[Frontiers in Bioscience 2, d343-352, July 15, 1997]

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Lawrence S. Chan

Medicine Service, Section of Dermatology, Lakeside Division, VA Chicago Health Care System, and Division of Immunodermatology, Department of Dermatology, Northwestern University Medical School, 300 E. Superior St., Chicago, IL 60611

Received 7/3/97 Accepted 7/10/97


3.1 Skin basement membrane structure:

Figure 1 is a schematic diagram of skin BMZ showing the relative location of various known components. (BP=bullous pemphigoid; Ag=antigen) Salt-split zone indicates the approximate location of separation when an intact skin is chemically separated by either 1 M NaCl or 20 mM Na-EDTA.

Figure 1. Schematic diagram of skin BMZ indicating the relative location of known BMZ components. BP=bullous pemphigoid, Ag=antigen.

3.1.1 Hemidesmosome:

Situated at the undersurface of basal keratinocytes, hemidesmosome contains half of the structures of a desmosmoe (a structure observed between two adjacent keratinocytes): single intracytoplasmic attachment plaque onto which tonofilament of the basal keratinocytes are attached (1). The BP230 (BPAg1) is located at the intracellular side of the hemidesmosmoe whereas the BP180 (BPAg2) is a transmembranous protein that contains an intracellular domain, a transmembranous segment, and an extracellular domain that projects into the lamina lucida (7-9). The extracellular domain of BP180 protein contains a collagenous domain interrupted by 16 small non-collagenous domains (9). The largest of these 16 non-collagenous domains, NC16A, is located adjacent to the transmembranous segment. In addition, a member of the integrin family, a6b4,and plectin (a cytoskeleton-associated attachment protein), are also located in this area (10-11).

3.1.2 Lamina lucida:

Situated between the hemidesmosome and the lamina densa, the lamina lucida is electron-lucent under electron microscope (1). Nevertheless, fine filamentous structures are observed in this area and are termed anchoring filaments (1). Anchoring filaments extend from the basal keratinocytes’ hemidesmosomes to lamina densa, thus traversing the lamina lucida (1). One of these anchoring filament components is a member of the laminin family, laminin-5 (12-13). The laminin family consists of a group of heterotrimers of various combinations of three chains,a, b, and g, and are synthesized and secreted by keratinocytes (Table I, 14-16). Laminin-6, previously named k-laminin, is another laminin variant, and its presence is restricted to anchoring filament-containing basement membranes (17). Laminin-6, a heterotrimer of a3b1g1chains secreted by epidermal cells, shares structural and immunological similarities with two other lamina lucida-located laminins, laminin-1 (heterotrimer of a1 b1 g1) and laminin-5 (heterotrimer of a3b3g2, previously named kalinin, epiligrin, nicein, BM600) (17). In addition, a 105-kDa protein, termed p105, has recently been identified as a result of studying autoimmune diseases (6). Further biochemical studies indicate that p105 is distinct from the truncatedg2 chain of laminin-5, which is also approximately 105-kDa in size (18). In addition, the N-terminal amino acids of p105 have been sequenced and shown to have substantial homology with a tumor associated antigen (19). Molecular cloning of p105 is now underway to delineate the structure and function of p105. Another glycoprotein, entactin/nidogen, is also located in this area (20).

Table I. Skin BMZ Laminins

Laminin Variants

a Chain b Chain g Chain


a1 b1 g1


a3 b3 g2


a3 b1 g1

3.1.3 Lamina densa:

Lamina densa, named according to its electron-dense appearance under electron microscope, is 35-45 nm-thick (1). This structure is considered to be the true basement membrane by some pathologists (1). The BMZ components that are located in this area include:type IV collagen, perlecan (heparan sulfate proteoglycan), and perhaps also laminin-6 (21-23). Type IV collagen is considered to be the major component in this area (1).

3.1.4 Sub-lamina densa:

Below the lamina densa, there are fibrillar structures that connect the lamina densa onto the dermal plaque-like structures (1). These fibrillar structures have been named anchoring fibrils (1). Type VII collagen is the major component of the anchoring fibril (24). Type VII collagen is a 290-kDa protein synthesized and secreted by both keratinocytes and fibroblasts. The newly synthesized type VII collagen consists of a 145-kDa non-collagenous (NC1) domain at the N-terminus, a 145-kDa central triple-helical collagenous domain, and a short 34-kDa non-collagenous (NC2) domain at its C-terminus (25-26). It appears that either a portion or all of NC2 domain is proteolytically removed before incorporated into the skin BMZ. This is supported by the finding that antibody raised against NC2 domain does not label skin BMZ (27). It is now clear that the triple helical type VII collagen forms anti-parallel dimers, joining two molecules at the C-terminus of the collagenous domains. Thus, the N-terminus-located NC1 domain serves as a binding site to interact with other BMZ components. Besides anchoring fibrils, there are other minor fibers that connect to the area beneath lamina densa: oxytalan, elaunin, and elastic fibers (1).

3.2 Skin basement membrane function:

The major function of BMZ is to serve as an adherent connection between the outer layer of epidermis and the inner layer of dermis. The evidence supporting this role of BMZ is observed in several heritable blistering diseases characterized by defective BMZ protein production secondary to mutation of the genes encoding BMZ proteins. Junctional epidermolysis bullosa, a skin disease characterized by either a defective laminin-5, a defective BP180, or a defective b4 integrin, is manifested clinically as skin fragility and subepidermal blister formation in trauma-prone areas of the skin (28-31). Dystrophic epidermolysis bullosa, another skin disease,characterized by defective type VII collagen synthesis secondary to genetic mutation, is also manifested clinically as skin fragility and subepidermal blister formation in trauma prone skin (32-33).

The adherent role of BMZ is also supported by laboratory evidence. Technical advancement in biochemical and molecular biological methods allow us to study interactions between isolated BMZ components in the well-controlled laboratory environment. Laminin-5, a major lamina lucida component, has been shown to be a preferred ligand for a3b1 anda6b4 integrins in the plama membrane of basal epithelial cells (34-35). However, it has a low affinity for entactin/nidogen, which serves as a connecting network between laminin-1 and type IV collagen (16,36-37). The high affinity of laminin-1 for entactin/nidogen is due to the fourth EGF-like repeat domain III in its g1subclass chain, which is not present in laminin-5 (38-39). Similarly high affinity for entactin/nidogen has been observed in two other laminins not present in skin BMZ, laminin-2 and -4, which also share theg1 subclass chain (37). Sharing the same g1 subclass chain, laminin-6 is also likely to have a high affinity for entactin/nidogen. Thus, laminin-5 may bridge epidermal cells to the lower BMZ by linking the integrins on the outer part and forming a complex with laminin-6 on the inner part (40).

Type VII collagen, the major component of anchoring fibril that connects lamina densa to the dermal structure, has a NC1 domain that contains multiple subdomains which share homology with known adhesion molecules, including the fibronectin type III-like repeats and the A domain of von Willebrand factor (41). An eukaroytic expressed recombinant full-length NC1 protein has been shown to exhibit specific interaction with the lamina lucida components, the laminin-5/6 complex, and with the dermal components, fibronectin and type I collagen (41).

Thus, the ineractions of various molecules of the BMZ could be envisioned according to the following sequence from the outer part to the inner part of skin: The two basal keratinocyte cell membrane-located integrin family members, a3b1 and a6b4, serve as ligands for laminin-5 and laminin-5/laminin-1, respectively. Laminin-5 forms a complex with laminin-6. Laminin-1 and laminin-6 both interact with entactin/nidogen, which in turn interacts with type IV collagen. Type IV collagen interacts with type VII collagen (41). Type VII collagen, in addition to interacting with type IV collagen, also interacts with laminin-5/laminin-6 complex on the outer part and with fibronectin and type I collagen on the inner part of skin. By this interconnecting network of molecules within the skin BMZ, an adherent connection between the outer layer, epidermis/epithelium and the inner layer, dermis is established. The interaction of the extracellular domain of BPAg2 with other BMZ components remains to be elucidated. Besides the major function of adherence of epidermis to dermis, minor functions of skin BMZ include structural support, permeability regulation, and embryonic differentiation.

The adherent role of BMZ is further supported by the clinical observation of autoimmune subepidermal blistering diseases, the pathologic conditions resulting from perturbation of BMZ by autoantibodies. We will now illustrate these in the following section.