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FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex-driven autoimmunity.

ABSTRACT: IgG immune complexes (ICs) promote autoimmunity through binding fragment crystallizable (Fc) γ-receptors (FcγRs). Of these, the highly prevalent FcγRIIa (CD32a) histidine (H)-131 variant (CD32aH) is strongly linked to human autoimmune diseases through unclear mechanisms. We show that, relative to the CD32a arginine (R)-131 (CD32aR) variant, CD32aH more avidly bound human (h) IgG1 IC and formed a ternary complex with the neonatal Fc receptor (FcRn) under acidic conditions. In primary human and mouse cells, both CD32a variants required FcRn to induce innate and adaptive immune responses to hIgG1 ICs, which were augmented in the setting of CD32aH. Conversely, FcRn induced responses to IgG IC independently of classical FcγR, but optimal responses required FcRn and FcγR. Finally, FcRn blockade decreased inflammation in a rheumatoid arthritis model without reducing circulating autoantibody levels, providing support for FcRn's direct role in IgG IC-associated inflammation. Thus, CD32a and FcRn coregulate IgG IC-mediated immunity in a manner favoring the CD32aH variant, providing a novel mechanism for its disease association.

SUBMITTER: Hubbard JJ

PROVIDER: S-EPMC7537387 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Blocking FcRn in humans reduces circulating IgG levels and inhibits IgG immune complex-mediated immune responses.

Project description:The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.

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FcRn augments induction of tissue factor activity by IgG-containing immune complexes.

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Neonatal Fc receptor for IgG (FcRn) regulates cross-presentation of IgG immune complexes by CD8-CD11b+ dendritic cells.

Project description:Cross-presentation of IgG-containing immune complexes (ICs) is an important means by which dendritic cells (DCs) activate CD8(+) T cells, yet it proceeds by an incompletely understood mechanism. We show that monocyte-derived CD8(-)CD11b(+) DCs require the neonatal Fc receptor for IgG (FcRn) to conduct cross-presentation of IgG ICs. Consequently, in the absence of FcRn, Fc? receptor (Fc?R)-mediated antigen uptake fails to initiate cross-presentation. FcRn is shown to regulate the intracellular sorting of IgG ICs to the proper destination for such cross-presentation to occur. We demonstrate that FcRn traps antigen and protects it from degradation within an acidic loading compartment in association with the rapid recruitment of key components of the phagosome-to-cytosol cross-presentation machinery. This unique mechanism thus enables cross-presentation to evolve from an atypically acidic loading compartment. FcRn-driven cross-presentation is further shown to control cross-priming of CD8(+) T-cell responses in vivo such that during chronic inflammation, FcRn deficiency results in inadequate induction of CD8(+) T cells. These studies thus demonstrate that cross-presentation in CD8(-)CD11b(+) DCs requires a two-step mechanism that involves Fc?R-mediated internalization and FcRn-directed intracellular sorting of IgG ICs. Given the centrality of FcRn in controlling cross-presentation, these studies lay the foundation for a unique means to therapeutically manipulate CD8(+) T-cell responses.

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Identification of a direct interaction between the Fab domains of IgG antibodies and human FcRn upon IgG-FcRn complex formation

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2024-12-03 | PXD044405 | Pride

Podocytes use FcRn to clear IgG from the glomerular basement membrane

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2008-01-01 | GSE10017 | GEO

MiRNA-127 Inhibits IgG Immune Complex-induced Lung Inflammation by Targeting IgG Fcγ Receptor I

Project description:The molecular mechanisms of acute lung injury are incompletely understood. MicroRNAs (miRNAs) are crucial biological regulators that act by suppressing their target genes and are involved in a variety of pathophysiologic processes. MiR-127 appeared to be down-regulated during lung injury. We set out to investigate the role of miR-127 in lung injury and inflammation. Expression of miR-127 significantly reduced cytokine release by macrophages. Looking into the mechanisms of the regulation of inflammation by miR-127, we found that IgG Fcγ Receptor I (FcγRI/CD64) was a target of miR-127, as evidenced by reduced CD64 protein expression in macrophages over-expressing miR-127. Furthermore, miR-127 significantly reduced the luciferase activity with a reporter construct containing the native 3’-UTR of CD64. Importantly, we demonstrated that miR-127 attenuated lung inflammation in an IgG immune complex (IgG IC) model in vivo. Collectively, these data show that miR-127 targets macrophage CD64 expression and promotes the reduction of lung inflammation. Understanding how miRNAs regulate lung inflammation may represent an attractive way to control inflammation induced by infectious or non-infectious lung injury. MH.S-miR127 and MH.S-Sico cells were cultured for RNA extraction.Total RNA were assessed for quality with Agilent 2100 Bioanalyzer G2939A (Agilent Technologies,Santa Clara, CA)) and Nanodrop 8000 spectrophotometer (Thermo Scientific/Nanodrop, Wilmington, DE). Hybridization targets were prepared with MessageAmp™ Premier RNA Amplification Kit (Applied Biosystems/Ambion, Austin, TX) from total RNA, hybridized to GeneChip® Mouse Genome 430 2.0 arrays in Affymetrix GeneChip® hybridization oven 645, washed in Affymetrix GeneChip® Fluidics Station 450 and scanned with Affymetrix GeneChip® Scanner 7G according to standard Affymetrix GeneChip® Hybridization, Wash, and Stain protocols. (Affymetrix, Santa Clara,CA).

2012-04-03 | E-GEOD-27642 | biostudies-arrayexpress

Evidence that FcRn mediates the transplacental passage of maternal IgE in the form of IgG anti-IgE/IgE immune complexes.

Project description:BackgroundThe mechanism(s) responsible for acquisition of maternal antibody isotypes other than IgG are not fully understood. This uncertainty is a major reason underlying the continued controversy regarding whether cord blood (CB) IgE originates in the mother or fetus.ObjectiveTo investigate the capacity of maternal IgE to be transported across the placenta in the form of IgG anti-IgE/IgE immune complexes (ICs) and to determine the role of the neonatal Fc receptor (FcRn) in mediating this process.MethodsMaternal and CB serum concentrations of IgE, IgG anti-IgE, and IgG anti-IgE/IgE ICs were determined in a cohort of allergic and non-allergic mother/infant dyads. Madin-Darby canine kidney (MDCK) cells stably transfected with human FcRn were used to study the binding and transcytosis of IgE in the form of IgG anti-IgE/IgE ICs.ResultsMaternal and CB serum concentrations of IgG anti-IgE/IgE ICs were highly correlated, regardless of maternal allergic status. IgG anti-IgE/IgE ICs generated in vitro bound strongly to FcRn-expressing MDCK cells and were transcytosed in an FcRn-dependent manner. Conversely, monomeric IgE did not bind to FcRn and was not transcytosed. IgE was detected in solutions of transcytosed IgG anti-IgE/IgE ICs, even though essentially all the IgE remained in complex form. Similarly, the majority of IgE in CB sera was found to be complexed to IgG.Conclusions and clinical relevanceThese data indicate that human FcRn facilitates the transepithelial transport of IgE in the form of IgG anti-IgE/IgE ICs. They also strongly suggest that the majority of IgE in CB sera is the result of FcRn-mediated transcytosis of maternal-derived IgG anti-IgE/IgE ICs. These findings challenge the widespread perception that maternal IgE does not cross the placenta. Measuring maternal or CB levels of IgG anti-IgE/IgE ICs may be a more accurate predictor of allergic risk.

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| S-EPMC8517961 | biostudies-literature

Investigation of the FcRn:IgG interaction by HDX-MS

Project description:Immunoglobulin Gs (IgGs) have become highly successful drug scaffolds by combining very specific target binding with the ability to induce cellular cytotoxicity. Of further advantage, IgGs possess unusually long half-lives in the blood (2-3 week). IgGs achieve such extraordinary half-lives through a pH-dependent interaction with the Neonatal Fc receptor (FcRn) whereby IgGs are recycled. No high-resolution structure of FcRn in complex with a full-length IgG is available, and the interaction was long thought to be mediated solely via the IgG Fc. However, some IgGs with identical Fc parts, but different Fab domains, exhibit different half-lives, suggesting involvement of the Fab domains in FcRn binding. Here, we have employed a combination of HDX-MS and cross-linking MS (XL-MS) to explore the interaction of a full-length IgG with FcRn. HDX-MS and XL-MS analysis confirms an interaction between FcRn and the Fc-domain of IgGs, as a reduction of HDX was observed in both the Fc-domain and FcRn upon complex formation, and three cross-links were identified between FcRn and the Fc-domain. However, FcRn-induced changes in HDX were also observed in the Fab domains, supported by multiple cross-links between the Fab domains and the C-terminal α3 domain of FcRn. Our results thus provide direct evidence for a Fab-FcRn interaction. We envision that these result could advance the engineering of therapeutic IgGs with tailored pharmacokinetics and enhanced efficacy.

2024-12-02 | PXD044285 | Pride

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