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Multiple modes of action mediate the therapeutic effect of IVIg in experimental epidermolysis bullosa acquisita

Published:November 15, 2021DOI:https://doi.org/10.1016/j.jid.2021.08.448

      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 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.

      Abbreviations:

      BP (bullous pemphigoid), CAT (catalase), COL7 (type VII collagen), DEJ (dermal-epidermal junction), EBA (epidermolysis bullosa acquisita), FcRn (neonatal Fc receptor), GOX (glucose/glucose oxidase), hIgG (human IgG), hd-hIgG (High-dose human IgG (intraperitoneal treatment)), IC (immune complexes), IVIg (intravenous IgG), Kd (equilibrium dissociation constant), Koff (molecular off rate constant), Kon (molecular on rate constant), mIgG (murine IgG), hd-mIgG (High-dose murine IgG (intraperitoneal treatment)), MMP2 (matrix metalloproteinase 2), MPO (myeloperoxidase), NH-IgG (IgG isolated from normal healthy blood donors), PMA (phorbol-myristate-acetate), rIgG (rabbit IgG), RLU (relative luminescence units), ROS (reactive oxygen species)
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