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

Elena Pipi, Anika Kasprick, Hiroaki Iwata, Stephanie Goletz, Jennifer E. Hundt, Hengameh Sadeghi, Leon F. Schmidt-Jiménez, Enno Schmidt, Jonathan Sjögren, Detlef Zillikens, Ralf J. Ludwig, Mattias Collin, Katja Bieber*

*Korrespondierende/r Autor/-in für diese Arbeit

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.

OriginalspracheEnglisch
ZeitschriftJournal of Investigative Dermatology
Jahrgang142
Ausgabenummer6
Seiten (von - bis)1552-1564.e8
ISSN0022-202X
DOIs
PublikationsstatusVeröffentlicht - 06.2022

Strategische Forschungsbereiche und Zentren

  • Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)
  • Zentren: Center for Research on Inflammation of the Skin (CRIS)

DFG-Fachsystematik

  • 204-05 Immunologie

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