We tested a forgotten 40-year old hypothesis that the Brambell receptor, the MHC-related Fc receptor for IgG (FcRn), protects albumin from intracellular catabolic degradation just is it does IgG, prolonging the half-lives of both molecules. Our preliminary studies affirmed three predictions of this hypothesis, showing that albumin binds FcRn at low pH, just as does IgG, at a site distinct from the IgG binding site, forming a trimolecular complex. Preliminary experiments indicate direct binding of albumin to the native receptor; SPR experiments show KD in fM range. Further, we found that FcRn-deficient (KO) mice degrade albumin more rapidly than WT mice, and that the serum albumin concentration in FcRn-deficient mice is about half that of WT controls. These data infer that many fold more albumin molecules are protected from degradation per IgG molecule per unit time, and that FcRn may somehow be involved in albumin biosynthesis.
Our specific aims are two fold. First, we will characterize the molecular interaction of albumin with FcRn by determining affinity, kinetic rate constants, specificity, and stoichiometry of interaction. Second, we will test six predictions or extensions of the hypothesis; namely, that native FcRn from tissue will bind albumin, that albumin may be transported from mother to offspring, that FcRn mediates trans-endothelial flux of albumin, that FcRn participates in hepatocyte production of albumin, that albumin transport across cell in vitro is FcRn mediated, and that a family deficient in albumin and IgG because of accelerated degradation rates of both molecules have a faulty FcRn gene. We apply a broad range of methods encompassing many disciplines. In the first aim, mostly biochemical, we use surface plasmon resonance, radioligand binding assays, size exclusion chromatography, isothermal titration calorimetry, and affinity chromatography.
The second aim, which includes several physiological goals, employs pharmacokinetic analysis, in vivo transport studies in KO mice, tissue culture, immunofluorescence, and molecular biology. The implications of these studies extend far on a broad range of health and disease topics. These include the homeostatic regulation of serum albumin concentration; the flux of albumin across endothelium between plasma and extravascular compartments arid across other tissue barriers; the mechanism of hepatocyte albumin production; the placental transport of proteins; and the evolution of the MHC family of proteins.
|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|
|Chiu, April; Xu, Weifeng; He, Bing et al. (2007) Hodgkin lymphoma cells express TACI and BCMA receptors and generate survival and proliferation signals in response to BAFF and APRIL. Blood 109:729-39|
|Qiao, Xugang; He, Bing; Chiu, April et al. (2006) Human immunodeficiency virus 1 Nef suppresses CD40-dependent immunoglobulin class switching in bystander B cells. Nat Immunol 7:302-10|
|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|
|He, Bing; Qiao, Xugang; Klasse, Per J et al. (2006) HIV-1 envelope triggers polyclonal Ig class switch recombination through a CD40-independent mechanism involving BAFF and C-type lectin receptors. J Immunol 176:3931-41|
|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|
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