Autoimmune Blistering Diseases

Basement Membrane Zone

The basement membrane zone (BMZ) of the epidermis is a beautiful and complex structure and a marvel of biological engineering. The zone acts to attach the overlying epidermis to the underlying stromal tissue, in this case the papillary dermis, which is made predominantly of collagen bundles. A plethora of unique and specialized proteins play critical roles in the proper functioning of the BMZ. Any defect or abnormal antibody that can cause disruption of the normal architecture can result in fracturing of the BMZ and blister formation.

The BMZ can be appreciated on routine hematoxylin and eosin (H&E) staining as an eosinophilic band below the basilar keratinocytes. The components of the BMZ are produced in two locations: the epidermal keratinocyte and the dermal fibroblast. These cells act to produce the required proteins in the correct ratio to maintain a functional basement membrane. The basement membrane's most important function is to keep the epidermis firmly attached to the underlying dermis. This is necessary for life. This specialized structure also acts to encourage migration of cells and repair of the epidermal-dermal barrier after trauma. Many other critical processes and physiological roles depend on the proper functioning of the BMZ, including permeability of water and other chemical substrates, proteins, and cellular elements. The BMZ is a highly organized structure that is consistent from person to person.

The structure of the BMZ can be subdivided into individual compartments for study, with the understanding that the entire unit functions as one. These are the epidermal basilar cell cytoskeleton, hemidesmosome, lamina lucida, lamina densa, and sublamina papillary dermis. Each of these components is made up of unique proteins that act in harmony to preserve the functional role of the BMZ. The basilar keratinocytes contain intracellular cytoskeleton components made of keratin intermediate filaments, predominantly keratin 5 and keratin 14. The keratin intermediate filaments are interwoven into the hemidesmosomal plaque to firmly adhere the basilar cell to the hemidesmosome.

The keratin intermediate filaments interact with bullous pemphigoid antigen 1 (BP230) and plectin. These two proteins are the main components of the hemidesmosomal plaque. Plectin and BP230 are bound tightly together. Plectin and bullous pemphigoid antibody 1 also bind to the integrin class of proteins and to bullous pemphigoid antigen 2 (BP180). Integrins and BP180 are transcellular proteins that bind to the intracellular molecules, plectin and BP230; they also extend out from the basilar keratinocyte and interact with the laminin 5 and collagen IV molecules in the lamina lucida and lamina densa.

The lamina lucida is so named because of its translucent appearance on electron microscopy. In comparison, the lamina densa is an electron-dense region that lies just below the lamina lucida. The lamina lucida is composed of the transversing parts of the integrin and BP180 proteins. These two molecules attach to the laminin class of proteins in the lamina densa. The lamina lucida is considered to be the weakest part of the BMZ, and it is the blister plane in suction blisters, junctional epidermolysis bullosa, and salt-split skin. The lamina densa is composed of a latticework of type IV collagen. Type IV collagen is found only in the lamina densa. It is unique in that it retains its globular regions on either end. These form attachments to other type IV collagen molecules to create the lattice. Collagen type IV binds strongly to a dumbbell-shaped protein named nidogen . This nidogen protein is critical in attaching to the laminin proteins in the lamina densa. Nidogen locks the type IV collagen to the laminins, which are bound to the overlying integrin and BP180.

The laminin proteins appear as inverted crosses and serve to attach the aforementioned proteins to the papillary dermis that underlies the lamina densa by interacting with type VII collagen. Type VII collagen, which is made up of three identical alpha chains, is also known as the anchoring fibril. These fibrils interweave among the type I and type II collagens of the papillary dermis and attach either end to the laminin proteins in the lamina densa, thus firmly anchoring the entire overlying epidermis and BMZ to the papillary dermal collagen.

Many blistering diseases are caused by genetic abnormalities in the BMZ proteins; these are classified as the epidermolysis bullosa group of blistering diseases. Each of these diseases is unique due to different protein defects that lead to the various phenotypes. Autoimmune blistering diseases of the pemphigoid class target the BMZ and its components, including the hemidesmosome. Autoimmune diseases in the pemphigus class of diseases target the desmosome.

Hemidesmosome

The hemidesmosome is one of the main components of the BMZ. Its purpose is to attach the basilar layer keratinocytes to the underlying stroma—that is, the papillary dermis. The hemidesmosome is made up of many unique and highly integrated groups of protein-to-protein connections. The main proteins in the hemidesmosomal plaque are the bullous pemphigoid antigens BP180 and BP230, integrin, plectin, and laminin. Their interactions and how they connect the keratinocyte cytoskeleton to the underlying collagen have already been described. Antibodies directed against the components of the hemidesmosome can be seen in the pemphigoid group of disease states.