Animal model of fetal and neonatal immune thrombocytopenia: role of neonatal Fc receptor in the pathogenesis and therapy

Blood ◽  
2010 ◽  
Vol 116 (18) ◽  
pp. 3660-3668 ◽  
Author(s):  
Pingguo Chen ◽  
Conglei Li ◽  
Sean Lang ◽  
Guangheng Zhu ◽  
Adili Reheman ◽  
...  
Keyword(s):  
Animal Model ◽  
Immunoglobulin G ◽  
Immune Thrombocytopenia ◽  
Fc Receptor ◽  
Maternal Antibodies ◽  
Severe Bleeding ◽  
Neonatal Fc Receptor ◽  
Igg Isotypes ◽  
Β3 Integrin

Abstract Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder in which maternal antibodies cross the placenta and destroy fetal/neonatal platelets. It has been demonstrated that the neonatal Fc receptor (FcRn) regulates immunoglobulin G (IgG) homeostasis and plays an important role in transplacental IgG transport. However, the role of FcRn in the pathogenesis and therapy of FNIT has not been studied. Here, we developed an animal model of FNIT using combined β3 integrin–deficient and FcRn-deficient (β3−/−FcRn−/−) mice. We found that β3−/−FcRn−/− mice are immunoresponsive to β3+/+FcRn−/− platelets. The generated antibodies were β3 integrin specific and were maintained at levels that efficiently induced thrombocytopenia in adult β3+/+FcRn−/− mice. FNIT was observed when immunized β3−/−FcRn+/+ females were bred with β3+/+FcRn+/+ males, while no FNIT occurred in β3−/−FcRn−/− females bred with β3+/+FcRn−/− males, suggesting that FcRn is indispensable for the induction of FNIT. We further demonstrated that fetal FcRn was responsible for the transplacental transport of various IgG isotypes. We found that anti-FcRn antibody and intravenous IgG prevented FNIT, and that intravenous IgG ameliorated FNIT through both FcRn-dependent and -independent pathways. Our data suggest that targeting FcRn may be a potential therapy for human FNIT as well as other maternal pathogenic antibody-mediated diseases.

The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody–mediated amelioration of murine immune thrombocytopenia

Blood ◽  
2011 ◽  
Vol 118 (24) ◽  
pp. 6403-6406 ◽  
Author(s):  
Andrew R. Crow ◽  
Sara J. Suppa ◽  
Xi Chen ◽  
Patrick J. Mott ◽  
Alan H. Lazarus
Keyword(s):  
Immune Thrombocytopenia ◽  
Low Dose ◽  
Fc Receptor ◽  
High Dose ◽  
Neonatal Fc Receptor ◽  
Antiplatelet Antibody ◽  
Antibody Treatment ◽  
Acute Itp ◽  
Deficient Mice ◽  
Cd44 Antibody

Abstract To definitively determine whether the neonatal Fc receptor (FcRn) is required for the acute amelioration of immune thrombocytopenia (ITP) by IVIg, we used FcRn-deficient mice in a murine ITP model. Mice injected with antiplatelet antibody in the presence or absence of IVIg displayed no difference in platelet-associated IgG between FcRn deficient versus C57BL/6 mice. FcRn-deficient mice treated with high-dose (2 g/kg) IVIg or a low–dose (2 mg/kg) of an IVIg-mimetic CD44 antibody were, however, protected from thrombocytopenia to an equivalent extent as wild-type mice. To verify and substantiate the results found with FcRn-deficient mice, we used β2-microglobulin–deficient mice (which do not express functional FcRn) and found that IVIg or CD44 antibody also protected them from thrombocytopenia. These data suggest that for both high-dose IVIg as well as low-dose CD44 antibody treatment in an acute ITP model, FcRn expression is neither necessary nor required.

scholarly journals Structural basis for pH-insensitive inhibition of immunoglobulin G recycling by an anti-neonatal Fc receptor antibody

2017 ◽  
Vol 292 (42) ◽  
pp. 17449-17460 ◽  
Author(s):  
Jon A. Kenniston ◽  
Brandy M. Taylor ◽  
Gregory P. Conley ◽  
Janja Cosic ◽  
Kris J. Kopacz ◽  
...  
Keyword(s):  
Immunoglobulin G ◽  
Fc Receptor ◽  
Structural Basis ◽  
Neonatal Fc Receptor ◽  
Receptor Antibody

scholarly journals Conformational Destabilization of Immunoglobulin G Increases the Low pH Binding Affinity with the Neonatal Fc Receptor

2015 ◽  
Vol 291 (4) ◽  
pp. 1817-1825 ◽  
Author(s):  
Benjamin T. Walters ◽  
Pernille F. Jensen ◽  
Vincent Larraillet ◽  
Kevin Lin ◽  
Thomas Patapoff ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Hydrogen Exchange ◽  
Dissociation Constants ◽  
Conformational Dynamics ◽  
Fc Receptor ◽  
Salt Bridges ◽  
Neonatal Fc Receptor ◽  
Intermolecular Contacts ◽  
Ph Dependent

Crystallographic evidence suggests that the pH-dependent affinity of IgG molecules for the neonatal Fc receptor (FcRn) receptor primarily arises from salt bridges involving IgG histidine residues, resulting in moderate affinity at mildly acidic conditions. However, this view does not explain the diversity in affinity found in IgG variants, such as the YTE mutant (M252Y,S254T,T256E), which increases affinity to FcRn by up to 10×. Here we compare hydrogen exchange measurements at pH 7.0 and pH 5.5 with and without FcRn bound with surface plasmon resonance estimates of dissociation constants and FcRn affinity chromatography. The combination of experimental results demonstrates that differences between an IgG and its cognate YTE mutant vary with their pH-sensitive dynamics prior to binding FcRn. The conformational dynamics of these two molecules are nearly indistinguishable upon binding FcRn. We present evidence that pH-induced destabilization in the CH2/3 domain interface of IgG increases binding affinity by breaking intramolecular H-bonds and increases side-chain adaptability in sites that form intermolecular contacts with FcRn. Our results provide new insights into the mechanism of pH-dependent affinity in IgG-FcRn interactions and exemplify the important and often ignored role of intrinsic conformational dynamics in a protein ligand, to dictate affinity for biologically important receptors.

scholarly journals Knockout of the neonatal Fc receptor in cultured podocytes alters IL-6 signaling and the actin cytoskeleton

2019 ◽  
Vol 317 (5) ◽  
pp. C1048-C1060 ◽  
Author(s):  
Pantipa Tonsawan ◽  
James Dylewski ◽  
Linda Lewis ◽  
Judith Blaine
Keyword(s):  
Immune Complexes ◽  
Fc Receptor ◽  
Actin Dynamics ◽  
Minimal Amount ◽  
Neonatal Fc Receptor ◽  
Scratch Assay ◽  
Immune Mediated ◽  
Actin Structure ◽  
Robust Response

The neonatal Fc receptor (FcRn) has been shown to be required for antigen presentation in dendritic cells, and global knockout of FcRn attenuates immune-mediated kidney disease. Podocytes express interleukin-6 (IL-6) receptor and produce IL-6 under proinflammatory conditions. Here we examined the role of FcRn in the IL-6-mediated inflammatory response in podocytes. We examined IL-6 production by ELISA and expression by qPCR in wild type (WT) and FcRn knockout (KO) podocytes after treatment with proinflammatory stimuli as well as IL-6-mediated signaling via the JAK/STAT pathway. We also examined podocyte motility in cultured WT and KO podocytes after a proinflammatory challenge. We found that FcRn KO podocytes produced minimal amount of IL-6 after treatment with albumin, IgG, or immune complexes whereas WT podocytes had a robust response. FcRn KO podocytes also had minimal expression of IL-6 compared with WT. By Western blotting, there was significantly less phosphorylated STAT3 in KO podocytes after treatment with IFNγ or immune complexes. In a scratch assay, FcRn KO podocytes showed increased motility comparted KO, suggesting a defect in actin dynamics. Cultured FcRn KO podocytes also demonstrated abnormal stress fibers compared with WT and the defect could be rescued by IL-6 treatment. This study shows that in podocytes, FcRn modulates the IL-6 mediated response to proinflammatory stimuli and regulates podocytes actin structure, motility and synaptopodin expression.

scholarly journals 035 Humanized anti-Desmoglein-3 antibodies as tools for research on the role of the neonatal Fc receptor in pemphigus vulgaris

2021 ◽  
Vol 141 (10) ◽  
pp. S154
Author(s):  
A. Zakrzewicz ◽  
C. Würth ◽  
B. Beckert ◽  
S. Feldhoff ◽  
P. Verheesen ◽  
...  
Keyword(s):  
Pemphigus Vulgaris ◽  
Fc Receptor ◽  
Neonatal Fc Receptor ◽  
Desmoglein 3

scholarly journals Differential trafficking of albumin and IgG facilitated by the neonatal Fc receptor in podocytes in vitro and in vivo.

2018 ◽  
Author(s):  
James Dylewski ◽  
Evgenia Dobrinskikh ◽  
Linda Lewis ◽  
Pantipa Tonsawan ◽  
Parmjit Jat ◽  
...  
Keyword(s):  
Plasma Proteins ◽  
Serum Proteins ◽  
Mesangial Cells ◽  
Smooth Muscle Actin ◽  
Fc Receptor ◽  
Neonatal Fc Receptor ◽  
Kidney Disease Progression

Proteinuria is strongly associated with kidney disease progression but the mechanisms underlying podocyte handling of serum proteins such as albumin and IgG remain to be elucidated. We have previously shown that albumin and IgG are transcytosed by podocytes in vitro. In other epithelial cells, the neonatal Fc receptor (FcRn) is required to salvage albumin and IgG from the degradative pathway thereby allowing these proteins to be transcytosed or recycled. Here we directly examine the role of FcRn in albumin and IgG trafficking in podocytes by studying handling of these proteins in FcRn knockout (KO) podocytes in vitro and in a podocyte-specific FcRn knockout mice in vivo. In vitro, we find that knockout of FcRn leads to IgG accumulation in podocytes but does not alter albumin trafficking. Similarly, in vivo, podocyte-specific knockout of FcRn does not result in albumin accumulation in podocytes in vivo as measured by mean albumin fluorescence intensity whereas these mice demonstrate significant intraglomerular accumulation of IgG over time. In addition we find that podocyte-specific FcRn KO mice demonstrate mesangial expansion as they age and activation of mesangial cells as demonstrated by increased expression of ?-smooth muscle actin. Taken together, these results suggest that trafficking pathways for albumin and IgG differ in podocytes and that sustained disruption of trafficking of plasma proteins alters glomerular structure.

scholarly journals Parameter Identification for a Model of Neonatal Fc Receptor-Mediated Recycling of Endogenous Immunoglobulin G in Humans

2019 ◽  
Vol 10 ◽  
Author(s):  
Felicity Kendrick ◽  
Neil D. Evans ◽  
Oscar Berlanga ◽  
Stephen J. Harding ◽  
Michael J. Chappell
Keyword(s):  
Parameter Identification ◽  
Immunoglobulin G ◽  
Fc Receptor ◽  
Neonatal Fc Receptor
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