Pathogenesis of Bullous Pemphigoid

Bullous pemphigoid, the most common autoimmune blistering disease, is induced by autoantibodies against type XVII collagen. Passive transfer of IgG or IgE antibodies against type XVII collagen into animals has revealed not only the pathogenicity of these antibodies but also the subsequent immune responses, including complement activation, mast cell degranulation, and infiltration of neutrophils and/or eosinophils. In vitro studies on ectodomain shedding of type XVII collagen have also provided basic knowledge on the development of bullous pemphigoid. The pathogenic role of autoreactive CD4+ T lymphocytes in the development of the pathogenic autoantibodies to type XVII collagen should also be noted.

Bullous pemphigoid (BP), the most common autoimmune blistering disorder, is induced by autoantibodies against the components of the skin basement membrane zone (BMZ). Clinically, tense blisters and erosions with itchy urticarial plaques and erythema develop on the whole body ( Fig. 1 A). Histologic examination of lesional skin reveals subepidermal blisters with inflammatory infiltration consisting of eosinophils and lymphocytes (see Fig. 1 B). Direct immunofluorescence (IF) shows linear deposition of IgG and complement C3 at the dermal-epidermal junction (DEJ) (see Fig. 1 C). In addition, indirect IF using the patient’s sera shows linear deposition of IgG at the DEJ of normal human skin, and the autoantibodies usually deposit on the roof side of the artificial split-skin blister induced by 1M sodium chloride (see Fig. 1 D). Immunoblotting reveals that the autoantibodies usually react with 180-kDa or 230-kDa proteins in epidermal extractions of normal human skin as candidate autoantigens. The 230-kDa protein, called BP230 or BPAG1, is a plakin family protein that was originally identified as the major antigen for BP. BP230 is a cytoplasmic component of hemidesmosomes that enhances the linkage of keratin intermediate filaments to hemidesmosomes. Although several studies have indicated that BP230 is pathogenic, it remains unclear whether the autoantibodies against BP230 are pathogenic. The 180-kDa protein is considered to be the main pathogenic antigen in BP.

The major pathogenic antigen in BP: type XVII collagen (COL17)

Autoantibodies against the hemidesmosomal antigen of type XVII collagen (COL17, also called BP180 or BPAG2), a 180-kDa protein, are believed to induce the inflammatory process, resulting in dermal-epidermal separation. COL17 is a type II transmembrane protein that spans the lamina lucida and projects into the lamina densa of the BMZ ( Fig. 2 A). COL17 has 15 collagenous domains in the extracellular domain (see Fig. 2 B). The noncollagenous 16A (NC16A) domain in the juxtamembranous extracellular part is considered to have the major pathogenic epitope for BP (see Fig. 2 B). The extracellular part of COL17 is constitutively shed from the cell surface within the NC16A domain.