3.4 Epidermolysis Bullosa Acquisita

3.4 Epidermolysis Bullosa Acquisita Mei Chen, Dafna Hallel-Halevy, Celina Nadelman, and David T. Woodley Introduction Epidermolysis bullosa acquisita (EBA) was first described before the turn of the century and was designated as an acquired form of epidermolysis bullosa (EB) because the clinical features were so reminiscent of children who were born with genetic forms of dystrophic EB (Elliott 1985). EBA is an acquired, subepidermal bullous disease and is classified as one of the “primary” bullous diseases of the skin. In its classical form, it is a mechanobullous disease with skin fragility and trauma-induced blisters that have minimal inflammation and heal with scarring and milia – features that are highly reminiscent of hereditary dystrophic forms of epidermolysis bullosa (DEB). In DEB, there is a hereditary defect in the gene that encodes for type VII (anchoring fibril) collagen leading to a paucity of anchoring fibrils. Anchoring fibrils are structures that anchor the epidermis and its underlying basement membrane zone (BMZ) onto the dermis (Briggaman and Wheeler 1975; Uitto and Christiano 1994). In EBA, there is also a paucity of anchoring fibrils, but this is because EBA patients have IgG autoantibodies targeted against the type VII collagen within anchoring fibrils. EBA represents an acquired autoimmune mechanism by which anchoring fibrils can be compromised rather than by a gene defect. Since EBA has become defined as autoimmunity to type VII collagen, it has become evident that EBA may also present with clinical manifestations reminiscent of bullous pemphigoid (BP), cicatricial pemphigoid (CP), and Brunsting- Perry pemphigoid. In the early 1970s, Roenigk et al. (1971) reviewed the EBA world litera- ture, reported three new cases and established the first diagnostic criteria for EBA: (1) spontaneous or trauma-induced blisters resembling hereditary DEB, (2) adult onset, (3) a negative family history for EB, and (4) the exclusion of all other bullous diseases. In the 1980’s Yaoita et al. (1981) and Nieboer et al. (1980) found that EBA, like BP, exhibited IgG deposits at the dermal-epidermal junction (DEJ). In EBA, however, the IgG deposits are found within and 110 Mei Chen et al below the lamina densa compartment of the BMZ, whereas in BP they are lo- cated higher, within hemidesmosomes and the lamina lucida. The sublamina densa location of the IgG deposits in EBA was understandable when it was recognized that the skin protein targeted by the IgG autoantibodies was type VII collagen within anchoring fibrils which emanate perpendicularly from the lamina densa into the high papillary dermis (Woodley et al. 1984, 1988). The primary unit of type VII collagen is a 290 kDa alpha chain which is the “EBA auto-antigen”. 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 sug- gested 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 character- ized 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 Epidermolysis Bullosa Acquisita 111 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 a homotrimer [ (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 homo- logy 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 112 Mei Chen et al 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 non-inflammatory 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 cas- cade which could result in proteolytic degradation of matrix components within the DEJ that are essential for epidermal-dermal adherence. There- fore, 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 interrup- tion 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). Alter- natively, 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 autoantibodies 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 (Gam- mon 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. Epidermolysis Bullosa Acquisita 113 Clinical Manifestations There is great diversity in the clinical presentation of EBA. The common de- nominator for patients with EBA is autoimmunity to type VII (anchoring fibrils) collagen and diminished anchoring fibrils (Woodley 1988; Woodley et al.

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