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End of the Century Overview of Skin Blisters
Luis A. Diaz, MD;
George J. Giudice, PhD
Arch Dermatol. 2000;136:106-112.
ABSTRACT
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A wide spectrum of diseases of the skin are manifested as a blistering process. Blistering may occur as a secondary event associated with viral or bacterial infections of the skin, eg, herpes simplex and impetigo, or with local injury of the skin, eg, burns, ischemia, and dermatitis. In other diseases, blistering of the skin occurs as a primary event and is associated with tissue injury and fluid accumulation within a specific layer of the skin: intraepidermal, dermal-epidermal junction, or subepidermal. Blister formation in this latter group of diseases is due to either genetic mutation or an autoimmune response. Genodermatoses associated with blisters are typically manifested in the neonate, whereas the autoimmune blistering disorders are acquired and usually expressed later in life. Recent advances have uncovered the relevance of the keratinocyte cytoskeleton, the desmosome, the hemidesmosome, and extracellular matrix proteins in blister formation. A pathogenetic classification of blistering diseases is presented.
INTRODUCTION
Patients with a variety of skin diseases manifest blisters as a component of their ailment. Blisters are formed as a result of a breakdown of tissue integrity and fluid accumulation in a specific compartment of the skin (ie, subcorneal, suprabasilar, dermal-epidermal junction [DEJ], or upper dermis). In some patients blister formation is caused by localized bacterial (eg, impetigo) or viral (eg, herpes simplex or herpes zoster) infection. Blisters can also develop after a chemical or physical burn or after necrosis of the skin due to thrombosis of cutaneous blood vessels (eg, disseminated intravascular coagulation). Occasionally, blisters might arise as a presentation of an underlying dermatologic disease, such as necrobiosis lipoidica diabeticorum, lichen planus, systemic lupus erythematosus, and mastocytosis. Therefore, the presence of blisters in many patients is secondary to another cutaneous disease.
Another group of blistering diseases that affects children and adults has the formation of blisters as the primary skin disorder. This cluster of diseases has been described for decades in a special chapter of most dermatology textbooks: "The Bullous Dermatoses" (Table 1). This group has been the focus of interest and work of dermatologists, dermatopathologists, immunonologists, and geneticists for several decades. As a consequence of the work of these investigators, remarkable advances have been made in elucidating the pathogenesis of these diseases and in developing new diagnostic tools and therapeutic approaches. To mark the end of the 20th century, we review the latest concepts in the pathogenesis of these diseases.
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Table 1. Bullous Dermatoses
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STRUCTURAL ASPECTS OF THE SKIN RELEVANT TO BLISTER FORMATION
There are 3 compartments in the skin where blisters might arise: the epidermis (limited by the stratum corneum on the outside and the basal cell layer on the inside), the DEJ or lamina lucida (limited by the cell surface of basal keratinocytes and the lamina densa), and the dermis (the tissue located below the lamina densa). Blisters can be classified, therefore, according to the location of the vesicle into intraepidermal, junctional, and subepidermal (below the lamina densa).
The epidermal compartment of the skin contains cells of different lineages that basically function as a multilayer defense barrier to prevent the escape of fluids, electrolytes, and proteins from within and the entrance of foreign environmental substances. Several layers of differentiating keratinocytes occupy more than 95% of the epidermal compartment. The basal cell layer is anchored to the dermis and remains undifferentiated, whereas suprabasal keratinocytes adhere to each other and terminally differentiate, forming the stratum corneum. A network of melanocytes closely interact with the keratinocyte cell system, providing the melanin pigment, which is important in filtering out harmful environmental UV radiation. Other cells, such as Langerhan cells, compose a network of antigen-presenting cells involved in immunologic mechanisms. As described in the next section, the keratinocyte cell system plays a central role in the pathogenesis of blister formation in lesions in the epidermal and DEJ compartments (Figure 1).
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Figure 1. Diagrammatic representation of the cutaneous framework. The images of the desmosome and hemidesmosome were inserted from original electron micrographs. Basal keratinocytes express keratins 5 and 14 (green cables) and suprabasilar keratinocytes express keratins 1 and 10 (yellow cables). The desmosomes are shown as red dots around the keratinocyte periphery and the hemidesmosomes as small gray rectangles at the dermal pole of basal cells.
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Basal keratinocytes interact with the extracellular matrix of the dermis, resulting in forces that maintain adherence of the epidermis to the dermis. The dermal pole of basal cells contains hemidesmosomes and focal contacts, which are organelles that function as attachment sites.1-2 Basal cell surfaces not in contact with the basement membrane possess desmosomes, which are organelles that attach neighboring keratinocytes.3-4 The keratinocyte cytoskeleton composed of intermediate filaments (keratins), microfilaments (actin and associated proteins), and microtubules (tubulin) represents another structural component of these cells that is important in blister formation. The molecular components of the cytoskeleton and its associated proteins link the nucleus with the cell periphery (ie, desmosomes, adherent junctions, hemidesmosomes, and focal contacts), providing the framework structure of the epidermis.5-6
At the ultrastructural level, the desmosome appears as an organelle that is shared by 2 neighboring keratinocytes, each providing half of the structure (Figure 2).3 Two parallel proteinaceous plaques are located just beneath the membrane of each cell and represent the site of insertion of intermediate filaments. The cell membrane of each keratinocyte is separated by a narrow space, the desmosomal core, which is contiguous with the epidermal intercellular spaces. The hemidesmosome also contains an intracellular attachment plaque in which intermediate filaments of the basal cells are inserted (Figure 3).7 The hemidesmosome equivalent of the desmosomal core is the lamina lucida, which separates the basal cell plasma membrane from the underlying lamina densa and is contiguous with the epidermal intercellular spaces. A group of fibers crosses the lamina lucida at the level of the hemidesmosome (anchoring filaments), and another group (anchoring fibers) seems to link the basal lamina to the underlying fibrous matrix of the dermis.1-2,7
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Figure 2. The image of the desmosome shown in Figure 1 depicting the molecular components of this organelle. Autoantibodies against desmogleins 1 and 3 are found in patients with pemphigus foliaceus and pemphigus vulgaris, respectively. Tf indicates tonofilaments (keratins).
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Figure 3. The image of the hemidesmosome (HD) shown in Figure 1 depicting the molecular components of this organelle. Tf indicates tonofilaments (keratins). The anchoring filaments, located in the lamina lucida, are not labeled.
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Remarkable advances have occurred in the past 2 decades in the areas of biochemical and molecular characterization of the elements composing the structural components of the epidermis, DEJ, and dermis. In the epidermis, the molecular components of the cytoskeleton and desmosomes are well characterized. Similarly, at the level of the DEJ, several molecules comprising the hemidesmosome, lamina lucida, lamina densa, and anchoring fibers have been well defined. It has been demonstrated6 that keratins 5 and 14 are expressed by basal keratinocytes and that keratins 1 and 10 are expressed by keratinocytes of the suprabasal layers of the epidermis.
The plaque components of the desmosome and hemidesmosome, and the transmembrane glycoproteins of these organelles, have been isolated and characterized at the molecular level (Figure 2 and Figure 3).7-14 Some of these molecules are unique to epithelial desmosomes, such as the desmogleins and desmocollins, whereas others belong to a family of proteins that link these organelles with the cytoskeleton (ie, the plakin family). The plakin family comprises desmoplakins 1 and 2, envoplakin, periplakin, plectin, and the BP230 antigen.15 The desmosomal plaque contains plakoglobin; desmoplakins 1 and 2; plakophilins 1, 2, and 3; desmocalmin; envoplakin; and periplakin.4, 7-11 The hemidesmosomal plaque contains the BP230 antigen (a protein recognized by autoantibodies from patients with bullous pemphigoid [BP])16 and plectin.17 The desmosomal core contains desmogleins 1, 2, and 3 and desmocollins 1, 2, and 3.7-9,12-14 Amino acid sequence analysis12 of these core proteins demonstrates that they belong to the cadherin multigene family of calcium-dependent cell adhesion molecules. The hemidesmosomal transmembrane glycoproteins are BP180 (a protein recognized by autoantibodies from patients with BP)18 and integrin  6 4.19-20 The relevant components of the lamina lucida are laminin isoforms21 and proteoglycans.22 The major component of the lamina densa is type IV collagen, and the anchoring fibers are composed of type VII collagen.1, 23
It was proposed in the late 1970s24 that the structural integrity of the epidermis (now referred to as the mechanical scaffold) results from a complex set of molecular interactions–intracellular interactions involving the keratinocyte cytoskeleton and the desmosomal plaque, and intercellular interactions between the transmembrane core glycoproteins of adjacent cells. Moreover, the interactions between the ectodomains of the desmosomal core glycoproteins are known to mediate cell-cell adhesion in the presence of calcium. Mechanical support is also provided to basal keratinocytes by the molecular interactions between the cytoskeleton, hemidesmosomal plaque components, transmembrane glycoproteins, and dermal constituents. The interactions of transmembrane glycoproteins, ie, integrin 64 and BP180 antigen, with extracellular matrix proteins such as laminin isoforms, fibronectin, and collagens are important in mediating the mechanisms of cell-matrix adhesion.
THE DUAL MECHANISMS OF BLISTER FORMATION
Under normal circumstances, the molecular interactions of the structural proteins of the epidermis, DEJ, and dermis sustain and strengthen the scaffolding of the skin. These molecular interactions, in turn, are governed by a genetically determined amino acid sequence of the constitutive proteins. Thus, any defect of these proteins (ie, those introduced by genetic mutation of a key domain of a molecule) weakens the mechanical framework of the skin. A "weak site" of the scaffolding, where the corresponding mutated molecule is located, becomes a potential site of blister formation. Blisters can occur by protease degradation of the structural protein or by alteration of the protein-protein interaction or adhesive function of the molecule. The phenotypic expression of an inherited blistering disease will be manifested early in life and will probably last for the life of the patient.
The structural proteins of the skin might also become the target of immunologic injury in a variety of autoimmune diseases. It is well established25 that under normal conditions the immune system recognizes and tolerates "self" and prevents any mechanism by which effector molecules or cells might be formed to attack self. In autoimmune diseases, however, immune tolerance breaks down and patients mount a humoral or cell-mediated response that is targeted at an antigenic molecule. The humoral autoimmune response is generally polyclonal and directed against several epitopes of the antigenic molecule. The epitopes recognized by autoantibodies might be small stretches of amino acids (sequential epitopes) or stretches of amino acids arranged in a secondary or tertiary form (conformational epitopes). In some autoimmune diseases, the autoantibody response is targeted to intracellular antigens. In others, the autoantibodies recognize extracellular epitopes located on the ectodomain of a transmembrane antigen (eg, BP180 antigen) or on a secreted protein (eg, type VII collagen). The pathogenicity of autoantibodies that recognize extracellular epitopes is sometimes mediated by complement activation and inflammatory cells (eg, anti-BP180 antibodies in BP). Autoantibodies might also produce cell damage by direct inhibition of the function of the antigenic molecule to which they bind (eg, antibodies against acetylcholine receptor in myasthenia gravis). The site of immunologic injury in each disease will be restricted to the area where the antigen is expressed and bound by the pathogenic autoantibodies of the patient (eg, the desmosome or hemidesmosome). The end result of an immunologic injury to these cell-cell or cell-matrix attachment structures is blister formation. It is more difficult to attribute a pathogenic role to autoantibodies that recognize intracellular epitopes. These autoantibodies might be specific markers of disease (autoantibodies against plakin proteins in paraneoplastic pemphigus). The autoimmune diseases are acquired rather than inherited and, with few exceptions, are expressed in adults. The underlying mechanisms involved in triggering human autoimmune diseases are largely unknown.
Certain structural molecules of the skin might cause blistering disease by 2 unrelated mechanisms: genetic mutation and autoantibody formation. For example, patients born with a mutation of the BP180 antigen might develop generalized atrophic benign epidermolysis bullosa during the early years of life.26 However, in patients who become sensitized to this same molecule, diseases such as BP, herpes gestationis, cicatricial pemphigoid, or linear IgA disease might develop later in life.19 The mechanisms that modulate the phenotypic expression of a particular disease remain unknown. Similarly, mutation of laminin 5 is associated with epidermolysis bullosa lethalis (Herlitz syndrome)27 and an autoantibody response to this molecule leads to a form of cicatricial pemphigoid28 and BP-like disease.29 Although it is unknown if mutation of type IV collagen is associated with blistering of the skin, autoantibody response to epitopes of the 3 (IV) chain of this molecule is associated with Goodpasture syndrome,30 and a recently reported BP-like disease is associated with autoantibodies against the 5 (IV) chain.31 Finally, mutation of type VII collagen results in epidermolysis bullosa dystrophica,32 whereas epidermolysis bullosa acquisita is a consequence of sensitization to this molecule.33 It seems that under normal circumstances a strict equilibrium is maintained between the function of these structural proteins and the immunologic tolerance to antigenic sites of the same molecules. Genetic mutation and a loss of function of the respective protein might trigger blister formation (genodermatoses). Similarly, a breakdown in immune tolerance to these antigens might trigger autoantibody formation, which, in turn, might induce blisters. In these patients, the blistering eruption would be acquired and manifested later in life. Figure 4 is a diagrammatic representation of this dual mechanism of blister formation. This hypothesis predicts that a genetic mutation of any of the structural proteins of the skin scaffolding or a possible autoimmune response to relevant epitopes of the same molecules can be expressed as a blistering disease. Future gene therapy efforts aimed at correcting a genetic defect of the genodermatoses might trigger an autoimmune response to the new gene product, which would be foreign to the patient, and could induce a new autoimmune blistering disease.
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Figure 4. The dual mechanisms of blister formation. This hypothesis predicts that a genetic mutation of any of the structural proteins of the skin scaffolding or a possible autoimmune response to relevant epitopes of the same molecules might be expressed as a blistering disease. GABEB indicates generalized atrophic benign epidermolysis bullosa; BP, bullous pemphigoid; HG, herpes gestationis; CP, cicatricial pemphigoid; JEB, junctional epidermolysis bullosa; EBD, epidermolysis bullosa dystrophica; and EBA, epidermolysis bullosa acquisita.
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PATHOGENESIS OF GENETIC AND AUTOIMMUNE BULLOUS DERMATOSES
Experimental animals have been used to study the pathogenesis of blistering disorders and to demonstrate the pathogenicity of antiepidermal autoantibodies present in the serum samples of patients (Table 2). The skin of neonatal mice became the target of pathogenic antibodies present in the serum samples of patients with pemphigus vulgaris,34 pemphigus foliaceus,35 and BP.36 These models37-38 demonstrated that pemphigus vulgaris and pemphigus foliaceus autoantibodies (and their Fab fragments) can induce disease, independent of complement activation, in the epidermis of these animals. These results suggested that simple binding of the antibody to the ectodomain of the antigens (desmogleins 1 and 3) triggers blister formation, perhaps by impairing the function of these molecules as predicted by Diaz and Marcelo39 in the late 1970s. In the BP animal model, however, we demonstrated that anti-BP180 antibody–mediated subepidermal blister formation depends on activation of complement and recruitment of neutrophils.40 Results of more recent studies41 suggest that neutrophil elastase and gelatinase B are key elements in the sequence of events leading to blister formation in this BP model. Other investigators42 demonstrated that antilaminin antibodies can induce subepidermal blisters by passive transfer studies in neonatal mice. The results of these studies suggest that anti–laminin 5 autoantibodies associated with a subset of patients with cicatricial pemphigoid29 and with a BP-like disease29 might indeed be pathogenic.
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Table 2. Passive Transfer of Pathogenic Antiskin Antibodies*
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Experimental animals have also been used to study the function of structural molecules of the epidermis, DEJ, and dermis. One approach involves ablating the gene encoding a particular structural molecule. In these cases, assessing the phenotypic expression of disease reveals the function of the respective molecule.43-50 The phenotype of the "knockout" animal will be shown in the skin as a blistering disorder that mimics the respective human disease. Table 3 shows some of these animals.
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Table 3. Experimentally Induced Genodermatoses in Mice*
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PROPOSED CLASSIFICATION OF BULLOUS DERMATOSES
The diseases included in the bullous dermatoses group can be classified as genodermatoses or autoimmune disorders. Table 4 lists the members of each subgroup and the molecular and immunologic systems involved. Figure 5 and Figure 6 show the levels of cleavage and blister formation in the genodermatoses and autoimmune groups, respectively.
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Table 4. Molecular and Immunologic Classification of Bullous Dermatoses*
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Figure 6. Diagrammatic representation of the cleavage site induced by autoantibodies in pemphigus foliaceus (desmoglein 1), pemphigus vulgaris (desmoglein 3), bullous pemphigoid (BP180 antigen), and possibly epidermolysis bullosa (EB) acquisita (type VII collagen). Autoantibodies against the plakin family of proteins are found in paraneoplastic pemphigus. More recently, autoantibodies against laminin 5 have been detected in cicatricial pemphigoid and a bullous pemphigoid–like syndrome. Autoantibodies against type IV collagen have also been reported recently in patients with a bullous pemphigoid–like disease.
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DIAGNOSTIC CRITERIA APPLIED TO BULLOUS DERMATOSES
It can be concluded from the previous discussion that precise diagnosis of a blistering disease can be accomplished by applying the following criteria.
Clinical Criterion
This is the oldest, and perhaps the least reliable, of the criteria because it relies on the clinical acumen of the individual practitioner. Clinical information obtained by history and physical examination is relevant in sorting patients into groups, one probable genetic and the other likely to be acquired or autoimmune.
Histological Criterion
This criterion is key in the evaluation of patients with a blistering disorder. Various diseases can be distinguished based on blister location: subcorneal, suprabasilar, and subepidermal areas of the skin. Immunomapping of the site of cleavage produced by a blistering disorder can be performed using specific antiskin antibodies and immunofluorescence techniques. More precise information might be gained by using electron microscopic and immunoelectron microscopic examination.
Immunologic Criterion
Testing skin and serum samples using immunofluorescence techniques is practical and extremely useful in the evaluation of patients with blistering diseases. Autoantibodies bound to the epidermal intercellular spaces are typical of pemphigus vulgaris and pemphigus foliaceus, whereas anti-DEJ autoantibodies are found in BP, herpes gestationis, cicatricial pemphigoid, linear IgA disease, and epidermolysis bullosa acquisita. More precise techniques such as enzyme-linked immunosorbent assay, immunoprecipitation, and immunoblotting using recombinant antigen(s) are currently available in certain specialized laboratories.
Pathogenetic Criterion
Finally, the pathogenetic criterion should be applied in the evaluation of patients with blistering disorders. Molecular biological techniques should be used to make a precise diagnosis of any of the genodermatoses. Passive transfer of autoantibodies should be performed in specialized laboratories.
AUTHOR INFORMATION
Accepted for publication September 27, 1999.
This study was supported in part by US Public Health Service grants R37-AR32081 (Dr Diaz), R01-AR32599 (Dr Diaz), and RO1-AR40410 (Dr Giudice) from the National Institutes of Health, Bethesda, Md, and by a merit review grant from the Department of Veterans Affairs, Washington, DC.
Reprints: Luis A. Diaz, MD, Department of Dermatology, University of North Carolina at Chapel Hill, Suite 3100, Thurston Building, Campus Box 7287, Chapel Hill, NC 27599-7287 (e-mail: ldiaz{at}med.unc.edu).
From the Department of Dermatology, Medical College of Wisconsin, Milwaukee. Dr Diaz is now with the Department of Dermatology, University of North Carolina at Chapel Hill.
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Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome
Jobard et al.
Hum Mol Genet 2003;12:925-935.
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