Sllll'RiillaryErythema multfforme (EM) represents a syndrome of chronic recurrent inflammatory skin disease. Depending on the severity and extent of skin and mucosal involvement, it is defined either as EM minor or EM major. In this study we demonstrate the presence of autoantibodies (aAbs) against desmoplakin I and II, two major proteins of the desmosomal plaque, in six of six patients with the severe variant of EM, EM major. Light microscopic studies of lesional skin and mucous membranes localized in vivo bound immunoglobulin G (IgG) in a dotted desmosomal pattern along the cytoplasmic membranes of keratinocytes. By immunoelectronmicroscopy, in vivo bound IgG was confined to the desmosomal plaques. These findings were confirmed by indirect immunolocalization studies that demonstrated the presence of IgG aAbs in the serum of patients during active disease. These aAbs did not only bind to desmosomal plaques of epithelial cells where they colocalized with defined murine monodonal antibodies directed against desmoplakin I and II, but also labeled the intercalated discs of myocardial cells. Biochemical characterization of circulating IgG aAbs revealed desmoplakin I and II as actual target autoantigens. By passive transfer of serum into newborn mice, in vivo binding of serum aAbs to keratinocytes was shown. The findings presented in this study imply a humoral immune response in certain patients with EM major and indicate a potential pathogenetic role of aAbs against desmoplakin I and II in this disease. utoantibodies (aAbs) 1 play a crudal role in the pathogenesis of autoimmune bullous diseases such as pemphigus vulgaris, pemphigus foliaceus, and buUous pemphigoid (1, 2). The target autoantigens of pemphigus vulgaris and foliaceus are members of the family of desmosomal cadherins, transmembrane glycoproteins that mediate cell-to-ceU adhesion (3-5). In bullous pemphigoid, two distinct antigens have been characterized (6, 7), of which the 230-kD protein is localized within the hemidesmosomal plaque of basal keratinocytes (8). This polypeptide shows extensive sequence homologies with desmoplakin I and II, two major constitutive proteins of the desmosomal plaque (9-12). Desmoplakin I and II have also been identified as components of the antigenic complex characteristic of a recently described bullous autoimmune disease designated paraneoplastic pemphigus (13,14).Erythema multiforme (EM) represents a syndrome of inflammatory skin eruptions with a broad spectrum of clinical 1Abbreviations used in this paper: aAb, autoantibody; EM, erythema multiforme; IF, immunofluorescence. 169 manifestations (15). Usually it runs an acute, self-limited, frequently recurrent course characterized by irislike erythemas and papules termed target lesions. This type of disease is designated EM minor. However, certain patients with EM, in addition to target lesions, develop widespread tense blisters and extensive erosions of the oro-genital mucosa and are thus dassified as EM major (15). Histopathology characteristically demonstrates single ce...

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