O N 8 Disorders of Epidermal and Dermal - Epidermal Cohesion and Vesicular and Bullous Disorders

The cell-cell and cell–basement membrane adhesion in the epidermis provides the skin with its resistance against environmental influences; epidermal integrity is required for protection of the entire organism against mechanical, physical, or microbial noxae. The major cellular structures involved are the desmosomes at cell-cell junctions in the epidermis and the hemidesmosome–basement membrane adhesion complexes and related structures at the epidermal-dermal junction. Ultrastructurally, the hemidesmosome closely resembles one-half of the desmosome; however, at the molecular level, these two structures are distinct. Both represent specifically organized assemblies of intracellular and transmembrane molecules, which on one hand anchor cytoskeletal filaments to the cell plasma membrane and on the other hand the plasma membrane to extracellular structures, i.e., another cell or the extracellular matrix. Our knowledge of the desmosomal, hemidesmosomal, and basement membrane molecules has expanded drastically in the last 10 to 15 years due to the great power of both molecular genetics and proteomics. After some of the proteins were initially identified as autoantigens in pemphigus and pemphigoid, a multitude of molecules have now been characterized at both protein and gene levels, and their expression, regulation, and functions have been discerned. The antigenic epitopes in different autoimmune blistering skin diseases have been carefully mapped and, to date, mutations in at least 18 different genes have been shown to underlie heritable disorders of epidermal or epidermaldermal adhesion in humans and mice. Morphologic, molecular and functional aspects of these adhesion structures are delineated in this chapter.