Abstract
Epidermolysis bullosa acquisita (EBA) is an autoimmune subepidermal blistering disease of mucous membranes and the skin caused by autoantibodies against collagen VII. In silico and wet laboratory epitope mapping studies revealed numerous distinct epitopes recognized by EBA patients' autoantibodies within the non-collagenous (NC)1 and NC2 domains of collagen VII. However, the distribution of pathogenic epitopes on collagen VII has not yet been described. In this study, we therefore performed an in vivo functional epitope mapping of pathogenic autoantibodies in experimental EBA. Animals (n = 10/group) immunized against fragments of the NC1 and NC2 domains of collagen VII or injected with antibodies generated against the same fragments developed to different extent experimental EBA. Our results demonstrate that antibodies targeting multiple, distinct epitopes distributed over the entire NC1, but not NC2 domain of collagen VII induce blistering skin disease in vivo. Our present findings have crucial implications for the development of antigen-specific B- and T cell-targeted therapies in EBA.
Highlights
Collagen VII is the main constituent of the anchoring fibrils, structures that mediate the adhesion of the epidermis onto the dermis, and has a critical role in providing skin stability and integrity [1]
Our results clearly demonstrate that antibodies targeting multiple, distinct epitopes distributed over the entire NC1 domain of collagen VII induce blistering skin disease in vivo
Studies, using epidermolysis bullosa acquisita (EBA) patients’ sera revealed that the epitopes recognized by their autoantibodies are distributed along the whole collagen VII molecule, still, the majority of antigenic determinants were shown to localize within the NC1 domain [12, 28,29,30,31,32]
Summary
Collagen VII is the main constituent of the anchoring fibrils, structures that mediate the adhesion of the epidermis onto the dermis, and has a critical role in providing skin stability and integrity [1]. Autoantibodies against collagen VII induce tissue damage in epidermolysis bullosa acquisita (EBA), an autoimmune chronic blistering disease of the skin and mucous membranes [7, 8]. Autoantibodies against collagen VII have been documented in patients with several autoimmune. After secretion into the extracellular space, collagen VII molecules form antiparallel, tail-to-tail dimers stabilized by disulphide bonding through a small carboxyl-terminal NC2 overlap, while a portion of the NC2 domain is proteolitically removed [13,14,15]. The NC1 domain consists of multiple subdomains including segments with homology to adhesion molecules, including the cartilage matrix protein (CMP), nine consecutive fibronectin type III-like repeats, and a segment with homology to the A domain of von Willebrand factor [16]
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