A New Perspective of Autoimmune Bullous Diseases: Molecular Cell Biology of Blistering Mechanisms and Logical Treatments

Pemphigus and pemphigoid are most distinct types of organ-specific acquired autoimmune diseases, and characterized by intraepidermal and subepidermal blistering, which are induced by autoantibodies against desmosomal cadherins, desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3), and a hemidesmosome adhesion protein, type XVII collagen, i.e., bullous pemphigoid antigen II (BP180), respectively. Blistering pathomechanisms after autoantibodies bind to their antigens are not yet clear. In pemphigus vulgaris (PV), the antibody binding is thought to cause steric hindrance to homophilic adhesion of Dsg3 leading to acantholysis, and/or to activate outside-in signaling pathways to induce phosphorylation of Dsg3, which may, in turn, lead to internalization of Dsg3 and inhibition of Dsg3 integration into desmosomes, resulting in the formation of Dsg3-depleted desmosomes. We have shown that this Dsg3-depletion from desmosomes, which is seen in animal model and patients, decreases the cell-cell adhesive strength, suggesting that this may cause acantholysis. In bullous pemphigoid, antibody binding is thought to activate complement cascade leading to the generation of inflammation, which may produce proteases and cause dermal epidermal separation. However, this does not yet explain why separation runs specifically along the intralamina lucida, but not sub-lamina densa or even not intercellular adhesion of basal cells, because proteolysis due to inflammatory enzymes are not believed to have any specificity to the lamina lucida, if antibody binding to BP180 should exert effects only of complement activation. We have shown that BP-IgG binding to BP180 causes internalization of BP180 in culture and patient basal cells and depletes cultured keratinocytes of BP180 resulting in the reduction of adhesive strength to the bottom of culture plates. These results suggest that BP-IgG reduces the BP180 content from hemidesmosomes resulting in decreasing the adhesive strength to the lamina densa and inflammation generated by BP180 immune-complex tears the weakened lamina lucida due to BP180 deficient. This may cause the BP-specific split at lamina lucida in combination with nonspecific inflammatory enzymatic activity exerted at dermal-epidermal zone. Blistering mechanisms of both pemphigus and pemphigoid appear to have a common point that autoantibody-target antigens are depleted form cells, leading to a decrease in the adhesive function. The depletion of specific adhesion peptides may determine the specificity of those diseases and myriad primary and/or secondary effects to autoantibody binding to antigens may exaggerate the diseases. Treatments should be determined by taking these two aspects into mind, to reduce or deplete pathogenic antibodies and to control the pathogenic reactions caused by antibody binding to the antigens.

並列關鍵字

Pemphigus ； Bullous pemphigoid ； Desmoglein ； Bullous pemphigoid antigen

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