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Dermoepithelial Interface

The basement membrane was defined first by conventional microscopy as a thin band situated immediately beneath basal keratocytes, a strip that was stained magenta by the periodic acid-Schiff method (Fig. 1.70). In time, with the aid of electron microscopy, it came to be recognized as a specialized structure that formed at the junction of epithelial cells and connective tissue adjacent to them. In the skin, a basement membrane like that at the interface of dermis and epidermis is found around all epithelial structures of adnexa, i.e., hair follicles, sebaceous units, apocrine units, and eccrine units. Moreover, the vasculature and Schwann cells of nerves also are surrounded by a basement membrane.

Figure 1.70

Basement membrane zone as seen through a conventional microscope, namely, a band of periodic acid-Schiff (PAS)-positive neutral mucopolysaccharides situated immediately beneath a row of epidermal basal cells.

The junction between epidermis and dermis nears maturity by the 12th week of gestation. Based on findings by examination ultrastructurally, the dermoepidermal interface has been divided, by convention, into four zones: (1) the cytoskeleton, that is, hemidesmosomes and plasma membrane of basal keratocytes that constitute the upper boundary of the interface; (2) the lamina lucida, an electron-lucent region that lies beneath basal keratocytes; (3) the lamina densa, an electron-dense plate situated below the lamina lucida and above the papillary dermis; and (4) the sub-lamina densa seated immediately below the lamina densa and consisting of the uppermost portion of the papillary dermis (Fig. 1.71). Structural components of these four zones are responsible for binding the epidermis to the dermis. Disruption of any of the components results in a variety of diseases, among them blistering disorders such as porphyria cutanea tarda, dermatitis herpetiformis, and bullous pemphigoid.

Figure 1.71

A. Schematic representation of the dermoepidermal junction as visualized by electron microscopy. Within a basal keratocyte, tonofilaments (TF) are attached to a hemidesmosome (HD) that parallels the cytoplasmic leaflet of the plasma membrane (PM). The lamina lucida (LL), an electron-lucent zone, separates the lower border of a plasma membrane from the electron-dense lamina densa (LD), known also as basal lamina. Within the lamina lucida, a sub-basal dense plaque (SBDP) is situated beneath a hemidesmosome and is traversed by fine anchoring filaments (AFT) that extend perpendicularly from the plasma membrane to mesh with the basal lamina. Cross-banded anchoring fibrils (AFL) and dermal microfibril bundles (DMB) extend downward from the basal lamina to interweave with type III collagen fibers (CF) in the papillary dermis. (Art by Mario DiLeonardo, M.D., from AB Ackerman, H Jacubovic. In: Moschella SL, Hurley HJ, eds. Dermatology, 3rd ed. Philadelphia: W.B. Saunders, 1992.) B. Electron micrograph of epidermal basement membrane zone. AF, anchoring fibrils; BC, basal cell; D, dermis; HD, hemidesmosome; LD, lamina densa; LL, lamina lucida; PM, plasma membrane; PV, pinocytotic vesicle. (x67,500) (Courtesy of Stephen Katz, M.D.)

The plasma membrane of basal keratocytes forms the roof of the structurally integrated unit known as the dermoepidermal junction. Hemidesmosomes, stationed at intervals along the plasma membrane, are formed of both intracellular and extracellular components. On the cytoplasmic side of the plasma membrane, a hemidesmosome consists of an electron-dense attachment plaque. Tonofilaments of keratin housed within the cytoplasm of basal cells converge on the attachment plaque. Another electron-dense plaque, referred to as a sub-basal dense plaque, is situated extracellularly. The basal plasma membrane is sandwiched between the intracellular attachment plaque and the extracellular sub-basal dense plaque. These components, in sum, make up hemidesmosomes. Proteins in hemidesmosomes are plectin, bullous pemphigoid antigen 1 (BPAg1), bullous pemphigoid antigen 2 (BPAg2), integrin subunit α6, and integrin subunit β4. Destruction of hemidesmosomes leads inevitably to development of a subepidermal blister as occurs, for example, in bullous pemphigoid. Patients with bullous pemphigoid synthesize antibodies to two of the antigens in a hemidesmosome. One antigen, bullous pemphigoid antigen 1, is a 230-KDa protein, a type of desmoplakin and constituent of the intracellular component of the hemidesmosome plaque and found in the sera of patients with bullous pemphigoid. Bullous pemphigoid antigen 2, a 180-KDa/Type XVII collagen, is targeted by autoantibodies in patients with bullous pemphigoid and herpes gestationis, as well as in some with linear IgA bullous dermatosis, and cicatricial pemphigoid.

Plectin, a 500-KDa protein and a constituent of the intracellular component of hemidesmosomes, attaches intermediate filaments to both hemidesmosomes and plasma membranes of basal keratocytes. Mutations in the gene that encodes plectin are responsible for epidermolysis bullosa simplex when that disease is associated with limb-girdle muscular dystrophy.

Integrins are transmembrane glycoproteins and a major component of hemidesmosomes. They mediate the transfer of information between the extracellular matrix and the interior of the cell, thereby aiding in modulating the organization of the cytoskeleton, proliferation, and differentiation. Integrins in keratocytes are most evident on basal cells, where they are found at loci of adhesion and on hemidesmosomes.

Hemidesmosomes are perched atop an approximately 50-nm-wide lamina lucida that appears to be homogenous, except in loci immediately beneath hemidesmosomes. There, thin filaments, called anchoring filaments, extend from the basal plasma membrane across the lamina lucida through the sub-basal dense plaque and end on the lamina densa. Within homogenous regions of the lamina lucida are positioned glycoproteins, among them being laminin and entactin/nidogen, and fibronectin. Fibronectin is a component of fetal basement membrane, but not of fully formed adult basement membrane. In healing wounds, fibronectin is laid down, serving as a substrate across which keratocytes migrate. During embryonic life, fibronectin may provide a scaffold for formation of components that comprise the interface between epidermis and connective tissue. Entactin and nidogen, first reported on independently, were determined subsequently to be the same protein. Because of its capability to bind to cells and Type IV collagen, entactin/nidogen is essential to the structural integrity of the basement membrane.

Laminins are a family, at least 14 of them being members, of heterotrimeric glycoproteins. Of the structural noncollagenous glycoproteins in the basement membrane, they are the most abundant. Laminins 5, 6, and 10 are present in the epidermal basement membrane. Laminin 5 plays an essential part in adhesion of the epidermis to the dermis, being localized to the interface of the lamina lucida and the lamina densa, where it is thought to form a critical link between hemidesmososme anchoring filament complexes, lamina densa, and anchoring fibrils. Inherited or targeted disruptions in gene-encoding laminin 5 units (LAMA3, LAMC2) result in a phenotype characterized by formation of a subepidermal blister, detachment of the epidermis, and, ultimately, death, and occur, for example, in junctional epidermolysis bullosa of the Herlitz type.

Type IV collagen is the major constituent of the lamina densa, a structure that appears magenta when exposed to the periodic acid-Schiff stain. Other components of the lamina densa are laminins 5, 6, and 10, heparin sulfate proteoglycan, and nidogen (entactin). Anchoring fibrils emanate from the lamina densa and assume a crosshatched configuration. They are present only within specific epithelial basement membranes, e.g., skin, oral mucosa, esophagus, and cervix. Anchoring fibrils, which terminate in the papillary dermis in electron-dense anchoring plaques, connect those plaques and form loops, both ends of which are attached to the lamina densa. Anchoring fibrils form an extensive network in the sub-lamina densa, one that acts to trap collagen and, in the process, attaches the lamina densa to the papillary dermis. Anchoring fibrils are made up of several components, among them Type VII collagen, those being restricted to the basement membrane of stratified squamous epithelium where they are localized to the sub-lamina densa in the uppermost part of the papillary dermis. Genetic defects in some patients with recessive and dominant dystrophic kinds of epidermolysis bullosa are responsible for an abnormality in Type VII collagen and immunologic damage to Type VII collagen is the cause of acquired epidermolysis bullosa and bullous lupus erythematosus.

Another important component of the sub-lamina densa, as it is viewed through an electron microscope, is bundles of microfibrils in the dermis. They correspond to fine, vertically oriented bundles of oxytalan fibers, a type of elastic fiber that is colored black by silver stain in sections visualized by conventional microscopy. These fibers attach the lamina densa to the network of elastic tissue in the dermis. Fine filaments, termed linkin, are those of an 80-KDa protein present in the zone beneath the lamina densa. They insert into the lamina densa, the surface of collagen fibers in the dermis, and the anchoring fibrils, thereby fortifying connections among structural elements of the sub-lamina densa. Last, mention should be made of fibrillin, a recently recognized microfibril associated with elastin, which is absent from the skin of patients with Marfan’s syndrome.

Although the dermoepithelial interface is known now to be composed of many elements, few of which were recognized 27 years ago when the first edition of this book was published, many more doubtless will come to be recognized in ensuing decades.