An FcRn-Dependent Role for Anti-flagellin Immunoglobulin G in Pathogenesis of Colitis in Mice

Kobayashi, Katsuaki; Qiao, Shuo‐Wang; Yoshida, Masaru; Baker, Kristi; Lencer, Wayne I.; Blumberg, Richard S.

doi:10.1053/j.gastro.2009.07.059

Cited by 79 publications

(71 citation statements)

References 41 publications

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“…Recently, FcRn in hematopoietic cells was shown to play a pathogenic role in colitis in the presence of flagellin containing IgG ICs (17,18). Furthermore, FcRn has been implicated in the pathogenesis of several CD8 + T cell-dependent inflammatory diseases, including glomerular disease, arthritis, and myasthenia gravis (29)(30)(31)(32)(33)(34).…”

Section: Cd11bmentioning

confidence: 99%

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

Baker

Qiao

Kuo

et al. 2011

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

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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, Fcγ receptor (FcγR)-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 crosspresentation 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 crosspresentation in CD8 − CD11b+ DCs requires a two-step mechanism that involves FcγR-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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Section: Cd11bmentioning

confidence: 99%

“…Despite the insinuation of its name, FcRn is expressed throughout life in a variety of cell types. These include mouse and human DCs (15,16), where it has been shown to play a role in MHC-IIrestricted presentation of IgG IC-derived antigens (17,18).…”

Section: Cd11bmentioning

confidence: 99%

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

Baker

Qiao

Kuo

et al. 2011

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

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195

245

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“…Thus, FcRn rescues both its ligands from intracellular degradation, whereas proteins that do not bind the receptor are directed to lysosomes. This recycling pathway has been shown to take place in hematopoietic cells and endothelial cells lining the vascular space (8,20,21).…”

Section: Albumin Is An Abundant Blood Protein That Acts As a Transpormentioning

confidence: 99%

Interaction with Both Domain I and III of Albumin Is Required for Optimal pH-dependent Binding to the Neonatal Fc Receptor (FcRn)

Sand

Bern

Nilsen

et al. 2014

Journal of Biological Chemistry

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“…FcRn is widely expressed in different cell types and tissues, as for instance the vascular endothelium that covers the interior of blood and lymphatic vessels and in hematopoietic cells such as dendritic cells, predominantly within endosomal compartments (21)(22)(23)(24)(25). Similar to other circulating proteins, IgG is continuously pinocytosed by these *Centre for Immune Regulation and Department of Biosciences, University of Oslo, 0316 Oslo, Norway; and other cells.…”

mentioning

confidence: 99%

Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions

Grevys

Bern

Foss

et al. 2015

The Journal of Immunology

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Engineering of the constant Fc part of monoclonal human IgG1 (hIgG1) Abs is an approach to improve effector functions and clinical efficacy of next-generation IgG1-based therapeutics. A main focus in such development is tailoring of in vivo half-life and transport properties by engineering the pH-dependent interaction between IgG and the neonatal Fc receptor (FcRn), as FcRn is the main homeostatic regulator of hIgG1 half-life. However, whether such engineering affects binding to other Fc-binding molecules, such as the classical FcγRs and complement factor C1q, has not been studied in detail. These effector molecules bind to IgG1 in the lower hinge–CH2 region, structurally distant from the binding site for FcRn at the CH2–CH3 elbow region. However, alterations of the structural composition of the Fc may have long-distance effects. Indeed, in this study we show that Fc engineering of hIgG1 for altered binding to FcRn also influences binding to both the classical FcγRs and complement factor C1q, which ultimately results in alterations of cellular mechanisms such as Ab-dependent cell-mediated cytotoxicity, Ab-dependent cellular phagocytosis, and Ab-dependent complement-mediated cell lysis. Thus, engineering of the FcRn–IgG1 interaction may greatly influence effector functions, which has implications for the therapeutic efficacy and use of Fc-engineered hIgG1 variants.

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An FcRn-Dependent Role for Anti-flagellin Immunoglobulin G in Pathogenesis of Colitis in Mice

Cited by 79 publications

References 41 publications

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

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

Interaction with Both Domain I and III of Albumin Is Required for Optimal pH-dependent Binding to the Neonatal Fc Receptor (FcRn)

Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions

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An FcRn-Dependent Role for Anti-flagellin Immunoglobulin G in Pathogenesis of Colitis in Mice

Cited by 79 publications

References 41 publications

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

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

Interaction with Both Domain I and III of Albumin Is Required for Optimal pH-dependent Binding to the Neonatal Fc Receptor (FcRn)

Fc Engineering of Human IgG1 for Altered Binding to the Neonatal Fc Receptor Affects Fc Effector Functions

Contact Info

Product

Resources

About

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

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