Acquired skin disease of hemidesmosomes
Introduction
The hemidesmosome is a membrane-associated supramolecular dermal–epidermal anchoring complex, that links the cytoskeleton of the basal keratinocyte to the anchoring structures of the papillary dermis (Fig. 1). A perturbation in any of the major components of this complex may result in disruption of the tissue architecture and a split formation at the level of the dermal–epidermal junction. The central component of the complex is an electron-dense, intracellular, disc-shaped structure called hemidesmosomal plaque. Keratin proteins utilize the hemidesmosomal plaque as their major point of association with the dermal pole of basal keratinocytes. The keratin filament network forms other attachments at the nuclear envelope and at the desmosomal plaque, providing a molecular framework that confers mechanical strength to the keratinocytes [1]. Proteins within the hemidesmosomal plaque link the cytoskeletal elements to transmembrane adhesion molecules (reviewed in Refs. [2], [3]).
Fine, filamentous structures, termed anchoring filaments, project from the basal cell plasma membrane beneath the hemidesmosomal plaque, traverse the lamina lucida and terminate within the lamina densa. The anchoring filaments function in cell-matrix interactions and involve laminin 5, the α6β4 integrin, BP180 and other molecules (reviewed in Ref. [4]). Directly or through other proteins, the anchoring filaments associate with thicker filamentous structures, the anchoring fibrils, which originate in the lamina densa of the basement membrane zone (BMZ), extend into the subjacent connective tissue and terminate at structures known as anchoring plaques [5]. The major component of anchoring fibrils is type VII collagen [6], [7].
Mutations for the different components of the dermal–epidermal anchoring complex as well as the formation of autoantibodies against these structures, result in a split formation at the level of the dermal–epidermal junction. This paper will review the different diseases that are characterized by autoantibodies to components of the dermal–epidermal anchoring complex. By immunofluorescence (IF) microscopy, the autoantibodies are found as linear deposits along the BMZ. A summary of these diseases is shown in Table 1.
Section snippets
Bullous pemphigoid
Based on recent studies from France and Germany, the most frequent acquired skin disease of the dermal–epidermal anchoring complex is bullous pemphigoid, followed by cicatricial pemphigoid, pemphigoid gestationis and linear IgA disease [8], [9]. Bullous pemphigoid (BP) is a disease of the elderly characterized by tense blisters and is usually associated with severe itching (reviewed in Ref. [10]). We recently demonstrated that the incidence of BP is rapidly increasing beyond the age of 60
Pemphigoid gestationis
Pemphigoid gestationis (PG), also referred to as herpes gestationis, is an acquired skin disease of hemidesmosomes that is associated with pregnancy. Numbers on incidence of PG range from one case in 1700 to one case in 50 000 pregnancies [70], [71]. Rarely, PG is associated with a hydatiform mole or chorion carcinoma [72]. The disease may present any time during pregnancy but is more common in the second and third trimesters. The clinical spectrum of PG is polymorphic and may include papules,
Lichen planus pemphigoides
The term ‘lichen ruber pemphigoides’ or lichen planus pemphigoides (LPP) was first used by Kaposi in 1892 for a disease characterized by lichen planus (LP) lesions and numerous bullae [81]. In addition to clinical and histological criteria, immunofluorescence microscopic findings are important in distinguishing between bullous LP and LPP. In bullous LP, blisters are confined to LP lesions and are a consequence of severe basal cell degeneration, as found on histopathology. In contrast, bullous
Cicatricial pemphigoid
Cicatricial pemphigoid (CP) is a chronic autoimmune blistering disease of mucous membranes and skin. It may involve oral, ocular, nasal, pharyngeal, laryngeal, esophageal and anogenital mucous membranes. Skin lesions appear in ≈30% of CP patients [94], [95]. Mucous membrane and skin lesions usually heal with scarring. CP is a heterogeneous disease with respect to the isotype of the autoantibodies in these patients (i.e. IgG, IgA, or both), the side of 1 M NaCl-split skin bound by their
Linear IgA disease
Linear IgA disease (LAD) is the fifth disease that is associated with autoantibodies to BP180. The immunopathological hallmark of LAD are linear deposits of IgA at the BMZ [132]. Clinically, considerable variations are seen with respect to the age of disease onset, morphology of bullous lesions and mucosal involvement which may heal with or without scarring [133], [134], [135]. LAD of childhood, also referred to as chronic bullous disease of childhood, is distinguished from LAD of adulthood.
Subepidermal blistering disease associated with autoantibodies to a plectin-like protein
Fujiwara et al. reported a patient that resembled bullous pemphigoid clinically, histopathologically and by IF analysis. Immunoblot analysis, however, showed that the patient’s serum did not react with 180 or 230 kDa BP antigens, but recognized exclusively a 400-kDa epidermal protein expressed in human keratinocytes. Cloning and characterization of the cDNA encoding a portion of this antigen demonstrated that it belonged to the plectin family. It remained unclear whether autoantibodies to this
Subepidermal blistering disease with autoantibodies to a 105-kDa protein of the lower lamina lucida
In 1993, Chan et al. reported a patient with autoantibodies to a 105-kDa antigen of the BMZ [156]. The association of this protein with the dermal–epidermal anchoring complex has not been formally demonstrated yet. Clinically, this patient resembled toxic epidermal necrolysis. By indirect IF on salt-split skin, autoantibodies to this protein bound to the dermal side of the split. By immunoelectron microscopy, the autoantibodies localized to the lower lamina lucida [156]. Subsequently, a second
Subepidermal bullous disease associated with autoantibodies to a 200-kDa protein of the lower lamina lucida
Recently, another novel pemphigoid-like disease was reported that was associated with autoantibodies to a 200-kDa protein of the lower lamina lucida. Meanwhile, a total of eight such patients have been described [161], [162], [163], [164], [165], [166], [167]. Clinically, most patients had BP-like features [161], [162], [166], [167]. In one patient, the clinical picture resembled LAD [165] and in another dermatitis herpetiformis Duhring [164]. In two patients, the disease was associated with
Epidermolysis bullosa acquisita
Epidermolysis bullosa acquisita (EBA) is a blistering disease of the skin characterized by autoimmunity to type VII collagen. There are three different clinical forms of EBA. Most commonly, it presents as a non-inflammatory disease, primarily affecting trauma-prone extensor surfaces including elbows, knees, ankles and dorsal aspects of hands. This is the chronic form of EBA, described by Roenigk et al. in 1971 [168]. Blisters and erosions heal with scarring and milia formation. Nail dystrophy
Acknowledgements
The author thanks Dr Luca Borradori, Geneva, Switzerland, Dr George J. Giudice, Milwaukee, USA, for helpful discussions. In addition, I thank Dr Kim B. Yancey, Bethesda, USA, for providing Fig. 6. The author is grateful to Iakov Chimanovitch, Würzburg, for help preparing this manuscript. This work has been supported by grant 98.073.1 from the Wilhelm Sander-Stiftung, Munich, Germany.
References (188)
- et al.
The molecular biology of intermediate filament proteins
Int Rev Cytol
(1992) - et al.
Hemidesmosomes: roles in adhesion, signaling and human diseases
Curr Opin Cell Biol
(1996) - et al.
The dermal–epidermal junction
Curr Opin Cell Biol
(1997) Adhesion molecules. II: Interactions of keratinocytes with epidermal basement membrane
J Invest Dermatol
(1995)- et al.
Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia
Cell
(1981) - et al.
Identification and partial characterization of pemphigoid antigen extracted from normal human skin
J Invest Dermatol
(1984) - et al.
A 230-kDa basic protein is the major bullous pemphigoid antigen
J Invest Dermatol
(1989) - et al.
Cloning and primary structural analysis of the bullous pemphigoid autoantigen BP180
J Invest Dermatol
(1992) - et al.
Bullous pemphigoid antigen (BGAG1): cDNA cloning and mapping of the gene to the short arm of human chromosome 6
Genomics
(1990) - et al.
Genomic organization of collagenous domains and chromosomal assignment of human 180-kDa bullous pemphigoid antigen-2, a novel collagen of stratified squamous epithelium
J Biol Chem
(1991)