Collagen XVII/BP180, an epidermal adhesion molecule, exists as a full-length transmembrane
protein and as a soluble 120-kd ectodomain that is shed from the keratinocyte surface by
furin-mediated proteolysis. Despite a number of studies on
autoantibody targets in blistering
skin diseases, it has remained unclear whether the physiologically shed ectodomain of
collagen XVII plays a role as an
autoantigen. Here we isolated the authentic, soluble form of human
collagen XVII and showed that it is an
autoantigen recognized by
IgG and
IgA autoantibodies in different blistering
skin diseases and is, in some cases, the preferential target. The ectodomain was isolated from the epidermis, keratinocyte media, amniotic fluid, and
pemphigoid blister fluid, and
autoantibodies affinity-purified with this ectodomain bound to the proximal surface of the epidermis in normal skin but not in
collagen XVII-deficient skin. The antibody reactivity was not dependent on the native conformation or the N-glycosylation of the soluble ectodomain, but was abolished by
collagenase treatment. Sera of 81 patients with a clinically active blistering
skin disease were reacted with full-length
collagen XVII, the authentic soluble ectodomain, and recombinant fragments. In bullous and
cicatricial pemphigoid,
IgG reactive with full-length
collagen XVII also recognized the soluble ectodomain. In
linear IgA dermatosis and chronic bullous
dermatosis of childhood,
IgA targeted the soluble ectodomain more efficiently than the full-length
protein. The use of recombinant fragments demonstrated that
epitopes were present in several noncollagenous and collagenous subdomains of the molecule, and that a significant portion of the sera targeted Col15 domain, a hitherto unrecognized
epitope region.