Gastroenterology

Chief, Gastroenterology Division
Director, Institutional Training Grant

(For further information on Dr. Blumberg’s research activity, you may consult his website at http://rsblumberg.bwh.harvard.edu ).  The intestinal epithelial cell surface represents a vast frontier of body surfaces that must be defended by the immune system.  The intestinal immune system must defend against the many infectious and toxic assaults that may breach the epithelium and cause intestinal injury.  The immune system also must recognize epithelial cell transformation, to which the intestine may be uniquely prone, because toxin exposure and the high proliferation rate of the epithelial cells increase the risk of cytogenetic error and malignant transformation.  The intestinal immune system must simultaneously ignore the multitude of commensal organisms and dietary antigens that are not threats to the host.

Because specific immunity is driven by antigen recognition, the components of the immune system that protect the gut are presented with a significant challenge in differentiating foreign or nonself material from self-antigens by responding to the former and ignoring the latter.  Except for a few other epithelial surfaces, no other organ system is presented with this combination of problems in such a dramatic fashion.  As a result of constant antigenic exposure, the gut possesses abundant lymphoid cells (i.e., B and T lymphocytes) and myeloid cells (i.e., macrophages, neutrophils, eosinophils, mast cells).  The mucosal immune system of the gastrointestinal tract represents one of the largest immunologic compartments in the body.

To deal with this challenge, the gut-associated lymphoid tissue (GALT) has evolved several important modifications of antigen processing, humoral immunity, and cellular immunity to cope with its organ-specific responsibilities.  These include flattened epithelial microfold (M) cells that transport antigens, the specialized epithelial cells of the domes overlying lymphoid aggregates that sample luminal antigens selectively, unique immunologic functions of the single layer of enterocytes (epithelial cells) that separate the outside from inside worlds, the IgG and IgA systems that helps to exclude and remove foreign antigens, and unique mechanisms of generating local specific secretory immunity in the context of systemic tolerance.  The functional segregation of intestinal from systemic compartments reiterates the separate role of the intestine as a unique lymphoid organ that is linked to other mucosal surfaces such as those of the lung, breast, and/or genitourinary tract to create a common mucosa-associated lymphoid tissue (MALT). 

The approach that the laboratory has taken to study mucosal immunity is to focus on several molecules that the laboratory believes are operative and especially relevant to the physiologic processes and diseases related to these compartments.  As such, the laboratory has a particular interest in the manner in which aberrations of these physiologic processes lead to the development of inflammatory bowel disease, the management of the luminal microbial ecology, intestinal barrier dysfunction and allergy, among others.  Particular areas of interest are in the following molecular pathways: 

• Characterization of the neonatal MHC class I-related Fc receptor (FcRn).  This receptor is responsible for the transport of IgG across the intestinal epithelium in a novel transcytotic pathway that is bidirectional in nature.  It has previously been suggested that this molecule is expressed developmentally only during antenatal and neonatal periods of life.  The laboratory, however, has shown that rodent and human FcRn is expressed beyond the neonatal period in adult animals in intestinal epithelial cells, dendritic cells and intestinal macrophages.  One logical interpretation of these data is that adult expression of FcRn may play a role in the uptake of immune complexes from the intestinal and/or other mucosal surfaces for the purposes of influencing subepithelial B and T cell responses.  The laboratory is therefore investigating the cell biologic pathways associated with FcRn transport of IgG across intestinal epithelia and the role that FcRn may have in regulating responses to luminal antigens.

• The nonclassical MHC class I-related molecule, CD1d. The laboratory has previously demonstrated the expression of human CD1d constitutively on normal human and rodent intestinal epithelia and the ability of CD1d to function as a restriction element for T cells in this compartment on these cell types. The major goals of the laboratory are to understand and characterize the cell biology (e.g. microsomal triglyceride transfer protein), biosynthesis and function of CD1d on intestinal epithelia and to define the role of CD1d-restricted pathways in regulating mucosal inflammation and responses to mucosal microbiota. The delineation of such knowledge will have important implications in understanding the pathogenesis of inflammatory bowel disease and other related conditions given the importance of the mucosal microbiota to the development of these diseases.
  
• Carcinoembryonic antigen cell adhesion molecule 1  (CEACAM1).  CEACAM1 has traditionally been viewed as an adhesion molecule associated with signal transduction pathways in epithelial surfaces that is involved in regulating epithelial cell growth and development.  Recent work from this laboratory has revealed a role for CEACAM1 in regulating of T cell responses.  The laboratory has found that CEACAM1 is expressed on activated T cells and regulates the activity of T cells in vitro and in vivo.  This regulation of T cells by CEACAM1 is consistent with the signaling properties of this molecule and the possession of two immune receptor tyrosine-based inhibitory motifs in the cytoplasmic tail of this molecule.  The laboratory is interested in defining the molecular mechanisms underlying T cell regulation by CEACAM1 and the manner in which CEACAM1 regulates inflammatory diseases of the intestine.