The many faces of epidermolysis bullosa acquisita after serration pattern analysis by direct immunofluorescence microscopy.

BACKGROUND: The inflammatory variant of epidermolysis bullosa may mimic a form of pemphigoid. OBJECTIVES: To estimate the frequency of epidermolysis bullosa acquisita (EBA) and bullous systemic lupus erythematosus (bSLE) among patients with subepidermal autoimmune bullous disease (sAIBD), and to correlate the isotype of in vivo antibody depositions to the clinical phenotype. METHODS: Patients with EBA or bSLE were systematically identified using serration pattern analysis by direct immunofluorescence microscopy in a prospective cohort of 364 patients with sAIBD. Correlation of the clinical phenotype to the isotype of the in vivo antibody depositions was investigated for 38 prospective and retrospective cases. RESULTS: The frequency of EBA or bSLE was 5·5% (n = 20), defined by the u-serration pattern, and reached only 1·9% (n = 7) when serological reactivity was the only criterion. The clinical phenotype of EBA was mechanobullous in 14 (37%) and inflammatory in 24 (63%) patients. Pure IgG-mediated cases (67%) were associated with the mechanobullous phenotype, whereas pure IgA-mediated cases (91%) were found more often in the inflammatory phenotype. Mucous membrane involvement was present in 22 (58%) patients, and neither correlated with IgG or IgA depositions, nor with a mechanobullous (64%) or inflammatory (54%) phenotype. CONCLUSIONS: The frequency of EBA is about one in 18 among patients with sAIBD. The clinical phenotype in two of three cases is inflammatory, thus mimicking other sAIBDs, e.g. bullous pemphigoid, mucous membrane pemphigoid, or linear IgA disease. The yield of diagnosed EBA cases almost triples when serration pattern analysis is used by direct immunofluorescence microscopy on skin biopsy.

Antiplectin autoantibodies in subepidermal blistering diseases.

BACKGROUND: Hemidesmosomal proteins may become targets of autoimmunity in subepidermal blistering diseases. Well-known recognized autoantigens are the intracellular plaque protein BP230, the transmembrane BP180 and its shed ectodomain LAD-1. OBJECTIVES: To establish the prevalence of autoimmunity against plectin, another intracellular plaque protein, and to investigate its antigenic sites. METHODS: Two hundred and eighty-two patients with subepidermal blistering diseases, investigated by routine immunoblot analysis for possible antiplectin antibodies, were included in the study. Epitope mapping was performed using recombinantly produced overlapping plectin domains from the actin-binding domain to the rod domain. The COOH-terminal region of plectin was not included in the study. RESULTS: In 11 of 282 (3.9%) patients an immunoblot staining pattern identical to that of antiplectin monoclonal antibody HD121 was found. Affinity-purified antibodies bound back to normal human skin in a pattern typical for plectin, i.e. to the epidermal basement membrane zone as well as to keratinocytes in the epidermis, and to myocytes. No binding was seen to plectin-deficient skin of a patient with epidermolysis bullosa simplex with muscular dystrophy. Epitope mapping of the plectin molecule showed that the central coiled-coil rod domain is an immunodominant hotspot as 92% of the sera with antiplectin antibodies reacted with it. Most patients with antiplectin antibodies also had antibodies to other pemphigoid antigens. CONCLUSIONS: Plectin is a minor pemphigoid antigen with an immunodominant epitope located on the central rod domain.

Inflammatory epidermolysis bullosa acquisita with coexistent IgA antibodies to plectin.

We present a case of inflammatory epidermolysis bullosa acquisita (EBA) with IgA antibodies to plectin. Analysis of lesional skin biopsies by electron microscopy revealed the split level to be in the sublamina densa zone, corresponding to the diagnosis of EBA. Direct immunofluorescence of perilesional skin demonstrated u-serrated depositions of IgG and IgA that under immunoelectron microscopy were shown to be located in the sublamina densa. In contrast, indirect immunofluorescence on salt-split skin revealed circulating IgA antibodies that stained the roof rather than the floor of the blister. Immunoblotting showed these serum antibodies to be directed to the cytoplasmic hemidesmosomal antigen plectin. The antiplectin specificity of these antibodies was confirmed by 'knockout' immunofluorescence analysis; the serum IgA did not bind to skin sections of a patient with plectin-deficient epidermolysis bullosa. To our knowledge, this case demonstrates for the first time the existence of IgA antibodies against plectin.