ERYTHEMA MULTIFORME ASSOCIATED HUMAN AUTOANTIBODIES AGAINST DESMOPLAKIN-I AND DESMOPLAKIN-II - BIOCHEMICAL-CHARACTERIZATION AND PASSIVE TRANSFER STUDIES INTO NEWBORN MICE

The demonstration of circulating autoantibodies directed against the c onstitutive desmosomal plaque proteins desmoplakin (dp) I and II in mu cocutaneous lesions in a subset of patients with erythema multiforme m ajor, suggests that humoral immune mechanisms may play a role in the p athogenesis of this severe skin disease. In this study we identified a specific peptide sequence YSYSYS - representing an antigenic binding site for the human autoantibodies. This epitope is localized at the ex treme carboxy terminal domain of dp thought to be responsible for the assembly of keratin filaments with desmosomes. To test the possibility whether these antibodies may exert any pathologic effects in vivo, hu man autoantibodies were affinity purified on a corresponding synthetic peptide matrix and peptide-specific antibodies were raised in rabbits . After repeated subcutaneous injections into newborn mice, affinity-p urified human autoantibodies and anti-peptide rabbit IgG were detected on desmosomal plaques of keratinocytes overlying the injection site. Histologic and electron microscopic examinations showed hydropic degen eration of basal and suprabasal keratinocytes, dyskeratosis, signs of suprabasal acantholysis, and keratin filaments detached from the desmo somal plaques clumping around the nucleus. We demonstrate that autoant ibodies are directed to an epitope within a dp domain crucial for the interaction of keratin filaments with desmosomes, and, when injected s ubcutaneously into newborn mice, produce pathologic changes. These fin dings imply that autoantibodies to dp could impair the function of des mosome - keratin filament complexes suggesting a pathogenic role in vi vo.