Our aim is to understand at the molecular level the mechanism behind the lengthy lifespan of IgG, which is 4 to 20 times greater than the other Ig classes. An understanding of the mechanism by which IgG lifespan is regulated will enable its therapeutic manipulation in a unique manner both to enhance the protective effects of antibodies and to temper the harmful aspects of autoantibodies. The hypothesis describing the mechanism, originally proposed by Brambell in the 1960s and updated by recent findings, says that IgG is pinocytosed nonspecifically by many cells of the body into acidic vesicles where at low pH, it binds to an integral membrane protein with high affinity for IgG; namely, the neonatal Fc receptor (FcRn), which is a beta2-microglobulin associated MHC class I-like heterodimer. IgG thus complexed with FcRn and saved from a degradative fate, is then trafficked in intracellular vesicles back to the plasma membrane where, at physiologic pH, it dissociates from the receptor and is free to recycle. Our recent findings have compelled us to modify this hypothesis in two ways. First, our anti-receptor antibodies localize FcRn not only to a cytoplasmic vesicular compartment but as well to the trans-Golgi network (TGN), which we propose, serves as a reservoir for trafficking FcRn. Second, we find abundant FcRn in cells of the extravascular space, such as epithelium, fibroblasts, macrophages, and some parenchyma, in addition to endothelium. Thus, while endothelium may be the accepted site of IgG degradation, the predominant site where IgG is protected from degradation is, we propose, in these cells of the extravascular space. Adaptively, it is here in the tissues at local sites of antibody action where IgG lifespan is longest. Our modified hypothesis presents a variety of predictions for us to test. We will determine precisely by several means where FcRn is expressed in the body and where it is localized at the subcellular level, colocalizing it with markers of various cellular compartments. We will determine the route IgG takes as it moves through a cell, being deflected from the degradative pathway by binding to FcRn. And we will test whether TGN serves as a reservoir for FcRn as it trafficks about the cell protecting IgG from a degradative fate. Our technical approaches to the various aims are broad-based and collaborative and include the methods of cellular and molecular biology, biochemistry, and immunology.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Immunological Sciences Study Section (IMS)
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Mufson, R Allan
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Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
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Mohanty, Sudhasri; Kim, Jonghan; Ganesan, Latha P et al. (2010) IgG is transported across the mouse yolk sac independently of FcgammaRIIb. J Reprod Immunol 84:133-44
Kim, Jonghan; Mohanty, Sudhasri; Ganesan, Latha P et al. (2009) FcRn in the yolk sac endoderm of mouse is required for IgG transport to fetus. J Immunol 182:2583-9
Kim, Jonghan; Bronson, C L; Wani, Manzoor A et al. (2008) Beta 2-microglobulin deficient mice catabolize IgG more rapidly than FcRn- alpha-chain deficient mice. Exp Biol Med (Maywood) 233:603-9
Kim, Jonghan; Hayton, William L; Robinson, John M et al. (2007) Kinetics of FcRn-mediated recycling of IgG and albumin in human: pathophysiology and therapeutic implications using a simplified mechanism-based model. Clin Immunol 122:146-55
Chaudhury, Chaity; Kim, Jonghan; Mehnaz, Samina et al. (2006) Accelerated transferrin degradation in HFE-deficient mice is associated with increased transferrin saturation. J Nutr 136:2993-8
Kim, Jonghan; Bronson, C L; Hayton, William L et al. (2006) Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces. Am J Physiol Gastrointest Liver Physiol 290:G352-60
Wani, Manzoor A; Haynes, Lynn D; Kim, Jonghan et al. (2006) Familial hypercatabolic hypoproteinemia caused by deficiency of the neonatal Fc receptor, FcRn, due to a mutant beta2-microglobulin gene. Proc Natl Acad Sci U S A 103:5084-9
Chaudhury, Chaity; Brooks, Charles L; Carter, Daniel C et al. (2006) Albumin binding to FcRn: distinct from the FcRn-IgG interaction. Biochemistry 45:4983-90
Takizawa, Toshihiro; Anderson, Clark L; Robinson, John M (2005) A novel Fc gamma R-defined, IgG-containing organelle in placental endothelium. J Immunol 175:2331-9
Roopenian, Derry C; Christianson, Gregory J; Sproule, Thomas J et al. (2003) The MHC class I-like IgG receptor controls perinatal IgG transport, IgG homeostasis, and fate of IgG-Fc-coupled drugs. J Immunol 170:3528-33

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