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. 1998 Aug 15;102(4):775–782. doi: 10.1172/JCI3647

Antibodies against desmoglein 3 (pemphigus vulgaris antigen) are present in sera from patients with paraneoplastic pemphigus and cause acantholysis in vivo in neonatal mice.

M Amagai 1, T Nishikawa 1, H C Nousari 1, G J Anhalt 1, T Hashimoto 1
PMCID: PMC508940  PMID: 9710446

Abstract

Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease that occurs in association with underlying neoplasms. Patients with PNP develop characteristic IgG autoantibodies directed against multiple antigens, most of which have been identified as cytoplasmic proteins of the plakin family (desmoplakin I, II, BPAG1, envoplakin, and periplakin). This study identified cell surface target antigens of PNP. We focused on desmoglein (Dsg) 3 and Dsg1, the autoantigens of pemphigus vulgaris and pemphigus foliaceus. ELISA using baculovirus-expressed recombinant Dsgs (rDsg3, rDsg1) has revealed that 25 out of 25 PNP sera tested were positive against Dsg3 and 16 of 25 were positive against Dsg1. All of 12 PNP sera tested immunoprecipitated Dsg3. Removal of anti-Dsg3 autoantibodies by immunoadsorption was sufficient to eliminate the ability of PNP sera to induce cutaneous blisters in neonatal mice in vivo. Furthermore, anti-Dsg3-specific antibodies that were affinity purified from PNP sera were proven to be pathogenic and caused blisters in neonatal mice. These findings indicate that Dsg3 and Dsg1 are the cell surface target antigens in PNP and that IgG autoantibodies against Dsg3 in PNP sera play a pathogenic role in inducing loss of cell adhesion of keratinocytes and causing blister formation.

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Selected References

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  1. Amagai M., Hashimoto T., Green K. J., Shimizu N., Nishikawa T. Antigen-specific immunoadsorption of pathogenic autoantibodies in pemphigus foliaceus. J Invest Dermatol. 1995 Jun;104(6):895–901. doi: 10.1111/1523-1747.ep12606168. [DOI] [PubMed] [Google Scholar]
  2. Amagai M., Hashimoto T., Shimizu N., Nishikawa T. Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced by baculovirus. J Clin Invest. 1994 Jul;94(1):59–67. doi: 10.1172/JCI117349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Amagai M., Klaus-Kovtun V., Stanley J. R. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell. 1991 Nov 29;67(5):869–877. doi: 10.1016/0092-8674(91)90360-b. [DOI] [PubMed] [Google Scholar]
  4. Amagai M., Koch P. J., Nishikawa T., Stanley J. R. Pemphigus vulgaris antigen (desmoglein 3) is localized in the lower epidermis, the site of blister formation in patients. J Invest Dermatol. 1996 Feb;106(2):351–355. doi: 10.1111/1523-1747.ep12343081. [DOI] [PubMed] [Google Scholar]
  5. Amagai M. Pemphigus: autoimmunity to epidermal cell adhesion molecules. Adv Dermatol. 1996;11:319–353. [PubMed] [Google Scholar]
  6. Anhalt G. J., Kim S. C., Stanley J. R., Korman N. J., Jabs D. A., Kory M., Izumi H., Ratrie H., 3rd, Mutasim D., Ariss-Abdo L. Paraneoplastic pemphigus. An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med. 1990 Dec 20;323(25):1729–1735. doi: 10.1056/NEJM199012203232503. [DOI] [PubMed] [Google Scholar]
  7. Anhalt G. J., Labib R. S., Voorhees J. J., Beals T. F., Diaz L. A. Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Engl J Med. 1982 May 20;306(20):1189–1196. doi: 10.1056/NEJM198205203062001. [DOI] [PubMed] [Google Scholar]
  8. Anhalt G. J. Paraneoplastic pemphigus. Adv Dermatol. 1997;12:77–97. [PubMed] [Google Scholar]
  9. Emery D. J., Diaz L. A., Fairley J. A., Lopez A., Taylor A. F., Giudice G. J. Pemphigus foliaceus and pemphigus vulgaris autoantibodies react with the extracellular domain of desmoglein-1. J Invest Dermatol. 1995 Mar;104(3):323–328. doi: 10.1111/1523-1747.ep12665364. [DOI] [PubMed] [Google Scholar]
  10. Eyre R. W., Stanley J. R. Identification of pemphigus vulgaris antigen extracted from normal human epidermis and comparison with pemphigus foliaceus antigen. J Clin Invest. 1988 Mar;81(3):807–812. doi: 10.1172/JCI113387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Fullerton S. H., Woodley D. T., Smoller B. R., Anhalt G. J. Paraneoplastic pemphigus with autoantibody deposition in bronchial epithelium after autologous bone marrow transplantation. JAMA. 1992 Mar 18;267(11):1500–1502. [PubMed] [Google Scholar]
  12. Hall R. P., 3rd, Murray J. C., McCord M. M., Rico M. J., Streilein R. D. Rabbits immunized with a peptide encoded for by the 230-kD bullous pemphigoid antigen cDNA develop an enhanced inflammatory response to UVB irradiation: a potential animal model for bullous pemphigoid. J Invest Dermatol. 1993 Jul;101(1):9–14. doi: 10.1111/1523-1747.ep12358276. [DOI] [PubMed] [Google Scholar]
  13. Hashimoto K., Shafran K. M., Webber P. S., Lazarus G. S., Singer K. H. Anti-cell surface pemphigus autoantibody stimulates plasminogen activator activity of human epidermal cells. A mechanism for the loss of epidermal cohesion and blister formation. J Exp Med. 1983 Jan 1;157(1):259–272. doi: 10.1084/jem.157.1.259. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hashimoto T., Amagai M., Ning W., Nishikawa T., Karashima T., Mori O., Jablonska S., Chorzelski T. P. Novel non-radioisotope immunoprecipitation studies indicate involvement of pemphigus vulgaris antigen in paraneoplastic pemphigus. J Dermatol Sci. 1998 Jun;17(2):132–139. doi: 10.1016/s0923-1811(98)00005-x. [DOI] [PubMed] [Google Scholar]
  15. Hashimoto T., Amagai M., Watanabe K., Chorzelski T. P., Bhogal B. S., Black M. M., Stevens H. P., Boorsma D. M., Korman N. J., Gamou S. Characterization of paraneoplastic pemphigus autoantigens by immunoblot analysis. J Invest Dermatol. 1995 May;104(5):829–834. doi: 10.1111/1523-1747.ep12607012. [DOI] [PubMed] [Google Scholar]
  16. Hashimoto T., Ogawa M. M., Konohana A., Nishikawa T. Detection of pemphigus vulgaris and pemphigus foliaceus antigens by immunoblot analysis using different antigen sources. J Invest Dermatol. 1990 Mar;94(3):327–331. doi: 10.1111/1523-1747.ep12874456. [DOI] [PubMed] [Google Scholar]
  17. Helou J., Allbritton J., Anhalt G. J. Accuracy of indirect immunofluorescence testing in the diagnosis of paraneoplastic pemphigus. J Am Acad Dermatol. 1995 Mar;32(3):441–447. doi: 10.1016/0190-9622(95)90066-7. [DOI] [PubMed] [Google Scholar]
  18. Ishii K., Amagai M., Hall R. P., Hashimoto T., Takayanagi A., Gamou S., Shimizu N., Nishikawa T. Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins. J Immunol. 1997 Aug 15;159(4):2010–2017. [PubMed] [Google Scholar]
  19. Joly P., Thomine E., Gilbert D., Verdier S., Delpech A., Prost C., Lebbe C., Lauret P., Tron F. Overlapping distribution of autoantibody specificities in paraneoplastic pemphigus and pemphigus vulgaris. J Invest Dermatol. 1994 Jul;103(1):65–72. doi: 10.1111/1523-1747.ep12389680. [DOI] [PubMed] [Google Scholar]
  20. Kim S. C., Kwon Y. D., Lee I. J., Chang S. N., Lee T. G. cDNA cloning of the 210-kDa paraneoplastic pemphigus antigen reveals that envoplakin is a component of the antigen complex. J Invest Dermatol. 1997 Sep;109(3):365–369. doi: 10.1111/1523-1747.ep12336235. [DOI] [PubMed] [Google Scholar]
  21. Kowalczyk A. P., Anderson J. E., Borgwardt J. E., Hashimoto T., Stanley J. R., Green K. J. Pemphigus sera recognize conformationally sensitive epitopes in the amino-terminal region of desmoglein-1. J Invest Dermatol. 1995 Aug;105(2):147–152. doi: 10.1111/1523-1747.ep12316680. [DOI] [PubMed] [Google Scholar]
  22. Liu A. Y., Valenzuela R., Helm T. N., Camisa C., Melton A. L., Bergfeld W. F. Indirect immunofluorescence on rat bladder transitional epithelium: a test with high specificity for paraneoplastic pemphigus. J Am Acad Dermatol. 1993 May;28(5 Pt 1):696–699. doi: 10.1016/0190-9622(93)70095-b. [DOI] [PubMed] [Google Scholar]
  23. Oursler J. R., Labib R. S., Ariss-Abdo L., Burke T., O'Keefe E. J., Anhalt G. J. Human autoantibodies against desmoplakins in paraneoplastic pemphigus. J Clin Invest. 1992 Jun;89(6):1775–1782. doi: 10.1172/JCI115781. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ruhrberg C., Hajibagheri M. A., Parry D. A., Watt F. M. Periplakin, a novel component of cornified envelopes and desmosomes that belongs to the plakin family and forms complexes with envoplakin. J Cell Biol. 1997 Dec 29;139(7):1835–1849. doi: 10.1083/jcb.139.7.1835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ruhrberg C., Hajibagheri M. A., Simon M., Dooley T. P., Watt F. M. Envoplakin, a novel precursor of the cornified envelope that has homology to desmoplakin. J Cell Biol. 1996 Aug;134(3):715–729. doi: 10.1083/jcb.134.3.715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ruhrberg C., Watt F. M. The plakin family: versatile organizers of cytoskeletal architecture. Curr Opin Genet Dev. 1997 Jun;7(3):392–397. doi: 10.1016/s0959-437x(97)80154-2. [DOI] [PubMed] [Google Scholar]
  27. Schiltz J. R., Michel B. Production of epidermal acantholysis in normal human skin in vitro by the IgG fraction from pemphigus serum. J Invest Dermatol. 1976 Aug;67(2):254–260. doi: 10.1111/1523-1747.ep12513454. [DOI] [PubMed] [Google Scholar]
  28. Shirakata Y., Amagai M., Hanakawa Y., Nishikawa T., Hashimoto K. Lack of mucosal involvement in pemphigus foliaceus may be due to low expression of desmoglein 1. J Invest Dermatol. 1998 Jan;110(1):76–78. doi: 10.1046/j.1523-1747.1998.00085.x. [DOI] [PubMed] [Google Scholar]
  29. Stanley J. R. Cell adhesion molecules as targets of autoantibodies in pemphigus and pemphigoid, bullous diseases due to defective epidermal cell adhesion. Adv Immunol. 1993;53:291–325. doi: 10.1016/s0065-2776(08)60503-9. [DOI] [PubMed] [Google Scholar]
  30. Tsukamoto T. Establishment and characterization of a cell line (KU-8) from squamous cell carcinoma of the penis. Keio J Med. 1989 Sep;38(3):277–293. doi: 10.2302/kjm.38.277. [DOI] [PubMed] [Google Scholar]

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