The Function of FcRn in Liver and the Role of N-Glycans

Brigham And Women'S Hospital, Boston MA

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Abstract

DESCRIPTION (provided by applicant): The neonatal Fc receptor, FcRn, is a critical regulator of IgG homeostasis. FcRn is a MHC class I- related Fc receptor with two well-known functions: mediating transport of IgG across the epithelium and acting as a saturable receptor that protects IgG from catabolism. Recent studies have suggested that FcRn can also deliver IgG-antigen complexes for immune presentation. Therapies to autoimmune diseases have involved generating recombinant antibodies that are also designed to better confer binding to FcRn to prolong its half-life. However, the molecular mechanism of FcRn trafficking is still incompletely understood. Therefore, further understanding of FcRn trafficking may lead to maximal exploitation of its therapeutic potential. In relation to liver disease, abnormal levels of IgG are commonly found in the serum and/or bile of autoimmune liver disease, viral hepatitis, liver cirrhosis, and cholelithiasis. The physiologic significance of the altered IgG level in disease progression and possible therapeutic implication is unknown. The proposed aims in this grant will help establish the foundation to answer these questions by first understanding the basic biology of FcRn, especially in relation to liver immunology. It is known that the biology and function of FcRn vary between the type of cells FcRn resides within and the species of FcRn expressed. Little is known about the biologic mechanism of FcRn in the liver and in controlling the directional transport of IgG. One of the major structural differences in rat and human FcRn is the three additional N-glycans in rat FcRn. N-glycans have known to be apical targeting signals. This grant is designed to examine the role of N-glycans in the cell biology and functions of FcRn in vitro as well as in vivo and the role of FcRn in liver. Aim 1 focuses on the role of N-glycans in regulation of the steady-state membrane distribution of FcRn and the directional transport of IgG. Knowing that FcRn is present and functional at the rat canalicular (apical) membrane, Aim 2 investigates the role of FcRn in the liver and hepatocyte, using mice deficient in FcRn and a polarized hepatocyte cell line, WIF-B9 cell. During the career development period, the investigator intends to 1) expand his knowledge and techniques in immunology and molecular biology, 2) explore and identify the role of the liver in immunology, 3) foster collaborations with other prominent scientists and clinical investigators, and 4) become a successful and productive independent liver immunologist.