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Of the Pemphigus Foliaceous Autoantigen Within Desmosomes

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Of the Pemphigus Foliaceous Autoantigen Within Desmosomes Itnmunomorphologic and Biochemical Identification of the Pemphigus Foliaceous Autoantigen Within Desmosomes Klemens Rappersberger, Norbert Roos, and John R. Stanley Electronmicroscopic Laboratories of Biological Sciences (KR, NR), Department of Biology, U niversiry of O slo, Oslo, Norway; Department of Dermatology I (KR), Universiry of Vienna, Vienna, Austria; and Dermatology Branch ORS), National Institutes of Health, National Cancer Institute, Bethesda, Maryland, U.S.A. Desmosomes are specialized domains of the plasma mem­ sera from five patients with pf. We first confirmed by immu­ bra?-e that playa fundamental role in intercellular adhesion. noprecipitation and immunoblotting that these sera bound This adhesive functi.on is mediated at least in part by the dg. Both IEM methods showed that pf-aab exclusively bind cadherin homologous cell adhesion molecule (CAM) des­ to desmosomes. Double-labeling IEM of several other con­ rn~glein (dg). Autoantibodies (aab) from patients with pem­ stitutive desmosomal proteins further suggests that most phigus foliaceous (pf), a blistering disease of the epidermis, likely pf-aab bind to an extracellular domain of the trans­ have been shown by immunochemical methods to bind to membrane CAM dg. Our studies suggest one possible patho­ ?esmoglein. However, the molecular localization of the bind­ physiologic mechanism for the clinical manifestations of pf: Ing sites of these antibodies, especially as it relates to the namely, that the binding of aab to an extracellular epitope of ultrastructure of the desmosomes, has not been definitively desmoglein might impair the adhesive properties of desmo­ characterized. We therefore performed pre-embedding di­ somes mediated by dg and result in the loss of cell adhesion rect immunoelectron microscopy (IEM) on perilesional skin leading to acantholysis and blister formation.] Invest Dermatol of patients with pf and post-embedding indirect IEM using 99:323 - 330, 1992 ---------------------------------------------------------------------------------------------------------- emphigus vulgaris (pv) and pemphigus foliaceous (pf) however, several investigators repeatedly reported an identical im­ are both autoimmune intraepidermal blist<:ring diseases munomorphology, i.e., an "intercellular staining pattern," in pv in which antigen-antibody reactions are considered criti­ and pf [7 - 11]. Both disorders have distinct and characteristic target cal events in the pathophysiology [1]. Despite the unify­ antigens: pv autoantibodies (aab) immunoprecipitate a complex of ing designation "pemphigus," each type (pf/pv) has polypeptides of 210 kD, 130 kD, and 85 kD of human epidermal Pcharacteristic clinicopathologic and immunologic features [1- 6]; extracts, whereas in pf the characteristic antigenic complex consists of polypeptides of 260 kD, 160 kD, 85 kD, and a minor polypep­ --------------------------------------------------- tide of 110 kD [12]. The 85-kD polypeptide in both the pv and pf Manuscript received December 10, 1991; accepted for publication April antigen complexes is plakoglobin, a protein in the plaques of both 15, 1992. types of adherens' junctions, involving actin-based microfilaments Presented atthe annual meeting of the ESDR,June 1-4, 1991, Copenha­ gen, Denmark. in intermediate-type junctions and intermediate filaments in des­ This work was supported, in part, by an Erwin Schrodinger Fellowship mosomes [13,14]. The 130-kD polypeptide, the actual binding site ~I<.R, grant number 0426-MED) from the Austrian Science Foundation, and for the circulating pv-aab, was most recently identified as 'a novel Ya grant to Klemens Rappersberger from Schering AG, Berlin, FRG. epidermal cadherin [15]. Previous light microscopic and pre- and Reprint requests to: Klemens Rappersberger, Department of Dermatol­ post-embedding !EM studies clearly have shown that this protein is Ogy I, Universiry of Vienna, Alserstr. 4, A-I090 Vienna, Austria. uniformly expressed on the entire cell surface of epidermal keratino­ Abbreviations: cytes [16,17]. In contrast, the aab characteristic ofrf patients have aab : autoantibody been shown to bind to the 160-kD component 0 the pf-antigen BSA: bovine serum albumin complex [13]. This transmembrane glycoprotein, termed dg, was CAM: cell adhesion molecule the first constitutive desmosomal protein that was identified by dg: desmoglein dp 1/11: desmoplakin 1/desmoplakin II molecular cloning as a member of the family of Ca++-dependent FCS: fetal calf serum CAM, the cadherins [18-20]. IF: immunofluorescence In view of the seemingly contradictory findings of several im­ Ig: immunoglobulin munomorphologic and biochemical studies regarding pf-aab and IEM: immunoelectronmicroscopy their interactions with desmosomes, we first tested pf sera by immu­ MoAb: monoclonal antibody(ies) noprecipitation of human epidermal protein extracts and by im­ NSS: normal swine serum munoblotting using bovine desmosome preparations to confirm PAGE: polyacrylamide gel electrophoresis that the sera we used did, indeed, bind desmoglein. We then used PBS: phosphate-buffered saline pf: pemphigus foliaceous immunofluorescence and IEM to immunolocalize accurately both pg: plakoglobin the aab deposits in diseased skin of pf patients and the binding sites pv: pemphigus vulgaris of the immunochemically characterized pf-aab in normal human SDS: sodium dodecyl sulfate skin, respectively. The aim of this study was to clarify, whether aab TBS: tris-buffered saline of pf patients bind to antigenic moieties, which are expressed uni- 0022-202X/92/S0S.00 Copyright © 1992 by The Sociery for Investigative Dermatology, Inc. 323 324 RAPPERSBERGER ET AL THE JOURNAL OF INVESTIGATIVE DERMATOLOGY formly on the entire surface ofkeratinocytes as shown for pv aabs, or and distilled water the enzyme reaction product was visualized as they are confined to desmosomes. If the latter assumption were true described [29). and because dg is a transmembrane glycoprotein, the binding sites of the aab could then either be located on the cytoplasmic desmosomal Light- and Electronmicroscopic Immunomorphology For plaque, along the cytoplasmic membrane, within the extracellular the detection of in vivo bound IgG, biopsies were taken from penle­ desmoglea or even be distributed throughout the desmosome both sional skin of patients with pf and processed for light- (five panents) extra- and intracellularly. To address this question, we first sought and electron microscopy (three patients) according to protocols r?U­ to clarify aspects of the morphomolecular organization of human tinely used in our laboratory [11,30,31); briefly, for pre-embeddmg epidermal desmosomes using immunomorphologic techniques on IEM, the specimens were washed in phosphate-buffered saline ultrathin cryosections; this method provides the requisite high reso­ (PBS), pH 7.4 at 4 ° C for 60 min. Sections 60 11m thick wer~ ob­ lution to get insight into the macromolecular composition of des­ tained with a Smith and Farquhar (S&F) tissue sectioner and mcu -) mosomes (21). For this study, we used monoclonal antibodies bated in PBS supplemented with 10% normal swine serum (NSS (MoAb) directed against the desmoplakin I/desmoplakin II (dpI/II) and 10% glucose for 1 h. We always performed this pre_incubatIOn molecules and pg and the desmosomal transmembrane glycoprotein step to reduce non-specific background staining. The pre-incuba­ dg, as well as the immunochemically characterized sera from five tion was followed by incubation of the specimens with rabblt­ patients with pf. Ultrastructural immunolocalization of the actual anti-human IgG (diluted 1: 100 in PBS, 5% NSS) for 3 h at room binding sites of pf-aab may provide further insight into the pathoge­ temperature followed by several washes in PBS/10% NSS; subse­ netic mechanisms operative in pf and in addition clarify aspects of quently the specimens were incubated with swine-anti-rabblt Ig/ cel l adhesion mediated by dg. (diluted 1: 100 in PBS/5% NSS) and, after several washes m PBS 10% NSS, incubated with the peroxidase-anti-peroxidase complex MATERIALS AND METHODS (diluted 1 : 100 in PBS). After several washes in PBS, the specimens Serum Samples and Antibodies Serum samples were obtained were fixed in 1 % glutaraldehyde in PBS pH 7.4 for 2 h at ~oorn from five patients with clinically, histologically, and immunologi­ temperature, washed again in PBS and TBS, pH 6.8, and then m~u­ cally typical pf and from four healthy volunteers. bated in 0.02% 3,3'-diaminobenzidine/hydrogen peroxide solution Mouse MoAb were raised against the desmosomal plaque mole­ in TBS for 30-60 min. The tissue was post-fixed in 2% osmiUm cules dpI/II; (dp 2.15), pg (pg 5.1), and the transmembrane desmo­ tetroxide-potassium ferro cyanide for 60 min at 4 ° C and fur~he: somal glycoprotein dg (dg 3.10). These antibodies are described in processed for Epon 812 embedding. As controls a) some sectIOn detail elsewhere [14,22-25). For immunofluorescence microscopy were incubated in PBS only without the anti-human reagent and/or we used Texas Red-conjugated goat-anti-human IgG F(ab)z and the anti-rabbit antibodies respectively, and b) shave biopsies from fluorescein isothiocyanate - conjugated goat -anti-mouse IgG the epidermis of healthy humans were processed for !EM exactly as F(ab)z (Dia.nova, Hamburg, FRG). Pre-embedding IEM studies described above. d were performed with rabbit-anti-human IgG followed by swine­ To demonstrate in vitro binding of pf-aab by indirect-IF, we used anti-rabbit Ig using the peroxidase anti-peroxidase
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