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.