Eveline E. Schneeberger, MD
Massachusetts General Hospital
Professor of Pathology
Harvard Medical School
Dr. Schneeberger is Professor of Pathology at Harvard Medical School. She received her BA degree from the University of Colorado and her M.D. with honors from the University of Colorado Medical School. She completed an internship in Internal Medicine at Barnes Hospital in St. Louis, MO, followed by a four year residency in Pathology at the University of Rochester. She then spent an NIH-funded year conducting research at the Sir William Dunn School of Pathology, Oxford England with Professor Henry Harris. This was followed by an NIH-funded year of research at Harvard Medical School in the laboratory of Professor Morris J. Karnovsky. After seven years in the Pathology Department at Children’s Hospital, Boston, during which time she conducted research and served as a renal pathologist, she joined the Pathology Department at MGH in 1979 where, from 1979 to 2010, she served as a renal pathologist. During that time, as well as currently, she has been and continues to be an independent investigator whose research is funded by two NIH RO-1 grants. Her research interests include the cell and molecular biology of pulmonary epithelial cells. She has been an invited speaker at both national and international symposia. She is on the Editorial Boards of the American Journal of Pathology and the American Journal of Physiology, Cell Physiology, as well as an ad hoc reviewer for circa 23 other journals. She has served on a number of NIH and NIEHS study sections both as a permanent member, as well as an ad hoc reviewer of NIH research grant applications.
A single layer of epithelial cells separates us from the harmful effects of inhaled pathogens and environmental toxic agents. Tight junctions determine the integrity, barrier function and polarity of this cell layer. Should the cellular barrier be breached, the immune system must then distinguish innocuous from pathogenic antigens. Dendritic cells are key to this process.
Our laboratory examines the molecular composition and regulation of tight junctions as they pertain to the permeability properties of the lung. These studies utilize cultured cells and rodent animal models. Using inducible expression systems, we examined the contribution of occludin and claudin-1 to the barrier function of cultured epithelial cells. More recently, using siRNA to suppress occludin expression by >95% we found that occludin transduces signals from neighboring apoptotic cells to the actin cytoskeleton via RhoA. In further studies, using cholesterol depleting agents combined with differential centrifugation and density gradients, we observed that the integral tight junction proteins appear to segregate into two classes: those whose physical properties are cholesterol dependent (occludin, claudin-2 and –3) and those that are cholesterol independent (claudin-1, -4 and –7). Defining the molecular composition of tight junctions is key to understanding the barrier function of epithelial cells, and to devising strategies that prevent these proteins from serving as portals of entry to a variety of pathogens.
A second major goal of our laboratory is to examine the biology of dendritic cells in the lung. These important antigen-presenting cells are intercalated between epithelial cells of airways and in the interstitium of the lung. We have shown that dendritic cell precursors are enriched in the pulmonary vasculature, they are involved in the initiation of granulomatous inflammation, they engulf inhaled pathogens and transport them to local lymph nodes where they initiate an immune response. Using a mouse tracheal epithelial cell line in an in vitro chemotaxis assay, we have shown that dendritic cells form transient tight junctions in order to maintain the epithelial barrier. The ability of dendritic cells to migrate through the interstitium is dependent on expression of matrix metalloproteases (MMP), a process that we examine in selected MMP null mice. Elucidating these processes are key to understanding the defense mechanisms that operate to protect the lung from environmental pathogens.
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