A Theoretical Model of γ-Globulin Catabolism

Brambell, F. W. Rogers; Hemmings, W. A.; Morris, I.

doi:10.1038/2031352a0

Cited by 409 publications

(246 citation statements)

References 5 publications

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“…This equation is equivalent to that proposed by Brambell [3] and Waldmann and Strober [2]. The kinetic parameters in the simplified model (Fig.…”

Section: Theoretical Considerations Of Recycling Of a Saturable Fcrnmentioning

confidence: 93%

“…These unique characteristics had been explained by a saturable receptor-mediated mechanism that protects both IgG [3] and albumin [4] from intracellular degradation after nonspecific pinocytic uptake, allowing them to be recycled to the cell surface and into the extracellular milieu for continuing circulation. In the last decade the responsible receptor was identified as FcRn, a nonclassical MHC class-I molecule, that bears distinct and independent binding sites for both ligands [5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

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Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Kim

Hayton

Robinson

et al. 2007

Clinical Immunology

176

122

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The nonclassical MHC class-I molecule, FcRn, salvages both IgG and albumin from degradation. Here we introduce a mechanism-based kinetic model for human to quantify FcRn-mediated recycling of both ligands based on saturable kinetics and data from the literature using easily measurable plasma concentrations rather than unmeasurable endosomal concentrations. The FcRn-mediated fractional recycling rates of IgG and albumin were 142% and 44% of their fractional catabolic rates, respectively. Clearly, FcRn-mediated recycling is a major contributor to the high endogenous concentrations of these two important plasma proteins. While familial hypercatabolic hypoproteinemia is caused by complete FcRn deficiency, the hypercatabolic IgG deficiency of myotonic dystrophy could be explained, based on the kinetic analyses, by a normal number of FcRn with lowered affinity for IgG but normal affinity for albumin. A simulation study demonstrates that the plasma concentrations of IgG and albumin could be dynamically controlled by both FcRn-related and -unrelated parameters.

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“…This equation is equivalent to that proposed by Brambell [3] and Waldmann and Strober [2]. The kinetic parameters in the simplified model (Fig.…”

Section: Theoretical Considerations Of Recycling Of a Saturable Fcrnmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Kim

Hayton

Robinson

et al. 2007

Clinical Immunology

176

122

View full text Add to dashboard Cite

show abstract

“…28,29 Despite a lack of direct evidence, it might be reasonable to assume that the bFcRn might thus bind to mouse IgG. FcRn is thought to be a saturable IgG receptor 30 and more FcRn may bind more pinocytosed IgG and effectively protect …”

Section: Discussionmentioning

confidence: 99%

Over‐expression of the bovine FcRn in the mammary gland results in increased IgG levels in both milk and serum of transgenic mice

Lü

Zhao

et al. 2007

Immunology

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SummaryThe neonatal Fc receptor (FcRn) protects immunoglobulin G (IgG) from catabolism and is also responsible for IgG absorption in the neonatal small intestine. However, whether it mediates the transfer of IgG from plasma to milk still remains speculative. In the present study, we have generated transgenic mice that over-express the bovine FcRn (bFcRn) in their lactating mammary glands. Significantly increased IgG levels were observed in the sera and milk from transgenic animals, suggesting that the over-expressed bFcRn could bind and protect endogenous mouse IgG and thus extend its lifespan. We also found that injected human IgG showed a significantly longer half-life (7-8 days) in the transgenic mice than in controls (2Á9 days). Altogether, the data suggested that bFcRn could bind both mouse and human IgG, showing a cross-species FcRnIgG binding activity. However, we found no selective accumulation of endogenous mouse IgG or injected bovine IgG in the milk of the transgenic females, supporting a previous hypothesis that IgG was transported from serum to milk in an inverse correlation to its binding affinity to FcRn.

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“…It was hypothesized that there may exist an IgG receptor responsible for this extended half-life and that this receptor may be saturable, thereby explaining the inverse correlation between IgG concentration and IgG half-life (2). The neonatal Fc receptor (FcRn) was finally cloned and characterized in the 1980s and was eventually determined to be the elusive receptor providing the long half-life to IgG molecules in vivo (3,4).…”

mentioning

confidence: 99%

Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn

Mezo

McDonnell

Hehir

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The neonatal Fc receptor FcRn provides IgG molecules with their characteristically long half-lives in vivo by protecting them from intracellular catabolism and then returning them to the extracellular space. Other investigators have demonstrated that mice lacking FcRn are protected from induction of various autoimmune diseases, presumably because of the accelerated catabolism of pathogenic IgGs in the animals. Therefore, targeting FcRn with a specific inhibitor may represent a unique approach for the treatment of autoimmune disease or other diseases where the reduction of pathogenic IgG will have a therapeutic benefit. Using phage display peptide libraries, we screened for ligands that bound to human FcRn (hFcRn) and discovered a consensus peptide sequence that binds to hFcRn and inhibits the binding of human IgG (hIgG) in vitro. Chemical optimization of the phage-identified sequences yielded the 26-amino acid peptide dimer SYN1436, which is capable of potent in vitro inhibition of the hIgG-hFcRn interaction. Administration of SYN1436 to mice transgenic for hFcRn induced an increase in the rate of catabolism of hIgG in a dose-dependent manner. Treatment of cynomolgus monkeys with SYN1436 led to a reduction of IgG by up to 80% without reducing serum albumin levels that also binds to FcRn. SYN1436 and related peptides thus represent a previously uncharacterized family of potential therapeutic agents for the treatment of humorally mediated autoimmune and other diseases.FcRn antagonist ͉ protein-protein interactions ͉ phage display ͉ autoimmune disease

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A Theoretical Model of γ-Globulin Catabolism

Cited by 409 publications

References 5 publications

Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Kinetics of FcRn-mediated recycling of IgG and albumin in human: Pathophysiology and therapeutic implications using a simplified mechanism-based model

Over‐expression of the bovine FcRn in the mammary gland results in increased IgG levels in both milk and serum of transgenic mice

Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn

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