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N-Terminal Adhesive Region of Desmogleins by Pemphigus

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N-Terminal Adhesive Region of Desmogleins by Pemphigus Dominant Autoimmune Epitopes Recognized by Pemphigus Antibodies Map to the N-Terminal Adhesive Region of Desmogleins This information is current as Maiko Sekiguchi, Yuko Futei, Yoshiko Fujii, Toshiro of October 4, 2021. Iwasaki, Takeji Nishikawa and Masayuki Amagai J Immunol 2001; 167:5439-5448; ; doi: 10.4049/jimmunol.167.9.5439 http://www.jimmunol.org/content/167/9/5439 Downloaded from References This article cites 31 articles, 6 of which you can access for free at: http://www.jimmunol.org/content/167/9/5439.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 4, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Dominant Autoimmune Epitopes Recognized by Pemphigus Antibodies Map to the N-Terminal Adhesive Region of Desmogleins1 Maiko Sekiguchi,*† Yuko Futei,* Yoshiko Fujii,* Toshiro Iwasaki,† Takeji Nishikawa,* and Masayuki Amagai2* Desmoglein (Dsg) is a cadherin-type adhesion molecule found in desmosomes. Dsg1 and Dsg3 are the target Ags in the autoimmune blistering diseases pemphigus foliaceus (PF) and pemphigus vulgaris (PV), respectively. To map conformational epitopes of Dsg1 and Dsg3 in PF and PV, we generated Dsg1- and Dsg3-domain-swapped molecules and point-mutated Dsg3 molecules with Dsg1-specific residues by baculovirus expression. The swapped domains were portions of the N-terminal extracellular domains of Dsg1 (1–496) and Dsg3 (1–566), which have similar structures but distinct epitopes. The binding of autoantibodies to the mutant Downloaded from molecules was assessed by competition ELISAs. Domain-swapped molecules containing the N-terminal 161 residues of Dsg1 and Dsg3 yielded >50% competition in 30/43 (69.8%) PF sera and 31/40 (77.5%) PV sera, respectively. Furthermore, removal of Abs against the 161 N-terminal residues of Dsg1 by immunoadsorption eliminated the ability of PF sera to induce cutaneous blisters in neonatal mice. Within these N-terminal regions, most of the epitopes were mapped to residues 26–87 of Dsg1 and 25–88 of Dsg3. Furthermore, a point-mutated Dsg3 molecule containing Dsg1-specific amino acid substitutions (His25, Cys28, Ala29) reacted with anti-Dsg1 IgG, thus defining one of the epitopes of Dsg1. Using the predicted three-dimensional structure of classic cadherins as http://www.jimmunol.org/ a model, these findings suggest that the dominant autoimmune epitopes in both PF and PV are found in the N-terminal adhesive surfaces of Dsgs. The Journal of Immunology, 2001, 167: 5439–5448. esmoglein (Dsg)3 is a desmosomal transmembrane gly- have circulating anti-Dsg3 IgG alone; those with mucocutaneous coprotein that belongs to the cadherin superfamily of PV have both anti-Dsg3 and anti-Dsg1 IgG; and those with PF D cell-cell adhesion molecules (1). Dsg has three isotypes: have anti-Dsg1 IgG alone (11, 12). Dsg1, Dsg2, and Dsg3. Expression of Dsg1 and Dsg3 is predom- Characterizing the Dsg binding sites of the pathogenic pemphi- inantly restricted to stratified squamous epithelia, whereas Dsg2 is gus autoantibodies is an essential step in understanding the patho- expressed in all desmosome-bearing cells, including simple epi- physiology of blister formation in pemphigus, as well as the basic by guest on October 4, 2021 thelial and myocardial cells (2, 3). Dsg1 and Dsg3 are the targets molecular mechanism of Dsg-mediated cell-cell adhesion. This of pemphigus, a life-threatening autoimmune blistering disease of characterization is hindered by the fact that binding of autoanti- the skin and mucous membranes (4, 5). Compelling evidence has bodies to Dsgs is dependent not only on amino acid sequence, but accumulated that IgG autoantibodies against Dsgs play a patho- also on molecular conformation (9, 13–15). This dependence on genic role in blister formation in pemphigus (6–10). Pemphigus molecular conformation is shown by the observation that recom- has two major subtypes: pemphigus vulgaris (PV) and pemphigus binant Dsg1 and Dsg3, when expressed in baculovirus as secreted foliaceus (PF). PV can be further divided into two clinical forms; proteins, immunoadsorbs heterogeneous autoantibodies from PF mucosal dominant PV is characterized by predominant mucosal and PV patients’ sera, and that this immunoadsorptive activity is involvement with minimal skin lesions, and mucocutaneous PV is lost upon denaturation by Ca2ϩ chelation, acid or alkaline treat- characterized by extensive lesions both in the skin and mucous ment, or boiling. Furthermore, the importance of conformational membranes. These three forms of pemphigus have different anti- epitopes was also demonstrated in the production of pathogenic Dsg autoantibody profiles. Patients with mucosal dominant PV Abs by mouse immunization (16–18). Therefore, a conventional approach using variously truncated Dsg molecules is inappropriate *Department of Dermatology, Keio University School of Medicine, Tokyo, Japan; for definition of the conformational epitopes of Dsgs in and †Department of Internal Medicine, Faculty of Veterinary Medicine, Tokyo Uni- versity of Agriculture and Technology, Tokyo, Japan pemphigus. Dsg1 and Dsg3 have similar structures, but distinct epitopes. Received for publication November 27, 2000. Accepted for publication August 31, 2001. Recently, we have shown that Dsg1- and Dsg3-domain-swapped The costs of publication of this article were defrayed in part by the payment of page molecules are useful for characterization of the conformational charges. This article must therefore be hereby marked advertisement in accordance epitopes of Dsg3 in PV (19). In this work, we extend the study, with 18 U.S.C. Section 1734 solely to indicate this fact. using 10 domain-swapped molecules and six point-mutated mol- 1 This work was supported by a Health Sciences Research Grant for Research on Specific Diseases from the Ministry of Health, Labour and Welfare of Japan (to M.A.) ecules to map conformational epitopes of Dsg1 and Dsg3. Com- and a grant-in-aid of Scientific Research from the Ministry of Education, Culture, petition ELISAs with these domain-swapped molecules reveal that Sports, Science and Technology, Japan (to M.A. and T.N.). dominant epitopes map to amino acid residues 26–87 of Dsg1 and 2 Address correspondence and reprint requests to Dr. Masayuki Amagai, Department 25–88 of Dsg3. Furthermore, within those regions we have iden- of Dermatology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku- ku, Tokyo 160-8582, Japan. E-mail address: [email protected] tified important conformational epitopes at which amino acid sub- 3 Abbreviations used in this paper: Dsg, desmoglein; PF, pemphigus foliaceus; PV, stitutions alter the binding specificity of pemphigus autoantibod- pemphigus vulgaris. ies. These findings are valuable for understanding the molecular Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 5440 CONFORMATIONAL EPITOPE MAPPING OF PEMPHIGUS ANTIGENS Table I. Primers used for domain-swapped moleculesa Primers Primers for Dsg1 Primers for Dsg3 Constructs 5Ј primers 3Ј primers 5Ј primers 3Ј primers Dsg11–24/Dsg325–566 Primer 1 Primer 2 Primer 3 Primer 4 Dsg11–64/Dsg365–566 Primer 1 Primer 5 Primer 6 Primer 4 Dsg11–87/Dsg387–566 Primer 1 Primer 7 Primer 8 Primer 4 Dsg31–26/Dsg126–496 Primer 9 Primer 10 Primer 11 Primer 12 Dsg31–63/Dsg163–496 Primer 13 Primer 10 Primer 11 Primer 14 Dsg31–88/Dsg189–496 Primer 15 Primer 10 Primer 11 Primer 16 a Primer 1, 5Ј-gaagatctcctataaatATGGACTGGAGTTTCTTCAGAG-3Ј; primer 2, 5Ј-cggactagtAATTTTGGCGATT GGGTT-3Ј; primer 3, 5Ј-gccactagtGATTACCAAGCAACCCAG-3Ј; primer 4, 5Ј-cctgctcgagCCTCCCTGAGTGCGGCCT-3Ј; primer 5, 5Ј-cggactagtTATATTAATTTCACCAGT-3; primer 6, 5Ј-gccactagtATAGTCGACCGGGAGGAA-3Ј; primer 7, 5Ј- cgggacgtcTTGGCCCATTGAGTTCAG-3Ј; primer 8, 5Ј-gccgacgtcGAGAAACCACTTATACTA-3Ј; primer 9, 5Ј-gccac tagtGATTGTGCTGCAAACCAG-3Ј; primer 10, 5Ј-cttgtcgacATGTACATTGTCTGATAACAAATC-3Ј; primer 11, 5Ј- gaagatctCCTATAAATATGGGGCTCTTCCCCAG-3Ј; primer 12, 5Ј-cggactagtAATCTTGGCAATTGGGTT-3Ј; primer 13, 5Ј-gccactagtATAGTTGATCGAGAGGTC-3Ј; primer 14, 5Ј-cggactagtTATGTTAATATCTCCAGT-3Ј; primer 15, 5Ј- gccgacgtcGAGAGGCCTCTAGAGCTC-3Ј; primer 16, 5Ј-cgggacgtcTAGTCCTTGGGCATTTAG-3Ј. Downloaded from mechanism of Dsg-mediated cell-cell adhesion, as well as for de- mid template coding the extracellular domain of Dsg3 (pEVmod-Dsg3- velopment of epitope-specific therapeutic strategies for pemphigus. His). This procedure eliminated a unique ScaI restriction site (shown in boldface) in the ampr gene (23). The megaprimer was then used to amplify the entire plasmid with the same plasmid template in a second round of Materials and Methods PCR. After DpnI digestion, the PCR product was used for transformation. Human sera All mutants were sequenced to verify the presence of mutation and to http://www.jimmunol.org/
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