Etiology and Pathogenesis

Etiology and Epidemiology

The etiology of EBA is unknown, but because the disease features IgG autoantibodies directed against type VII collagen, it is thought that EBA has an autoimmune pathogenesis (Woodley et al. 1984,1988). Another autoimmune bullous skin disease which may exhibit auto-antibodies against type VII collagen is bullous systemic lupus erythematosus (SLE) (Gammon et al. 1985). Both EBA and bullous SLE patients often have a common human leukocyte antigen (HLA) major histocompatibility (MHC) class II cell surface protein, HLA-DR2 (Gammon et al. 1988b). This HLA phenotype has been associated with hyperimmunity which again suggests an autoimmune etiology for EBA.

EBA is a rare disease with an incidence of 0.17-0.26 per million people in Western Europe (Bernard et al. 1995; Zillikens et al. 1995). EBA appears to be less common than BP, but it may be at least as common as CP, pemphigoid gestationis and linear IgA bullous dermatosis. Although there is no racial or gender predilection (Gammon and Briggaman 1993), it has recently been suggested to have higher predilection in the Korean population (Lee 1998). The age of onset varies widely from early childhood to late adult life, but most cases begin between the fourth and fifth decades (Gammon 1988a; Arpey et al. 1991).

Type VII collagen is composed of three identical alpha chains wound into a triple helical structure. Each alpha chain is 290 kDa. However, half of the size of each alpha chain is consumed by a large, globular, non-collagenous domain at the amino end of the molecule. This globular domain is 145 kDa and is called the non-collagenous 1 domain (NC1). At the other end of the alpha chain, the carboxyl terminus, there is a much smaller non-collagenous globular domain called NC2 which is only 34 kDa. In between these two globular domains, there is a long rod-shaped, helical, collagenous domain characterized by repeating Gly-X-Y amino acid sequences (Fig. 1) (Sakai et al. 1986; Burgeson 1993).

Within the extracellular space, type VII collagen molecules form antiparallel, tail-to-tail dimers stabilized by disulfide bonding through the small carboxyl-terminal NC2 overlap between two type VII collagen molecules. A portion of

Collagen Overlap

Fig. 1. A schematic representation of the type VII collagen alpha chain and assembly into anchoring fibril structures. The NC1 non-collagenous domain at the amino terminus has several segments with homologies to adhesive proteins including cartilage matrix protein (CMP), nine fibronectin type III like repeats (FNIII-9), and von Willibrand factor A (VWF). Then, there is a long triple helical collagenous segment (TH) and a smaller second non-collagenous globular domain called NC2. 1. Three type VII collagen alpha chains form a homotrimer [a(C-VII)]3. 2. In the extracellular space, two procollagen molecules align to form antiparallel dimers which are stabilized by the formation of disulfide bonds. The NC2 domain is then proteolytically cleaved. 3. Several of these dimer molecules laterally aggregate to assemble into anchoring fibrils

Fig. 1. A schematic representation of the type VII collagen alpha chain and assembly into anchoring fibril structures. The NC1 non-collagenous domain at the amino terminus has several segments with homologies to adhesive proteins including cartilage matrix protein (CMP), nine fibronectin type III like repeats (FNIII-9), and von Willibrand factor A (VWF). Then, there is a long triple helical collagenous segment (TH) and a smaller second non-collagenous globular domain called NC2. 1. Three type VII collagen alpha chains form a homotrimer [a(C-VII)]3. 2. In the extracellular space, two procollagen molecules align to form antiparallel dimers which are stabilized by the formation of disulfide bonds. The NC2 domain is then proteolytically cleaved. 3. Several of these dimer molecules laterally aggregate to assemble into anchoring fibrils the NC2 domain is then proteolytically removed (Bruckner-Tuderman et al. 1995). The antiparallel dimers then aggregate laterally to form anchoring fibrils with large globular NC1 domains at both ends of the structure (Fig. 1).

Pathogenesis

The NC1 domain contains the major antigenic epitopes for EBA and bullous SLE autoantibodies (Gammon et al. 1993; Jones et al. 1995; Lapiere et al. 1996). The NC1 domain contains a series of domains within it that have homology with adhesive proteins such as cartilage matrix protein, fibronectin and the A domain of von Willebrand factor (VWF-A) (Christiano et al. 1994). Therefore, the NC1 domain may facilitate binding of type VII collagen to other

BMZ and matrix components. It is possible that autoantibodies directed against NC1 compromise the function of these adhesive proteins so that anchoring fibril collagen cannot interact well and bind to other connective tissue components of the BMZ and papillary dermis. This compromised function would lead to epidermal - dermal disadherence because of loss of anchoring fibril function. The recent observation that some EBA autoantibodies from children with EBA target other domains within the alpha chain besides NC1 suggests that the helical collagenous domain and perhaps the NC2 domain may also play important roles in maintaining fully functional type VII collagen and anchoring fibrils (Tanaka et al. 1997). For example, some EBA patients' autoantibodies recognize antigenic epitopes within both the NC1 and NC2 domains, and the latter domain appears to be important in the formation of antiparallel dimers and anchoring fibril assembly (Chen et al. 2000).

We now understand that EBA does not always present as a noninflammatory mechanobullous disease reminescent of DEB. Although less common, EBA may present as an inflammatory, widespread, vesiculobullous disease reminiscent of BP. Therefore, it is possible that autoantibody recognition of one or several domains of type VII collagen may invoke an inflammatory cascade which could result in proteolytic degradation of matrix components within the DEJ that are essential for epidermal-dermal adherence. Therefore, within the spectrum of EBA and autoimmunity to type VII collagen, there are several possible mechanisms for autoantibody-induced blister formation. First, because EBA often occurs with minimal clinical or histologic inflammation, it has been hypothesized that defective epidermal-dermal adherence in EBA involves autoantibodies that target and compromise functional epitopes on the NC1 domain. This then interferes with the normal interactions between NC1 and its extracellular matrix ligands such as laminin 5 and fibronectin (Chen et al. 1997a, 1999). Also, there may be an interruption in the type VII collagen-fibronectin interaction in the collagenous domain which may be important for the adherence of basement membrane and the overlying epidermis onto the papillary dermis (Lapiere et al. 1994). Alternatively, the autoantibodies might interfere directly with antiparallel dimer formation and anchoring fibril assembly (Chen et al. 2000). These mechanisms are attractive possibilities for explaining skin fragility and trauma-induced blisters in patients with classical EBA who lack significant inflammation but have markedly defective epidermal-dermal adherence.

Another possible mechanism in some EBA patients is that the EBA autoan-tibodies generate blisters by inducing localized inflammation with or without the amplification of complement fixation. The induced inflammatory response then causes tissue damage at DEJ, which results in blister formation (Gammon et al. 1984). This mechanism may explain those EBA and bullous SLE patients with acute inflammation at the BMZ, particularly when neutrophils are predominant in the inflammatory response because that type of inflammation is characteristic of experimental forms of immune complex and complement-mediated inflammation.

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