Human skin basement membrane in health and in autoimmune diseases

Skin basement membrane zone (BMZ) is an ultrastructurally defined area situated between the outer layer of skin, the epidermis, and the inner layer of skin, the dermis. The major function of skin BMZ is to serve as an adherent connection between the epidermis and the dermis. Heritable skin diseases characterized by genetic mutations that result in defective BMZ protein production, such as junctional and dystrophic epidermolysis bullosa, manifest clinically as skin fragility and subepidermal blister formation inducible by minor trauma. Many distinct, yet interconnected BMZ components, have been identified and studied extensively. Some of these essential components, interestingly, were discovered because they were targeted by an autoimmune reaction. As a result of studying the autoimmune diseases, these BMZ components involved in autoimmune reaction, or autoantigens, were isolated by molecular biology techniques. The isolation of these autoantigens, in turn, facilitates our studies of the normal structures and functions of skin BMZ. The skin BMZ can be divided into four ultrastructurally distinct areas: the hemidesmosome/upper lamina lucida, the lower lamina lucida, the lamina densa, and the sub-lamina densa. Well-characterized BMZ components include the hemidesmosome/upper lamina lucida-located bullous pemphigoid antigens (BP230 and BP180), a 6b4 integrin, and plectin; the lower lamina lucida-located laminin-1, laminin-5 (previously named kalinin, epiligrin, nicein, BM600), laminin-6 (previously named k-laminin), p105, and entactin/nidogen; the lamina densa-located type IV collagen and perlecan; and the sub-lamina densa-located type VII collagen (epidermolysis bullosa acquisita antigen). Mucosal BMZ also contain identical components as skin BMZ. Autoantibodies targeting skin and/or mucosal BMZ components, like that of genetic mutation of BMZ components, result in a histopathologically defined subepidermal blistering disease, that is, a blister which occurs just below the epidermis/epithelium. Well-characterized autoimmune subepidermal blistering diseases include bullous pemphigoid (BP), linear IgA bullous dermatosis, cicatricial pemphigoid (with subsets of patients characterized by autoantibodies targeting either BP antigens or laminins), anti-p105 pemphigoid, and epidermolysis bullosa acquisita. Using a simple method of direct or indirect immunofluorescence testing on a skin section chemically separated at the middle portion of lamina lucida, in combination with immunoelectron microscopy and target antigen determination, accurate diagnoses for various autoimmune subepidermal blistering diseases can be obtained.