of these investigators in immunology and reproductive biology provide a framework for inter-disciplinary training of WRHR candidates across a wide spectrum of reproductive disorders, from infertility and early pregnancy loss to later pregnancy complications such as preeclampsia and intrauterine growth restriction. All three would provide exceptional mentors for WRHR scholars.