Chapter 2. Review of the literature
2.1. Mucocutaneous basement membrane zone
The mucocutaneous basement membrane zone (BMZ) is a thin, continuous, sheet-like extracellular matrix structure composed of hemidesmosomes, basement membrane and anchoring fibrils. Basement membranes are specialized structures located at the junction between epithelial cells and the underlying connective tissue stroma (Fig. 1). As defined by electron microscopy, basement membranes consist of two layers, lamina lucida and lamina densa. Lamina lucida is a layer with low electron density located adjacent to the cell membrane. Lamina densa is observable as an electron-dense layer next to the connective tissue stroma. However, it is possible that these two layers do not exist in vivo: lamina lucida is proposed to be an artefact resulting from rapid dehydration during tissue processing (Chan et al. 1993). The molecular structure of basement membranes is mainly composed of type IV collagen and laminin networks, connected with nidogen, and the proteoglycans perlecan and agrin. In addition, there are several minor connecting or adhesive constituents. Basement membranes have many important functions. They both separate and connect two distinct tissue compartments. Basement membranes allow migrating cells to pass under physiological conditions, but act as barriers against tumor cell invasion and regulate the passage of molecules based on their electronic charge and molecular size. Many BMZ ligands interact with cell surface receptors, influencing epithelial cell behavior during morphogenesis, fetal development, and wound healing by regulating cell shape, proliferation, differentiation, and motility as well as gene expression and apoptosis. (Timpl 1996, Burgeson & Christiano 1997, Ghohestani et al. 2001)
2.1.1. Hemidesmosomal adhesion complex
Hemidesmosomes are multi-protein complexes that connect the basal keratinocytes to the basement membrane (Fig. 1). Together with the anchoring filaments and anchoring fibrils, they form a functional unit of the hemidesmosomal adhesion complex, which integrates the cytoskeleton of the epithelial cell to the ECM. Ultrastructurally, hemidesmosomes appear as small electron-dense complexes at the ventral cell membrane of basal keratinocytes, composed of an internal plaque, an external plaque, and a sub-basal dense plate. In epidermal keratinocytes, actin, intermediate, and microtubule filament systems form a cytoskeletal network, which is connected to adjacent keratinocytes via desmosomes and to the underlying basement membrane via hemidesmosomes. The internal plaque of the hemidesmosome consists of two plakin family proteins, plectin and BP230, and a novel accessory protein erbin (Favre et al. 2001). Plectin functions as a cross-linker of the three cytoskeletal filament networks, binding them to cell membrane structures, including the hemidesmosomes. BP230 attaches the intermediate filaments to the hemidesmosomal adhesion complex. Plectin and BP230 bind to the transmembrane proteins of the external plaque, i.e. 64 integrin and collagen XVII (BP180). The association of BP230 and 64 integrin may be mediated by erbin. The cytoplasmic as well as the extracellular part of 64 integrin binds to collagen XVII. A third transmembrane component of the external plaque is tetraspanin CD151, which is thought to participate in the clustering of integrin receptors to facilitate cell binding. (Jones et al. 1998, Hirako & Owaribe 1998, Nievers et al. 1999, Borradori & Sonnenberg 1999, McMillan et al. 2003)
Outside the basal keratinocyte, thread-like anchoring filaments extend from the hemidesmosomes to the basement membrane (Fig. 1). Laminin-5 is the major constituent of the anchoring filaments, which connect hemidesmosomes to the basement membrane. Laminin-5 is a heterotrimer composed of 3, 3, and 2 chains. Association of laminin-5 with hemidesmosomal 64 integrin is likely to occur via the carboxy(C)-terminal globular G-domain of the 3 chain. Laminin-5/64 integrin interaction is essential for hemidesmosome formation in vivo and the maintenance of epithelial adhesion, as emphasized by the fact that mutations in the genes encoding laminin-5 chains result in a hereditary blistering skin disease, junctional epidermolysis bullosa. In addition to 64 integrin, laminin-5 also binds the extracellular domain of collagen XVII. For a review, see (Franzke et al. 2003). Unlike other laminins, laminin-5 is unable to bind nidogen and therefore incapable of being directly attached to the collagen IV/perlecan network of the basement membrane. Instead, it is likely that laminin-5 is incorporated in the basement membrane via laminins 6 and 7, which are able to connect to nidogen. Laminin-5 binds to the amino(N)-terminal domain of collagen VII, providing a bridge between hemidesmosomal 64 integrin and collagen VII of anchoring fibrils. (Jones et al. 1998, Nievers et al. 1999)
Anchoring fibrils extend from the basement membrane to the structures called anchoring plaques in the connective tissue matrix or loop back to the basement membrane, connecting it to the underlying connective tissue (Fig. 1). The anchoring fibrils entrap collagen fibrils in the connective tissue, which is a way of ensuring epithelial anchorage. Anchoring fibrils are mainly composed of collagen VII polymers, which are connected to the hemidesmosomal anchoring complex via attachment to laminin-5 within the basement membrane. The role of anchoring fibrils is vital for the function of the anchoring complex: mutations in the collagen VII gene result in a heritable blistering skin disease, dystrophic epidermolysis bullosa, in which the epithelium is detached below the basement membrane. (Bruckner-Tuderman 1999)
