Autoimmune bullous skin disorders represent a group of severe, chronic skin diseases which are characterized by the presence of autoantibodies targeting distinct adhesion molecules of the epidermis and dermoepider-mal basement membrane zone leading to a loss of adhesive function of the target antigen(s) (Fig. 8.1). The appearance ofblisters and erosions of the skin and/ or mucous membranes is the leading clinical sign of autoimmune bullous skin disorders (Fig. 8.2). While histopathology reveals the location of the blister formation, the detection of tissue bound autoantibodies by immunofluorescent staining of uninvolved perile-sional skin biopsies is mandatory for diagnosing autoimmune bullous skin disorders. Circulating autoanti-bodies can be visualized by indirect immunofluores-cence using tissue substrates such as monkey esophagus and sodium chloride-split human skin. Based on the specificity of the targeted antigens, several clinically and immune serologically distinct bullous disorders have been defined (Fig. 8.2).
Desmogleins (Dsg) are transmembranous components of desmosomes, adhesion units specialized in conferring epidermal keratinocyte adhesion, and are linked to intercellular molecules of the desmosomal plaque which in turn interact with components ofthe cytoskel-eton (Fig. 8.1a). Among several forms of pemphigus, pemphigus vulgaris (PV) and pemphigus foliaceus (PF) represent the major subtypes. IgG autoantibodies against Dsg3 in PV and Dsgl in PF lead to loss of des-mosomal adhesion of epidermal keratinocytes and intraepidermal blister formation (Fig. 8.2A-C). In PV patients suffer from flaccid blister/erosions of the mucous membranes, primarily the oral mucosa and the skin. PF is characterized by crusted painful erosions typically of the seborrheic areas such as scalp, face,
Fig. 8.1. Schematic overview of desmosomal and hemi-desmosomal autoantigens in autoimmune bullous skin disorders. Shown are the major components of desmo-somes which have been identified as autoantigens in the different clinical variants of pemphigus (a)
Basal / Keratinocyte/
Fig. 8.1. (cont.) The integrity of epidermal cohesion is largely dependent on desmo-somes, plaque-like intercellular adhesion structures that connect transmembra-nous adhesion molecules such as the des-mogleins and desmocollins with keratins of the cytoskeleton through interaction with intracellular components of the des-mosomal plaque, such as desmoplakin, plakoglobin, plakophilin, envoplakin and periplakin. In addition to desmoglein 3 and 1, which are autoantigens in pemphigus, all the other aforementioned components of desmosomes have been identified as autoantigens of different clinical variants of pemphigus (b). Components ofhemidesmosomes and the basement membrane are autoantigens of the pemphigoids and epidermolysis bullosa acquisita. Basal keratinocytes adhere to the basement membrane zone by the interaction of cytoplasmic andtransmembranous components of hemidesmosomes, such as BP180, BP230 and |34 integrin, respectively, with ligands such as laminin 5 located in the dermoepidermal basement membrane zone. The intracellular hemidesmosomal components BP230 and plectin are linked to keratins of the cytoskeleton and interact with the cytoplasmic domains of BP180 and a6|34 integrin which in turn interact with laminin 5 via their ectodo-mains. Type VII collagen is the major component of anchoring fibrils which link the basement membrane to the dermis by direct interaction with laminin 5 in the lamina densa of the basement membrane (modified from Hertl et al. 2006)
Lamina lucida Lamina densa
Lamina lucida Lamina densa
Keratin 5 & 14
Keratin 5 & 14
Plectin afiß 4- Integrin
"Anchoring Fibrils (Collagen VII)
Fig. 8.2. Diagnostic and clinical characteristics of autoimmune bullous skin disorders. Pemphigus is characterized by the presence of IgG (and occasionally IgA) specific for desmosomal target antigens (as shown here by direct immunofluorescence, (A) resulting in a loss ofintraepi-dermal adhesion (as shown by histopathology, (B) and blisters/erosions of the mucous membranes and skin (C). In the pemphigoids, including linear IgA bullous dermatosis, IgG (or IgA) autoantibodies bind to antigens ofhemidesmosomes and the dermoepidermal junction (D), resulting in a loss of subepidermal adhesion (E) and tense blisters (F). Epidermolysis bullosa acquisita is associated with IgG (and sometimes IgA) binding to the anchoring fibrils underneath the der-moepidermal junction (G), resulting in a subepidermal loss of adhesion (H) and tense blisters with a tendency to scarring and milia formation (I). Dermatitis herpetiformis is associated with IgA deposits in the papillary dermis (the dotted line indicates the dermoepidermal junction) reactive with epidermal transglutaminase (K), a subepidermal loss of adhesion (L), and herpetiform blisters or pruritic papules (M)
chest and upper back whereas mucosal lesions are absent in PF. In general, the treatment of pemphigus is based on immunosuppressive treatment regiments consisting of high dose glucocorticoids and immunosuppressive "steroid-sparing" adjuvants, including aza-thioprine or mycophenolate mofetil.
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