Erythema Multiforme Associated Human Autoantibodies Against Desmoplakin I and II: Biochemical Characterization and Passive Transfer Studies Into Newborn.

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Erythema Multiforme Associated Human Autoantibodies Against Desmoplakin I and II: Biochemical Characterization and Passive Transfer Studies Into Newborn Mice Dagmar Foedinger, Barbara Sterniczky, Maria Lackner, Klaus Wolff, Klemens Rappersberger Journal of Investigative Dermatology Volume 111, Issue 3, Pages 503-510 (September 1998) DOI: 10.1046/j.1523-1747.1998.00328.x Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Epitope mapping on SPOTs membranes representing the 68 amino acids at the extreme end of the COOH terminus of dp reveals YSYSYS as target sequence for EM autoantibodies. Immunoblotting with IgG fractions of patient 1 (a) and patient 2 (b) shows strong reactivity with spots 51–55. The same cluster of spots was labeled when rabbit anti-peptide IgG was applied (c). For control, IgG fractions of a patient with pemphigus vulgaris was immunoblotted, showing no reactivity on these spots (d). The consensus sequence as recognized by reactive antibodies is given in (e). Journal of Investigative Dermatology 1998 111, 503-510DOI: (10.1046/j.1523-1747.1998.00328.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Immunoprecipitation. Protein extracts of radiolabeled cultured human keratinocytes were immunoprecipitated with sera of patients 1 (lane b) and 2 (lane c), affinity-purified peptide-specific human IgG of patients 1 (lane d) and 2 (lane e), and rabbit anti-peptide IgG (lane f). Precipitated proteins represent dp I and II as shown by control precipitation with monoclonal antibody dp 2.15 (lane g). Lane h shows immunoprecipitation with serum of patient 1 after depletion of peptide-specific autoantibodies recognizing only traces of dp I and II. Lanes i and j show absence of reactivity with normal human IgG and rabbit preimmune IgG, respectively. Lane a gives a high molecular weight standard indicating 200kDa. Journal of Investigative Dermatology 1998 111, 503-510DOI: (10.1046/j.1523-1747.1998.00328.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Indirect immunolabeling of normal human skin. A distinct dotted desmosomal staining pattern is seen after probing sera of patient 1 (a), affinity-purified peptide-specific IgG of patient 1 (b), and rabbit anti-peptide IgG (c). When cryostat sections of normal human skin were incubated with peptide-specific IgG of patient 1 in the presence of excess free synthetic peptide, no desmosomal staining pattern could be observed (d). On ultrathin cryosections peptide-specific autoantibodies (e) as well as rabbit anti-peptide IgG (f) indicated by 10nm colloidal gold particles are associated with the inner dense plaques of desmosomes were keratin filaments insert. Scale bars: (a–d) 20μm; (e, f) 0.2μm. Journal of Investigative Dermatology 1998 111, 503-510DOI: (10.1046/j.1523-1747.1998.00328.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 Direct immunolabeling of lesional mouse skin after antibody injection. Direct IF shows the characteristic desmosomal staining pattern of the entire murine epidermis 24h after subcutaneous injection into mouse skin of serum from EM major patients 1 (a) and 2 (d), affinity-purified peptide-specific antibody of patients 1 (b) and 2 (e), and anti-peptide rabbit IgG (c). Injection of IgG from patient 1 after depletion of peptide-specific autoantibodies gave no desmosomal staining pattern (f). Direct IEM on ultrathin cryosections of lesional mouse skin confines the human (g, h) as well as the rabbit IgG (i) to the inner portion of the desmosomal plaque. Scale bars: (a–f) 40μm; (g–i) 0.1μm. Journal of Investigative Dermatology 1998 111, 503-510DOI: (10.1046/j.1523-1747.1998.00328.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Histopathology of lesional mouse skin after antibody injection. Following two consecutive injections with serum of patient 2 (a) we could observe dyskeratosis and focal necrosis of the epidermis. Part (b) shows dyskeratosis, focal necrosis, and blister formation after two injections with serum of patient 1. The blister floor is formed by flattened keratinocytes indicating regeneration (b). Dyskeratotic cells are shown after the injection of affinity-purified peptide-specific autoantibodies of patient 1 (c) and anti-peptide rabbit antibody (e). These cells display a condensed eosinophilic cytoplasm and pyknotic nuclei and had lost their intercellular contacts with neighboring cells (c, e, arrows). In (d), focal epidermal necrosis is shown after injection of serum of patient 2. Early signs of suprabasal cleft formation are seen in (e;open arrows). Part (f) shows unaltered skin of a newborn BALB/C mouse injected with IgG fractions from serum of patient 1 after depletion of peptide-specific autoantibodies. Scale bars: 20μm. Journal of Investigative Dermatology 1998 111, 503-510DOI: (10.1046/j.1523-1747.1998.00328.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 Ultrastructure of individual keratinocytes within lesional mouse epidermis. By electron microscopy affected cells show shrinkage of nuclei and a condensation of keratin filaments that were mostly disassembled from desmosomes (arrows) but found as dense, filamentous aggregates around the nucleus (arrowheads). Scale bar: 1μm. Journal of Investigative Dermatology 1998 111, 503-510DOI: (10.1046/j.1523-1747.1998.00328.x) Copyright © 1998 The Society for Investigative Dermatology, Inc Terms and Conditions