Autoantibodies to desmoplakin I and II in patients with erythema multiforme.

Abstract

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...

Paraneoplastic Pemphigus

“…A small number of patients with recurrent erythema multiforme major have antibodies against desmoplakins and will therefore have a positive indirect IF on bladder epithelium. These cases are distinguished from PNP in several ways: (1) they do not have an underlying malignancy; (2) they do not have antibodies against the plakin proteins that are more speci¢c for PNP, that is, envoplakin and periplakin; and (3) the antibodies are transient and are only detecable during episodes of active disease (Foedinger et al, 1995). The autoantibodies in PNP are constantly present.…”

Lack of a Specific Humoral Autoreactivity in Sera from Patients with Early Erythema Exsudativum Multiforme Majus

“…One reason for the different outcome of our study compared with the initial work (Foedinger et al, 1995(Foedinger et al, , 1996 might be the tight window between diagnosis of the disease and serum sampling in our cohort. This may have reduced the detection of epiphenoma following the preceding tissue destruction due to an extended inflammatory response (Cozzani et al, 2011).…”

“…Infiltrating TO THE EDITOR Erythema exsudativum multiforme majus (EEMM) is a rare condition affecting both skin and mucous membranes. It is assumed that humoral immune reponses may contribute to the pathogenesis of the disease, and the presence of autoantibodies was described in 7 of 10 EEMM patients (Foedinger et al, 1995(Foedinger et al, , 1996. These autoantibodies were associated with desmosomal staining by direct immunofluorescence microscopy of skin and by indirect immunofluorescence tests using monkey esophagus as a substrate, and they produced 210/ 250 kDa bands by immunoblotting of epidermal extracts, and immunoprecipitated proteins of apparently 210/250 kDa from lysates of human keratinocytes.…”

Development of antigen-specific ELISA for circulating autoantibodies to extracellular matrix protein 1 in lichen sclerosus

“…In fact, several reports demonstrate penetration of IgG autoantibody into living cells (19,20). Notably in keratinocytes, by using passive transfer and in vitro cell culture systems, a series of recent investigations have also demonstrated that IgG autoantibodies to desmoplakin I/II, entirely intracellular desmosomal antigens, can get into living cells and reach the target antigens (21)(22)(23). Moreover, anti-nuclear IgG antibodies from patients with systemic lupus erythematosus have been shown to penetrate into living epithelial cells via receptor-mediated endocytosis and subsequently localize to the corresponding intracellular target antigens (24).…”