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Multiple Modes of Action Mediate the Therapeutic Effect of Intravenous IgG in Experimental Epidermolysis Bullosa Acquisita.

Authors
  • Pipi, Elena1
  • Kasprick, Anika1
  • Iwata, Hiroaki2
  • Goletz, Stephanie1
  • Hundt, Jennifer E1
  • Sadeghi, Hengameh3
  • Schmidt-Jiménez, Leon F1
  • Schmidt, Enno1
  • Sjögren, Jonathan4
  • Zillikens, Detlef5
  • Ludwig, Ralf J1
  • Collin, Mattias6
  • Bieber, Katja7
  • 1 Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. , (Germany)
  • 2 Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany; Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. , (Germany)
  • 3 Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany; Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, USA. , (Germany)
  • 4 Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden; Genovis AB, Lund, Sweden. , (Sweden)
  • 5 Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany; Department of Dermatology, University of Lübeck, Lübeck, Germany. , (Germany)
  • 6 Division of Infection Medicine, Department of Clinical Sciences, Lund University, Lund, Sweden. , (Sweden)
  • 7 Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany. Electronic address: [email protected] , (Germany)
Type
Published Article
Journal
Journal of Investigative Dermatology
Publisher
Elsevier
Publication Date
Jun 01, 2022
Volume
142
Issue
6
Identifiers
DOI: 10.1016/j.jid.2021.08.448
PMID: 34793820
Source
Medline
Language
English
License
Unknown

Abstract

Substitution of IgG in antibody deficiency or application of high-dose intravenous IgG in patients with autoimmunity is a well-established treatment. However, data on the mode of action of intravenous IgG are controversial and may differ for distinct diseases. In this study, we investigated the impact and molecular mechanism of high-dose IgG (hd-IgG) treatment in murine autoantibody‒induced skin inflammation, namely, epidermolysis bullosa acquisita. Epidermolysis bullosa acquisita is caused by antibodies directed against type VII collagen and is mediated by complement activation, the release of ROS, and proteases by myeloid cells. In murine experimental epidermolysis bullosa acquisita, the disease can be induced by injection of anti‒type VII collagen IgG. In this study, we substantiate that treatment with hd-IgG improves clinical disease manifestation. Mechanistically, hd-IgG reduced the amount of anti‒type VII collagen in the skin and sera, which is indicative of an FcRn-dependent mode of action. Furthermore, in a nonreceptor-mediated fashion, hd-IgG showed antioxidative properties by scavenging extracellular ROS. Hd-IgG also impaired complement activation and served as a substrate for proteases, both key events during epidermolysis bullosa acquisita pathogenesis. Collectively, the nonreceptor-mediated anti-inflammatory properties of hd-IgG may explain the therapeutic benefit of intravenous IgG treatment in skin autoimmunity. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

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