Epidermolysis bullosa and skin structure
Skin basement membrane zone (BMZ) is an ultrastructurally defined area situated between the outer layer of skin, the epidermis, and the inner layer of skin, the dermis. The major function of skin BMZ is to serve as an adherent connection between the epidermis and the dermis.
Depending on the type of Epidermolysis Bullosa, blistering may occur in the epidermis, the basement membrane zone or in the dermis.
In Epidermolysis Bullosa Simplex, cytolysis causes blisters in the basal or spinous layers of the epidermis, and keratinocytes often have abnormal density and organization of keratin filaments. The membrane is not altered.
In Junctional Epidermolysis Bullosa, the epidermis separates from the basal lamina, forming a blister cavity in the plane of the lamina lucida, where the hemidesmosome structure and density are frequently diminished.
In Dystrophic Epidermolysis Bullosa, the basal lamina remains attached to the epidermis, but the blister cavity forms beneath the lamina densa of the dermoepidermal junction and anchoring fibrils may appear abnormal, reduced in number, or absent altogether.
Composition of basement membrane zone
Many multi-layered tissues like the skin and the oral mucous membrane include a BMZ (basement membrane zone).
The BMZ is composed of many specialized components that combine to form anchoring complexes. At the superior aspect of the BMZ, keratin-containing intermediate filaments of the basal cell cytoskeleton, insert on basal cell plasma membrane condensations called hemidesmosomes. Anchoring filaments extend from the basal cell plasma membrane into the extracellular environment and span the lamina lucida, connecting the hemidesmosomes with the lamina densa. At the most inferior aspect of the BMZ, type VII collagen-containing anchoring fibrils extend from the lamina densa into the papillary dermis, connecting the lamina densa to anchoring plaques, trapping interstitial collagen fibrils. The cutaneous BMZ, therefore connects the extensive basal cell cytoskeletal network with an abundant network of interstitial collagen fibrils in the dermis.
- Keratin filaments: Keratins 5 and 14 combine to form intermediate filaments in basal keratinocytes. Keratins contain a central alpha-helical rod with several nonhelical interruptions, as well as nonhelical carboxyterminal and aminoterminal regions. The regions of highest conservation between the keratins are located on the ends of the keratin rod in the helix boundary motifs. Keratin intermediate filaments insert upon electron-dense structures termed hemidesmosomes.
- Hemidesmosomes: These structures contain intracellular proteins, including plectin and BP230. Plectin (HD1) is a 500-kd protein that binds intermediate filaments. BP230, also termed BPAG1, is a 230-kd protein that has homology to both desmoplakin and plectin. BP230, like plectin, functions in the connection between hemidesmosomes and intermediate filaments. Hemidesmosomes also contain the intracellular portions of the transmembrane proteins collagen XVII (BP180) and a 6 β 4 integrin. The β 4 integrin subunit performs a central role in hemidesmosome formation and contains an especially large cytoplasmic domain, which interacts with other proteins of the hemidesmosomal plaque. Collagen XVII is a transmembrane collagenous protein that interacts with β 4 integrin and BP230 intracellularly and with laminin 5 extracellularly.
- Anchoring filaments: These structures contain the extracellular portions of collagen XVII (BP180) and a 6 β 4 integrin. In addition, anchoring filaments contain the molecules laminin 5 and laminin 6. Similar to all members of the family of laminin proteins, laminin 5 is a large heterotrimeric molecule, containing a 3, β 3, and γ 2 chains. Laminin 5 forms a disulfide-bonded attachment to laminin 6, the other known anchoring filament laminin, which contains a 3, β 1, and γ 1 chains. Laminin 5 also forms a strong association with type VII collagen, which connects anchoring filaments with anchoring fibrils.
- Anchoring fibrils: Type VII collagen is the primary component of anchoring fibrils. Type VII collagen contains a large N-terminal globular domain (NC-1), which interacts with laminin 5 in the lamina densa; a long collagenous domain; and a smaller C-terminal globular domain (NC-2), which is cleaved proteolytically during anchoring fibril formation. Type VII collagen chains form a triple helix; then, 2 molecules join together in an antiparallel fashion. Next, anchoring fibrils are formed by lateral associations of antiparallel dimers. Anchoring fibrils wind around the dermal interstitial collagen fibrils and reinsert back upon the lamina densa, attaching the BMZ to the underlying dermis.
Molecular and genetic dysfunction
The cells which make up the skin are held together by proteins. Each of these cohesive skin proteins is created by a gene. Epidermolysis Bullosa is caused by the malfunction of specific genes. Typically:
- The malfunction of the keratin 5 gene of keratin 14 gene causes Epidermolysis Bullosa Simplex
- The malfunction of the integrin α5 gene, integrin β4 gene, one of the genes that produces laminin 5 (LAMA3, LAMB3 or LAMC2), the BP180 protein gene (or collagen 17), causes Junctional Epidermolysis Bullosa
- The malfunction of the plectin gene can cause Epidermolysis Bullosa Simplex with muscular dystrophy or Junctional Epidermolysis Bullosa
Modern biological laboratories aim to identify the malfunctioning gene in each case for each of the families. Although this research is sometimes time-consuming, it allows for the prediction of possible prenatal or pre-implant diagnostic techniques.