Multiple modes of action mediate the therapeutic effect of IVIg in experimental epidermolysis bullosa acquisita
(2022) In Journal of Investigative Dermatology 142(6). p.8-1564- Abstract
Substitution of IgG in antibody deficiency or application of high-dose intravenous IgG (IVIg) in patients with autoimmunity are well-established treatments. Data on the mode of action of IVIg are, however, controversial and may differ for distinct diseases. In this study, we investigated the impact and molecular mechanism of high-dose IgG treatment in murine autoantibody-induced skin inflammation, namely, epidermolysis bullosa acquisita (EBA). EBA is caused by antibodies directed against type VII collagen (COL7) and is mediated by complement activation, release of reactive oxygen species, and proteases by myeloid cells. In murine experimental EBA the disease can be induced by injection of anti-COL7 IgG. Here, we substantiate that... (More)
Substitution of IgG in antibody deficiency or application of high-dose intravenous IgG (IVIg) in patients with autoimmunity are well-established treatments. Data on the mode of action of IVIg are, however, controversial and may differ for distinct diseases. In this study, we investigated the impact and molecular mechanism of high-dose IgG treatment in murine autoantibody-induced skin inflammation, namely, epidermolysis bullosa acquisita (EBA). EBA is caused by antibodies directed against type VII collagen (COL7) and is mediated by complement activation, release of reactive oxygen species, and proteases by myeloid cells. In murine experimental EBA the disease can be induced by injection of anti-COL7 IgG. Here, we substantiate that treatment with high-dose IgG improves clinical disease manifestation. Mechanistically, high-dose IgG reduced the amount of anti-COL7 in skin and sera, which is indicative for an FcRn-dependent mode-of-action. Furthermore, in a non-receptor-mediated fashion, high-dose IgG showed antioxidative properties by scavenging extracellular reactive oxygen species. High-dose IgG also impaired complement activation and served as substrate for proteases, both key events during EBA pathogenesis. Collectively, the non-receptor-mediated anti-inflammatory properties of high-dose IgG may explain the therapeutic benefit of IVIg treatment in skin autoimmunity.
(Less)
- author
- organization
- publishing date
- 2022
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Investigative Dermatology
- volume
- 142
- issue
- 6
- pages
- 8 - 1564
- publisher
- Elsevier
- external identifiers
-
- scopus:85121437632
- pmid:34793820
- ISSN
- 1523-1747
- DOI
- 10.1016/j.jid.2021.08.448
- language
- English
- LU publication?
- yes
- additional info
- Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.
- id
- 2e2d0771-b032-43d6-b5c6-42fa995c67ed
- date added to LUP
- 2021-12-06 09:37:12
- date last changed
- 2024-09-08 06:15:13
@article{2e2d0771-b032-43d6-b5c6-42fa995c67ed, abstract = {{<p>Substitution of IgG in antibody deficiency or application of high-dose intravenous IgG (IVIg) in patients with autoimmunity are well-established treatments. Data on the mode of action of IVIg are, however, controversial and may differ for distinct diseases. In this study, we investigated the impact and molecular mechanism of high-dose IgG treatment in murine autoantibody-induced skin inflammation, namely, epidermolysis bullosa acquisita (EBA). EBA is caused by antibodies directed against type VII collagen (COL7) and is mediated by complement activation, release of reactive oxygen species, and proteases by myeloid cells. In murine experimental EBA the disease can be induced by injection of anti-COL7 IgG. Here, we substantiate that treatment with high-dose IgG improves clinical disease manifestation. Mechanistically, high-dose IgG reduced the amount of anti-COL7 in skin and sera, which is indicative for an FcRn-dependent mode-of-action. Furthermore, in a non-receptor-mediated fashion, high-dose IgG showed antioxidative properties by scavenging extracellular reactive oxygen species. High-dose IgG also impaired complement activation and served as substrate for proteases, both key events during EBA pathogenesis. Collectively, the non-receptor-mediated anti-inflammatory properties of high-dose IgG may explain the therapeutic benefit of IVIg treatment in skin autoimmunity.</p>}}, author = {{Pipi, Elena and Kasprick, Anika and Iwata, Hiroaki and Goletz, Stephanie and Hundt, Jennifer E and Sadeghi, Hengameh and Schmidt-Jiménez, Leon F and Schmidt, Enno and Sjögren, Jonathan and Zillikens, Detlef and Ludwig, Ralf J and Collin, Mattias and Bieber, Katja}}, issn = {{1523-1747}}, language = {{eng}}, number = {{6}}, pages = {{8--1564}}, publisher = {{Elsevier}}, series = {{Journal of Investigative Dermatology}}, title = {{Multiple modes of action mediate the therapeutic effect of IVIg in experimental epidermolysis bullosa acquisita}}, url = {{http://dx.doi.org/10.1016/j.jid.2021.08.448}}, doi = {{10.1016/j.jid.2021.08.448}}, volume = {{142}}, year = {{2022}}, }