Robert A. Briggaman

Revised clinical and laboratory criteria for subtypes of inherited epidermolysis bullosa: A consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis Bullosa Registry

Inherited epidermolysis bullosa encompasses a number of diseases, with the common finding of blister formation after minor mechanical trauma to the skin. In some forms significant, if not eventually fatal, extracutaneous disease activity may occur. In recent years application of newer technologies has contributed substantially to an overall understanding of this collection of inherited diseases. Concurrently, many new phenotypes have been recognized, in part the result of ongoing prospective patient registries in the United States and abroad. Unfortunately, this has resulted in a massive literature that may appear to be confounded by seemingly excessive or arbitrary subdivision of epidermolysis bullosa variants. With these concerns in mind a subcommittee was established by the National Epidermolysis Bullosa Registry to summarize the current literature and to make recommendations as to the best clinical and laboratory criteria for the practical diagnosis and subclassification of patients with inherited epidermolysis bullosa.

Identification of the Skin Basement-Membrane Autoantigen in Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is an acquired chronic blistering disease of the skin, in which separation of the skin occurs in the basement-membrane zone between the epidermis and the dermis. There is evidence that blistering is initiated by an immune process. Using serum samples from nine patients as a source of antibodies, we have identified a major protein of the basement membrane of human skin that serves as the antigen (or target) for autoantibodies in this disorder. This previously unrecognized protein, which consists of two components of 290,000 and 145,000 daltons, is distinct from other known components of the basement membrane. These studies provide evidence that epidermolysis bullosa acquisita is a specific disease that is different from other primary bullous diseases, such as bullous pemphigoid and pemphigus vulgaris, and suggest that the basement-membrane component that has been identified may have a role in normal epidermal-dermal adherence.

Epiligrin, the major human keratinocyte integrin ligand, is a target in both an acquired autoimmune and an inherited subepidermal blistering skin disease

Epiligrin, the major component of human keratinocyte extracellular matrix, serves as the preferred integrin ligand for alpha 3 beta 1 in plasma membranes and focal adhesions, and colocalizes with alpha 6 beta 4 in hemidesmosomes. In human skin, epiligrin is found in the lamina lucida subregion of epidermal basement membrane, where it is thought to be associated with anchoring filaments. We have identified three patients with an acquired mucosal predominant subepidermal blistering disease who have IgG anti-basement membrane autoantibodies that bind the lamina lucida/lamina densa interface of epidermal basement membrane, stain cultured human keratinocyte extracellular matrix, and immunoprecipitate disulfide linked polypeptides of 170, 145, 125, and 95 kD in human keratinocyte culture media in a pattern identical to that of P1E1, a murine monoclonal antiepiligrin antibody. Comparative immunoprecipitation studies of patient sera, P1E1, and GB3 monoclonal antibody show that epiligrin is identical to the antigen (i.e., BM600 or GB3 antigen) previously reported to be absent from the skin of patients with lethal junctional epidermolysis bullosa, an inherited subepidermal blistering disease. Moreover, skin from a fetus with this disease shows no evidence of reactivity to patient antiepiligrin autoantibodies or P1E1. These studies show that antiepiligrin autoantibodies are a specific marker for a novel autoimmune blistering disease and that the epidermal basement membrane antigen absent in patients with lethal junctional epidermolysis bullosa is epiligrin.

Direct immunofluorescence studies of sodium chloride—separated skin in the differential diagnosis of bullous pemphigoid and epidermolysis bullosa acquisita

Bullous pemphigoid and epidermolysis bullosa acquisita may have indistinguishable clinical, histologic, and routine immunohistologic features. In those cases these two diseases can be reliably distinguished in routine diagnostic studies only in seropositive cases by tests on lamina lucida-split skin and in research studies by direct immunoelectron microscopy or, in patients with circulating autoantibodies, by immunoblotting studies. The use of these methods is limited by the expense and unavailability of the methods, the requirement for circulating autoantibodies, or both. We describe a method to distinguish between the two diseases on the basis of findings of direct immunofluorescence of a biopsy specimen after separation through the lamina lucida with 1.0 mol/L sodium chloride. The IgG appeared in the dermal side of the split specimens in epidermolysis bullosa acquisita and predominantly or exclusively in the epidermal side in pemphigoid. The method was found to be relatively simple, inexpensive, applicable to specimens preserved in transport media, and 100% reliable in our group of 22 patients.

Passive Transfer of Anti-Laminin 5 Antibodies Induces Subepidermal Blisters in Neonatal Mice

Patients with a recently identified subepithelial blistering disease have IgG anti-laminin 5 autoantibodies. To determine if such antibodies can be pathogenic in vivo, we developed and characterized rabbit anti-laminin 5 IgG, and passively transferred these antibodies to neonatal mice. Immune rabbit IgG specifically bound human and murine epidermal basement membranes, immunoblotted and immunoprecipitated all laminin 5 subunits from extracts of human and murine keratinocytes, and showed no reactivity to other keratinocyte proteins or epithelial basement membranes that do not contain laminin 5. Mice (n = 29) receiving purified anti-laminin 5 IgG developed, in a dose-related fashion, circulating anti-laminin 5 antibodies, deposits of rabbit IgG and murine C3 in epidermal basement membranes, and subepidermal blisters of skin and mucous membranes. No alterations developed in controls (n = 14) receiving identical amounts of normal rabbit IgG. Passive transfer of anti-laminin 5 (but not control) IgG to neonatal C5- (n = 3) or mast cell-deficient (n = 3) mice produced subepidermal blisters with the same clinical, histologic, and immunopathologic features as those documented in BALB/c mice. These studies establish an animal model of a human blistering disease that can be used to define disease mechanisms and treatment modalities.

Immunofluorescence on split skin for the detection and differentiation of basement membrane zone autoantibodies

The autoimmune subepidermal bullous diseases are characterized by autoantibodies to the basement membrane zone of stratified squamous epithelium. Recent studies have shown that the antibodies have characteristic ultrastructural and antigenic binding properties and that differentiating between those properties can be useful in distinguishing one disease from another. Immunofluorescence microscopy is widely used to detect basement membrane zone autoantibodies. The test has traditionally used tissue substrates with an intact basement membrane zone. Those substrates are limited because autoantibody binding cannot always be detected and because autoantibodies with different ultrastructural and antigenic binding properties cannot be distinguished from each other. Normal human skin that has been separated through the basement membrane zone (i.e., split skin) has recently been used as a substrate for detecting and characterizing basement membrane zone autoantibodies by immunofluorescence. Studies indicate that split skin is a more sensitive substrate than intact skin for detecting the antibodies and that antibodies with different ultrastructural binding sites can often be differentiated from one another on split skin. Those studies suggest split skin is the substrate of choice for the routine immunofluorescence evaluation of autoimmune subepidermal bullous diseases.

Epidermolysis bullosa acquisita presenting as an inflammatory bullous disease

A patient is described with the histologic, immunohistologic, and immunoelectron microscopic features of epidermolysis bullosa acquisita (EBA). Although she eventually developed the clinical features of that disease, she differs from previously reported patients by initially having an inflammatory dermatoses and a generalized erythematous bullous eruption clinically indistinguishable from bullous pemphigoid. The presentation suggests that the clinical spectrum of EBA may include a generalized inflammatory bullous disease and that EBA should be considered in the differential diagnosis of chronic acquired inflammatory bullous dermatoses.

Transplantation of Psoriatic Skin onto Nude Mice

Involved psoriatic epidermis maintains its histologic appearance, increased labeling index, and increased level of plasminogen activator after grafting onto athymic nude mice. Epidermis from clinically uninvolved psoriatic skin develops an increase in plasminogen activator activity after grafting for 6 weeks on nude mice and demonstrates an increased labeling index. Normal control skin maintains its low level of plasminogen activator and labeling index after grafting. These results indicate that psoriatic skin can maintain and develop markers of psoriatic skin independent of the host.

Bullous eruption of systemic lupus erythematosus

Chronic vesiculobullous eruptions are relatively uncommon in systemic lupus erythematosus (SLE). Their incidence among patients with skin lesions has been estimated at less than 5% [1–3]. Blistering eruptions in SLE can be divided into three categories. The first includes a number of primary blistering diseases that have been reported in association with SLE. These include bullous pemphigoid (BP) [4–9], dermatitis herpetiformis (DH) [10–14], pemphigus vulgaris/foliaceous [15–20], epidermolysis bullosa acquisita (EBA) [21, 22], erythema multiforme [23, 24], porphyria cutanea tarda [25], toxic epidermal necrolysis [26] and dystrophic epidermolysis bullosa [27]. Each of these diseases has its own diagnostic features and the association with SLE is generally regarded as fortuitous and not a specific manifestation of SLE. Many of the primary blistering diseases are associated with autoimmune features that may be difficult to distinguish from the cutaneous immunological features of SLE.

Epidermolysis bullosa: gastrointestinal manifestations

Abstract Eight patients with epidermolysis bullosa dystrophica (recessive) and dysphagia were studied. Cases are described to illustrate that dysphagia may be reversible when caused by bullae forma...