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• W1973497455 abstract "bullous pemphigoid desmocollin desmoglein extracellular pemphigus foliaceus paraneoplastic pemphigus pemphigus vulgaris TO THE EDITOR Paraneoplastic pemphigus (PNP) is a frequently lethal autoimmune bullous disease characterized by severe polymorphous mucocutaneous lesions and is commonly associated with hematologic malignancies, particularly non-Hodgkin lymphomas, chronic lymphatic leukemia, and Castleman's disease (Anhalt, 2004Anhalt G.J. Paraneoplastic pemphigus.J Investig Dermatol Symp Proc. 2004; 9: 29-33Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar). The autoantibody profile of PNP is less restricted and includes recognition of the autoantigens of pemphigus vulgaris (PV), pemphigus foliaceus (PF), and bullous pemphigoid (BP). Whereas the sera of patients with PV, PF, and BP nearly selectively recognize the desmogleins (Dsg) or bullous pemphigoid antigens 1 (BP230) and 2 (BP180), respectively, PNP sera exhibit IgG (and IgA) reactivity against an array of intracellular and transmembrane adhesion proteins including plakins (desmoplakin I and II, BP230, envoplakin, periplakin), desmosomal cadherins such as Dsg3, Dsg1, desmocollins (Dsc) 1–3, as well as plakophilin 3, and a 170-kDa protein, which was recently identified as a α-macroglobulin-like 1 protease inhibitor (Oursler et al., 1992Oursler J.R. Labib R.S. Ariss-Abdo L. et al.Human autoantibodies against desmoplakins in paraneoplastic pemphigus.J Clin Invest. 1992; 89: 1775-1782Crossref PubMed Scopus (162) Google Scholar; Nagata et al., 2001Nagata Y. Karashima T. Watt F.M. et al.Paraneoplastic pemphigus sera react strongly with multiple epitopes on the various regions of envoplakin and periplakin, except for the c-terminal homologous domain of periplakin.J Invest Dermatol. 2001; 116: 556-563Crossref PubMed Scopus (63) Google Scholar; Lambert et al., 2010Lambert J. Bracke S. van Roy F. et al.Serum plakophilin-3 autoreactivity in paraneoplastic pemphigus.Br J Dermatol. 2010; 163: 630-632Crossref PubMed Scopus (16) Google Scholar; Schepens et al., 2010Schepens I. Jaunin F. Begre N. et al.The protease inhibitor alpha-2-macroglobulin-like-1 is the p170 antigen recognized by paraneoplastic pemphigus autoantibodies in human.PLoS ONE. 2010; 5: e12250Crossref PubMed Scopus (78) Google Scholar). As PNP is clinically heterogeneous and may mimic a variety of inflammatory skin disorders, such as PV, BP, graft-versus-host disease, or lichen planus (Anhalt, 2004Anhalt G.J. Paraneoplastic pemphigus.J Investig Dermatol Symp Proc. 2004; 9: 29-33Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar), more detailed knowledge about the fine specificity of the autoantibody profile may help identify PNP more readily. In this study, a total of 39 sera from 15 patients with the clinical diagnosis of PNP (Table 1) along with 24 patients with acute-onset PV were studied. The clinical diagnosis of PNP was confirmed by histopathology, direct immunofluorescence, and, additionally, proven by positive immunoreactivity with the 190-kDa antigen periplakin and the 210-kDa antigen envoplakin. The study was conducted in accordance with the Declaration of Helsinki Principles, approved by the local ethics committees of the participating institutions, and all patients gave written informed consent.Table 1Clinical features of investigated PNP patientsMucosal lesionsSkin lesionsPatient no.Age (years)SexOralOcularFlaccid vesiclesLichenoidMultiformePulmonary involvementUnderlying malignancy143M+++--+Follicular lymphoma256F+----+Epitheloid leiomyosarkoma349F+-++--Low-grade NHL461M+++---Malignant fibrohistiocytoma557M+-+---NHL686M+-+---Larynx-Ca770M+-++--Follicular NHL878M+-+-+-Large B-cell NHL965M+++---Low-grade B-cell NHL1057F+-++--Leukemia1142F++---+Castleman tumor1269M+++---Low-grade B-cell NHL13ØØØØØØØØØ14ØØØØØØØØØ1546F+++-+-Follicular NHLAbbreviations: F, female; M, male; NHL, non-Hodgkin lymphoma; PNP, paraneoplastic pemphigus.Ø, clinical data not available/accessible. Open table in a new tab Abbreviations: F, female; M, male; NHL, non-Hodgkin lymphoma; PNP, paraneoplastic pemphigus. Ø, clinical data not available/accessible. Initially, total IgG and IgA reactivites of the PNP and PV sera were tested by ELISA against Dsg3, Dsg1, and Dsc1–3 proteins as described previously (Muller et al., 2008Muller R. Svoboda V. Wenzel E. et al.IgG against extracellular subdomains of desmoglein 3 relates to clinical phenotype of pemphigus vulgaris.Exp Dermatol. 2008; 17: 35-43PubMed Google Scholar, Muller et al., 2009Muller R. Heber B. Hashimoto T. et al.Autoantibodies against desmocollins in European patients with pemphigus.Clin Exp Dermatol. 2009; 34: 898-903Crossref PubMed Scopus (64) Google Scholar). As expected, all PNP and PV sera showed IgG reactivity against Dsg3, which is in line with previous findings (Amagai et al., 1998Amagai M. Nishikawa T. Nousari H.C. et al.Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice.J Clin Invest. 1998; 102: 775-782Crossref PubMed Scopus (271) Google Scholar; Futei et al., 2003Futei Y. Amagai M. Hashimoto T. et al.Conformational epitope mapping and IgG subclass distribution of desmoglein 3 in paraneoplastic pemphigus.J Am Acad Dermatol. 2003; 49: 1023-1028Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar; Mentink et al., 2007Mentink L.F. de Jong M.C. Kloosterhuis G.J. et al.Coexistence of IgA antibodies to desmogleins 1 and 3 in pemphigus vulgaris, pemphigus foliaceus and paraneoplastic pemphigus.Br J Dermatol. 2007; 156: 635-641Crossref PubMed Scopus (37) Google Scholar). In contrast, only 2 out of 15 (13.3%) PNP sera exhibited IgG reactivity against Dsg1 (Figure 1a), whereas 13 out of 24 (54.2%) PV sera reacted with Dsg1 (Figure 1b). In addition, PNP (Figure 1a), but not PV sera (Figure 1b) contained IgG, and in one case IgA autoantibodies (Figure 1c), directed against Dsc, of which Dsc3 (8/15) was the most common antigen. In addition, five PNP sera showed IgA against Dsg3, and three PNP sera exhibited IgA reactivity against Dsg1 (Figure 1c). In light of these findings, we sought to identify potential differences in epitope recognition of the Dsg3 ectodomain by IgG autoantibodies from PV and PNP sera. Using recombinant forms of the Dsg3 extracellular (EC) subdomains 1–5, IgA and IgG autoantibodies from the PNP sera were found to preferentially recognize the COOH-terminal EC4 and EC5 domains of Dsg3 (Figures 1d and e), whereas the PV sera preferentially showed IgG reactivity directed against the NH2 terminus of Dsg3 (EC1 and EC2; Figure 1f). These findings are in contrast to previous observations that identified the NH2-terminal EC domains of Dsg3 (EC1 and EC2) as the primary targets for both PNP and PV sera (Futei et al., 2003Futei Y. Amagai M. Hashimoto T. et al.Conformational epitope mapping and IgG subclass distribution of desmoglein 3 in paraneoplastic pemphigus.J Am Acad Dermatol. 2003; 49: 1023-1028Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). The reason for this discrepancy may be that the authors of the previous study used domain-swapped molecules of Dsg3 and Dsg1 in a competition ELISA, whereas we used Dsg3 recombinants that represented only distinct Dsg3 subdomains (Muller et al., 2008Muller R. Svoboda V. Wenzel E. et al.IgG against extracellular subdomains of desmoglein 3 relates to clinical phenotype of pemphigus vulgaris.Exp Dermatol. 2008; 17: 35-43PubMed Google Scholar). Several PNP sera also recognized the EC domain of Dsc3 (Figure 1a). This observation is of particular interest as several authors recently demonstrated the importance of the adhesive function of Dsc for the integrity of the epidermis, and reported that loss of Dsc function results in impaired cell–cell adhesion leading to intraepidermal blistering (Spindler et al., 2009Spindler V. Heupel W.M. Efthymiadis A. et al.Desmocollin 3-mediated binding is crucial for keratinocyte cohesion and is impaired in pemphigus.J Biol Chem. 2009; 284: 30556-30564Crossref PubMed Scopus (92) Google Scholar; Rafei et al., 2011Rafei D. Muller R. Ishii N. et al.IgG autoantibodies against desmocollin 3 in pemphigus sera induce loss of keratinocyte adhesion.Am J Pathol. 2011; 178: 718-723Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar). Furthermore, these results confirm previously published data of our group and others showing that Dsc-specific IgG or IgA autoantibodies are exclusively detected in paraneoplastic, atypical, and IgA pemphigus (Hisamatsu et al., 2004Hisamatsu Y. Amagai M. Garrod D.R. et al.The detection of IgG and IgA autoantibodies to desmocollins 1-3 by enzyme-linked immunosorbent assays using baculovirus-expressed proteins, in atypical pemphigus but not in typical pemphigus.Br J Dermatol. 2004; 151: 73-83Crossref PubMed Scopus (54) Google Scholar; Muller et al., 2009Muller R. Heber B. Hashimoto T. et al.Autoantibodies against desmocollins in European patients with pemphigus.Clin Exp Dermatol. 2009; 34: 898-903Crossref PubMed Scopus (64) Google Scholar). Antibodies of the IgG isotype predominate in several autoimmune diseases; IgG1 autoantibodies have been associated with the pathogenesis of BP, whereas IgG4 is the major autoantibody isotype in pemphigus (Mihai et al., 2007Mihai S. Chiriac M.T. Herrero-Gonzalez J.E. et al.IgG4 autoantibodies induce dermal-epidermal separation.J Cell Mol Med. 2007; 11: 1117-1128Crossref PubMed Scopus (61) Google Scholar). In the studied PNP sera, IgG1 reactive with Dsg3 was detectable in 100% of the sera, whereas IgG2 was found in 33.3%, IgG3 in 53.3%, and IgG4 in 26.6% of the sera (Figure 1g). These results are in line with a previous study demonstrating a predominance of IgG1 in PNP and IgG4 autoantibodies in PV sera (Futei et al., 2003Futei Y. Amagai M. Hashimoto T. et al.Conformational epitope mapping and IgG subclass distribution of desmoglein 3 in paraneoplastic pemphigus.J Am Acad Dermatol. 2003; 49: 1023-1028Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar). As IgG1 is a potent recruiter and activator of leukocytes and possesses a high blister-inducing capacity, it is tempting to speculate that the more severe course seen in PNP compared with PV may at least in part be explained by different IgG autoantibody subclasses involved. Recently, it has been shown that autoantibodies of the IgE class are associated with acute-onset PV and have been previously also linked to the pathogenesis of BP (Fairley et al., 2007Fairley J.A. Burnett C.T. Fu C.L. et al.A pathogenic role for IgE in autoimmunity: bullous pemphigoid IgE reproduces the early phase of lesion development in human skin grafted to nu/nu mice.J Invest Dermatol. 2007; 127: 2605-2611Crossref PubMed Scopus (137) Google Scholar). As PNP clinically shares features of PV and BP, we sought to identify IgE autoantibodies in the studied PNP sera (for details see Supplementary Material online). However, neither IgE reactivity against Dsg1/3 nor against Dsc1-3 or BP180/BP230 was detected in the PNP sera (data not shown). Download .pdf (.06 MB) Help with pdf files Supplementary Information Finally, we were interested in whether a correlation between the clinical manifestation of PNP (Table 1) and individual autoantibody profiles exists. However, we were unable to detect any relationship between clinical signs and defined autoantibody patterns. In summary, the present study demonstrates that, in PNP, IgG autoantibodies show a distinct autoantibody profile that is characterized by (1) IgG reactivity against the major target antigens of pemphigus, Dsg3 and Dsg1, (2) preferential recognition of the COOH terminus of the Dsg3 ectodomain (in contrast to PV sera which preferentially target the NH2-terminus), (3) occasional recognition of Dsc1, 2, and 3 (which were not found in PV sera), and (4) IgG1 as the dominant autoantibody subclass. Our findings may help distinguish PNP from other pemphigus variants by the autoantibody profile and may provide new insight into the relative role of IgG autoantibody profiles in the pathogenesis of PNP. The study was supported in part by the Coordination Theme 1 (Health) of the European Community's FP7, Grant agreement number HEALTH-F2-2008-200515 (MH). We thank T. Hashimoto for kindly providing the plasmids necessary for the expression of the recombinant desmocollins 1, 2, and 3. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid" @default.
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• W1973497455 date "2012-06-01" @default.
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• W1973497455 title "Differential IgG Recognition of Desmoglein 3 by Paraneoplastic Pemphigus and Pemphigus Vulgaris Sera" @default.
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