Cross-reactivity of autoantibodies from patients with epidermolysis bullosa acquisita with murine collagen VII
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The pathomechanism of antibody-mediated tissue damage in autoimmune diseases can be best studied in experimental models by passively transferring specific autoantibodies into animals. The reproduction of the disease in animals depends on several factors, including the cross-reactivity of patient autoantibodies with the animal tissue. Here, we show that autoantibodies from patients with epidermolysis bullosa acquisita (EBA), a subepidermal autoimmune blistering disease, recognize multiple epitopes on murine collagen VII. Indirect immunofluorescence microscopy revealed that EBA patients’ IgG cross-reacts with mouse skin. Overlapping, recombinant fragments of murine collagen VII were used to characterize the reactivity of EBA sera and to map the epitopes on the murine antigen by ELISA and immunoblotting. The patients’ autoantibody binding to murine collagen VII triggered pathogenic events as demonstrated by a complement fixing and an ex vivo granulocyte-dependent dermal–epidermal separation assay. These findings should greatly facilitate the development of improved disease models and novel therapeutic strategies.
KeywordsAutoimmunity Autoantigen Basement membrane zone Collagen Extracellular matrix
The authors acknowledge support by grants from the Deutsche Forschungsgemeinschaft SI-1281/2-1, SI-1281/4-1 and BIOSS-B13 (CS), from the Medical Faculty of the University of Freiburg (C.S.) and by an ERASMUS stipend (V.F.). We thank Dr. Leena Bruckner-Tuderman, Freiburg, Germany, for critical reading of the manuscript and helpful advice.
- 11.Ishii N, Yoshida M, Hisamatsu Y, Ishida-Yamamoto A, Nakane H, Iizuka H, Tanaka T, Hashimoto T (2004) Epidermolysis bullosa acquisita sera react with distinct epitopes on the NC1 and NC2 domains of type VII collagen: study using immunoblotting of domain-specific recombinant proteins and postembedding immunoelectron microscopy. Br J Dermatol 150:843–851CrossRefPubMedGoogle Scholar
- 21.Li K, Tamai K, Tan EM, Uitto J (1993) Cloning of type XVII collagen. Complementary and genomic DNA sequences of mouse 180-kilodalton bullous pemphigoid antigen (BPAG2) predict an interrupted collagenous domain, a transmembrane segment, and unusual features in the 5′-end of the gene and the 3′-untranslated region of the mRNA. J Biol Chem 268:8825–8834PubMedGoogle Scholar
- 29.Shimanovich I, Mihai S, Oostingh GJ, Ilenchuk TT, Bröcker E, Opdenakker G, Zillikens D, Sitaru C (2004) Granulocyte-derived elastase and gelatinase B are required for dermal–epidermal separation induced by autoantibodies from patients with epidermolysis bullosa acquisita and bullous pemphigoid. J Pathol 204:519–527CrossRefPubMedGoogle Scholar
- 33.Gandhi K, Chen M, Aasi S, Lapiere JC, Woodley DT, Chan LS (2000) Autoantibodies to type VII collagen have heterogeneous subclass and light chain compositions and their complement-activating capacities do not correlate with the inflammatory clinical phenotype. J Clin Immunol 20:416–423CrossRefPubMedGoogle Scholar