The neonatal Fc receptor for IgG (FcRn) is a major histocompatibility complex (MHC) class 1-related molecule that is responsible for maintaining steady-state levels of IgG in adult rodents and, possibly, all mammals through its ability to specifically protect IgG from catabolism. FcRn has also been proven to mediate the vectorial transport of IgG across the intestinal epithelial cell barrier in suckling mice and rats and, likely, the placenta in humans. These effects on the physiology of IgG result from the action of FcRn as an intracellular trafficking receptor. Expression of FcRn is developmentally regulated in rodent intestine and for many years FcRn was considered to be absent from adult tissues. It is now known that FcRn is expressed in the epithelium and macrophages of the adult human; an observation that challenges the paradigm of strict developmental expression of FcRn and raises the question as to the role of FcRn and IgG at mucosal surfaces. One of mucosal immunology's greatest deficiencies is that significant levels of IgG occur in human secretions with almost no understanding of either how this molecule arrives or is functional in mucosal effector sites. This grant addresses the overall hypothesis that FcRn mediates (by bi-directional transepithelial transport) a steady-state distribution of IgG across mucosal surfaces of the intestine and lung for the purpose of functioning in immune surveillance and host defense.
Aim 1 investigates the intracellular itinerary taken by FcRn in the transepithelial transport of IgG and the basic structure-function relationships of FcRn in this process. It is proposed to: (1) define the steady-state distribution of FcRn; (2) define whether FcRn transits through the golgi en route from the apical or basolateral surfaces; (3) define the structural characteristics of the FcRn cytoplasmic tail that defines FcRn function, and; (4) characterize the major structural features of FcRn biogenesis and function through assessment of the major domains of FcRn.
Aim 2 examines the presence of FcRn-dependent transepithelial transport of IgG in vivo in adult life. It is proposed to test for IgG transport across the mucosal barrier of the respiratory tract and/or intestine of wild-type mice and rabbits and mice expressing a human FcRn transgene using either a wild-type Fc or a Fc mutated in the FcRn binding site linked to a polypeptide hormone as a probe.
Aim 3 seeks to define the role of FcRn in immunosurveillance and host defense by examining whether FcRn can sample antigens from the lumen in an in vitro model system and whether FcRn can deliver model immune complexes to subjacent epithelial tissues and elicit an immune response.
Aim 4 seeks to determine whether macrophages contribute to the protection of IgG from catabolism by examining IgG half-life in op/op mice.
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