Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease of the skin and mucous membranes, characterized by
autoantibodies against
type VII collagen (COL7), a major component of anchoring fibrils. Different clinical EBA phenotypes are described, including mechanobullous and inflammatory variants. Most EBA patients' sera react with
epitopes located within the non-collagenous 1 (NC1) domain of human COL7. However, it has remained unclear whether antibody binding to these different
epitopes is pathogenically relevant. To address this issue, we generated
recombinant proteins covering the entire NC1 domain.
IgG reactivity with these
proteins was analyzed in sera of 69 EBA patients. Most recognized clusters of
epitopes throughout the NC1 domain. No correlation was detected between antibody specificity and clinical phenotype. To study the pathogenicity of
antibodies specific to different NC1 subdomains, rabbit
antibodies were generated. All these
antibodies caused dermal-epidermal separation ex vivo.
Antibodies against two of these subdomains were injected into mice carrying null mutations of mouse COL7 and the human COL7 transgene and induced subepidermal
blisters. We here document that
autoantibodies to COL7, independent of the targeted
epitopes, induce
blisters both ex vivo and in vivo. In addition, using COL7-humanized mice, we provide in vivo evidence of pathogenicity of
autoantibodies binding to human COL7.