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Recent advances in the study of the pathophysiology of pemphigus

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Abstract

Recent rapid advances in the basic research into pemphigus have provided many insights into its pathophysiology. In particular, a recently developed enzyme-linked immunosorbent assay (ELISA) for desmogleins 1 and 3 (Dsg1 and Dsg3), antigens for pemphigus foliaceus (PF) and pemphigus vulgaris (PV), respectively, has led to great progress in the diagnosis and classification of pemphigus, as well as in understanding its pathomechanisms. Studies with the anti-Dsg1 and anti-Dsg3 antibodies have indicated that there are two types of PV, the mucosal dominant type and the mucocutaneous type. The same ELISA has identified the antigens in pemphigus herpetiformis. The autoantigens detected by this ELISA correlate well with the clinical features in pemphigus patients in showing the shift between PV and PF. In addition, the Dsg compensation theory proposed by Stanley and Amagai can reasonably explain the different depths of skin lesions and the different occurrences of skin and oral mucosal lesions between PV and PF. Furthermore, a complicated profile of autoantigens in paraneoplastic pemphigus (PNP) has been indicated in various biochemical studies, and IgG anti-Dsg1 and anti-Dsg3 antibodies have been detected in serum from all the PNP patients by the above ELISA. On the other hand, serum from subcorneal pustular dermatosis type IgA pemphigus patients have been shown to react with Dsc1, another type of desmosomal cadherin, by a novel cDNA transfection method. In addition, IgA anti-Dsg1 and anti-Dsg3 antibodies have been detected in a few patients with IgA pemphigus by an ELISA for IgA antibodies. Various autoimmune bullous diseases, including several types of pemphigus, are the only diseases in which the pathogenic role of circulating autoantibodies has been confirmed using the newborn mouse animal model. Therefore, studies of the pathophysiology of pemphigus are extremely important as a paradigm for research into various types of autoimmune diseases in other fields.

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References

  1. Koch PJ, Franke WW (1994) Desmosomal cadherins: another growing multigene family of adhesion molecules. Curr Opin Cell Biol 6:682–687

    CAS  PubMed  Google Scholar 

  2. Buxton RS, Cowin P, Franke WW, Garrod DR, Green KJ, King IA, Koch PJ, Magee AI, Rees DA, Stanley JR, Steinberg MS (1993) Nomenclature of the desmosomal cadherins. J Cell Biol 121:481–483

    CAS  PubMed  Google Scholar 

  3. Amagai M (1995) Adhesion molecules: I: Keratinocyte-keratinocyte interactions; cadherins and pemphigus. J Invest Dermatol 104:146–152

    CAS  PubMed  Google Scholar 

  4. Garrod D, Chidgey M, North A (1996) Desmosomes: differentiation, development, dynamics and disease. Curr Opin Cell Biol 8:670–678

    Article  CAS  PubMed  Google Scholar 

  5. Zillikens D (1999) Acquired skin disease of hemidesmosomes. J Dermatol Sci 20:122–133

    Article  PubMed  Google Scholar 

  6. Beutner EH, Jordon RE, Chorzelski TP (1968) The immunopathology of pemphigus and bullous pemphigoid. J Invest Dermatol 51:63–80

    CAS  PubMed  Google Scholar 

  7. Robinson ND, Hashimoto T, Amagai M, Chan LS (1999) Continuing medical education: the new pemphigus variants. J Am Acad Dermatol 40:649–671

    CAS  PubMed  Google Scholar 

  8. Hashimoto T (1999) Skin diseases related to abnormality in desmosomes and hemidesmosomes (editorial review); special issue of review articles in Journal of Dermatological Science. J Dermatol Sci 20:81–84

    Article  CAS  PubMed  Google Scholar 

  9. Koch PJ, Walsh MJ, Schmelz M, et al (1990) Identification of desmoglein, a constitutive desmosomal glycoprotein, as a member of the cadherin family of cell adhesion molecules. Eur J Cell Biol 53:1–12

    CAS  PubMed  Google Scholar 

  10. Hashimoto T, Ogawa MM, Konohana A, Nishikawa T (1990) Detection of pemphigus vulgaris and pemphigus foliaceus antigens by immunoblot analysis using different antigen sources. J Invest Dermatol 94:327–331

    CAS  PubMed  Google Scholar 

  11. Hashimoto T, Konohana A, Nishikawa T (1991) Immunoblot assay as an aid to the diagnoses of unclassified cases of pemphigus. Arch Dermatol 127:843–847

    CAS  PubMed  Google Scholar 

  12. Amagai M, Klaus-Kovtun V, Stanley JR (1991) Autoantibodies against a novel epithelial cadherin in PV, a disease of cell adhesion. Cell 67:869–877

    CAS  PubMed  Google Scholar 

  13. Hashimoto T, Amagai M, Garrod DR, et al (1995) Immunofluorescence and immunoblot studies on the reactivity of pemphigus vulgaris and pemphigus foliaceus sera with desmoglein 3 and desmoglein 1. Epithelial Cell Biol 4:63–69

    CAS  PubMed  Google Scholar 

  14. Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T (1999) The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol 40:167–170

    CAS  PubMed  Google Scholar 

  15. Mahoney MG, Wang Z, Rothenberger K, Koch PJ, Amagai M, Stanley JR (1999) Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J Clin Invest 103:461–468

    CAS  PubMed  Google Scholar 

  16. Jablonska S, Chorzelski TP, Beutner EH, Chorzelska J (1975) Herpetiform pemphigus, a variable pattern of pemphigus. Int J Dermatol 14:353–359

    CAS  PubMed  Google Scholar 

  17. Brenner S, Bialy-Golan A, Anhalt GJ (1997) Recognition of pemphigus antigens in drug-induced pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol 36:919–923

    CAS  PubMed  Google Scholar 

  18. Kawana S, Hashimoto T, Nishikawa T, Nishiyama S (1994) Changes in clinical features, histologic findings, and antigen profiles with development of pemphigus foliaceus from pemphigus vulgaris. Arch Dermatol 130:1534–1538

    CAS  PubMed  Google Scholar 

  19. Ishii K, Amagai M, Ohata Y, Shimizu H, Hashimoto T, Ohya K, Nishikawa T (2000) Development of pemphigus vulgaris in a patient with pemphigus foliaceus anti-desmoglein antibody profile shift by enzyme-linked immunosorbent assay. J Am Acad Dermatol 42:859–861

    CAS  PubMed  Google Scholar 

  20. Anhalt GJ, Kim S-C, Stanley JR, Korman NJ, Jabs DA, Kory M, Izumi H, Ratrie H III, Mutasim D, Ariss-Abdo L, Labib RS (1990) An autoimmune mucocutaneous disease associated with neoplasia. N Engl J Med 323:1729–1735

    CAS  PubMed  Google Scholar 

  21. Anhalt GJ (1997) Paraneoplastic pemphigus. Adv Dermatol 12:77–96

    CAS  PubMed  Google Scholar 

  22. Iwatsuki K, Hashimoto T, Ebihara T, Teraki Y, Nishikawa T, Kaneko F (1991) Intercellular IgA vesiculo-pustular dermatosis and related disorders: diversity of IgA anti-intercellular autoantibodies. Eur J Dermatol 3:7–11

    Google Scholar 

  23. Ebihara T, Hashimoto T, Iwatsuki K, Takigawa M, Ando M, Ohkawara A, Nishikawa T (1991) Autoantigens for IgA anti-intercellular antibodies of intercellular IgA vesiculopustular dermatosis. J Invest Dermatol 97:742–745

    CAS  PubMed  Google Scholar 

  24. Hashimoto T (2001) Immunopathology of IgA pemphigus. Clin Dermatol 19:683–689

    Article  CAS  PubMed  Google Scholar 

  25. Prost C, Intrator L, Wechsler J (1991) IgA autoantibodies bind to pemphigus vulgaris antigen in a case of intraepidermal neutrophilic IgA dermatosis. J Am Acad Dermatol 25:846–848

    CAS  PubMed  Google Scholar 

  26. Wang J, Kwon J, Ding X, Fairley JA, Woodley DT, Chan LS (1997) Nonsecretory IgA1 autoantibodies targeting desmosomal component desmoglein 3 in intraepidermal neutrophilic IgA dermatosis. Am J Pathol 150:1901–1907

    CAS  PubMed  Google Scholar 

  27. Karpati S, Amagai M, Li LW, Dmochowski M, Hashimoto T, Horvath A (2000) Identification of desmoglein 1 as an autoantigen in a patient with intraepidermal neutrophilic IgA dermatosis type of IgA pemphigus. Exp Dermatol 9:224–228

    Article  CAS  PubMed  Google Scholar 

  28. Chorzelski TP, Hashimoto T, Nishikawa T (1994) Unusual acantholytic bullous dermatosis associated with neoplasia and antibodies of IgG and IgA classed against bovine desmocollins I and II. J Am Acad Dermatol 31:351–355

    CAS  PubMed  Google Scholar 

  29. Miyagawa S, Hashimoto T, Ohno H, Nakagawa A, Watanabe K, Hashimoto T, Shirai T (1995) Atypical pemphigus associated with monoclonal IgA gammopathy. J Am Acad Dermatol 32:352–357

    CAS  PubMed  Google Scholar 

  30. Ogawa MM, Hashimoto T, Nishikawa T, Castro RM (1989) IgG subclasses of intercellular antibodies in Brazilian pemphigus foliaceus—the relationship to complement fixing capability. Clin Exp Dermatol 14:29–31

    CAS  PubMed  Google Scholar 

  31. Morini JP, Jomaa B, Gorgi Y, Saguem MH, Nouira R, Roujeau JC, et al (1993) Pemphigus foliaceus in young women. An endemic focus in the Sousse area of Tunisia. Arch Dermatol 129:69–73

    CAS  PubMed  Google Scholar 

  32. Abreu AM, Maldonado JG, Jaramillo A, Patiño PJ, Prada S, Leon W, et al (1998) Immunological characterization of a unique focus of endemic pemphigus foliaceus in the rural area of El Bagre, Colombia (abstract). J Invest Dermatol 110:516

    Google Scholar 

  33. Anhalt GJ, Labib RS, Voorhees JJ, et al (1982) Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Engl J Med 306:1189–1196

    CAS  PubMed  Google Scholar 

  34. Amagai M, Hashimoto T, Shimizu N, Nishikawa T (1994) Absorption of pathogenic autoantibodies by the extracellular domain of PV antigen (Dsg3) produced by baculovirus. J Clin Invest 94:59–67

    CAS  PubMed  Google Scholar 

  35. Amagai M, Hashimoto T, Green K, Shimizu N, Nishikawa T (1995) Antigen-specific immunoadsorption of pathogenic autoantibodies in pemphigus foliaceus. J Invest Dermatol 104:895–901

    CAS  PubMed  Google Scholar 

  36. Ishii K, Amagai M, Hall RP, Hashimoto T, Takayanagi A, Gamou S, Shimizu N, Nishikawa T (1997) Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins. J Immunol 159:2010–2017

    CAS  PubMed  Google Scholar 

  37. Amagai M, Hashimoto T, Komai A, Hashimoto K, Kitajima Y, Ohya K, Iwanami H, Nishikawa T (1999) Usefulness of enzyme-linked immunosorbent assay (ELISA) using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus. Br J Dermatol 140:351–357

    Article  CAS  PubMed  Google Scholar 

  38. Ishii K, Amagai M, Komai A, Ebihara T, Chorzelski TP, Ohya K, Nishikawa T, Hashimoto T (1999) Desmoglein 1 and desmoglein 3 are the target autoantigens in herpetiform pemphigus. Arch Dermatol 135:943–947

    CAS  PubMed  Google Scholar 

  39. Komai A, Amagai M, Ishii K, Nishikawa T, Chorzelski T, Matsuo I, Hashimoto T (2001) The clinical transition between pemphigus foliaceus and pemphigus vulgaris correlates well with the changes in autoantibody profile assessed by an enzyme-linked immunosorbent assay. Br J Dermatol 144:1177–1182

    Article  CAS  PubMed  Google Scholar 

  40. Koch PJ, Mahoney MG, Ishikawa H, Pulkkinen L, Uitto J, Shultz L, Murphy GF, Whitaker-Menezes D, Stanley JR (1997) Targeted disruption of the pemphigus vulgaris antigen (desmoglein 3) gene in mice causes loss of keratinocyte cell adhesion with a phenotype similar to pemphigus vulgaris. J Cell Biol 137:1091–1102

    CAS  PubMed  Google Scholar 

  41. Singer KH, Sawka NJ, Samowitz HR, Lazarus GS (1980) Proteinase activation: a mechanism for cellular dyshesion in pemphigus. J Invest Dermatol 74:363–367

    CAS  PubMed  Google Scholar 

  42. Hashimoto K, Shafran KM, Webber PS, Lazarus GS, Singer KH (1983) Anti-cell surface pemphigus autoantibody stimulates plasminogen activator activity of human epidermal cells. J Exp Med 157:259–272

    CAS  PubMed  Google Scholar 

  43. Aoyama Y, Owada MK, Kitajima Y (1999) A pathogenic autoantibody, pemphigus IgG, induces phosphorylation of desmoglein 3, and its dissociation from plakoglobin in cultured keratinocytes. Eur J Immunol 29:2233–2240

    Article  CAS  PubMed  Google Scholar 

  44. Aoyama Y, Kitajima Y (1999) Pemphigus vulgaris-IgG causes a rapid depletion of desmoglein 3 (Dsg3) from the triton X-100 soluble pools, leading to the formation of Dsg3-depleted desmosomes in a human squamous cell carcinoma cell line, DJM-1 cells. J Invest Dermatol 112:67–71

    Article  CAS  PubMed  Google Scholar 

  45. Caldelari R, de Bruin A, Baumann D, Suter MM, Bierkamp C, Balmer V, Muller E (2001) A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris. J Cell Biol 153:823–834

    Article  CAS  PubMed  Google Scholar 

  46. Amagai M, Tsunoda K, Suzuki H, Nishifuji K, Koyasu S, Nishikawa T (2000) Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus. J Clin Invest 105:625–631

    CAS  PubMed  Google Scholar 

  47. Emmerson RW, Wilson-Jones E (1968) Eosinophilic spongiosis in pemphigus. Arch Dermatol 97:252–257

    CAS  PubMed  Google Scholar 

  48. Kubo A, Amagai M, Hashimoto T, Doi T, Higashiyama M, Hashimoto K, Yoshikawa K (1997) A case of herpetiform pemphigus showing reactivity with pemphigus vulgaris antigen (desmoglein 3). Br J Dermatol 137:109–113

    CAS  PubMed  Google Scholar 

  49. O'Toole EA, Mak LL, Guitart J, Woodley DT, Hashimoto T, Amagai M, Chan LS (2000) Induction of keratinocyte interleukin-8 expression and secretion by IgG autoantibodies as a novel mechanism of epidermal neutrophil recruitment in a pemphigus variant. Clin Exp Immunol 119:217–224

    Article  CAS  PubMed  Google Scholar 

  50. Chorzelski TP, Hashimoto T, Jablonska S, Nishikawa T, Kozlowska A, Krainska T, Osiecki M, Olszewska M, Rywik H (1995) Pemphigus vulgaris transforming into pemphigus foliaceus and their coexistence. Eur J Dermatol 5:386–390

    Google Scholar 

  51. Nishibori Y, Hashimoto T, Ishiko A, Shimizu H, Korman NJ, Nishikawa T (1995) Paraneoplastic pemphigus: the first report from Japan. Dermatology 191:39–42

    CAS  PubMed  Google Scholar 

  52. Horn TD, Anhalt GJ (1992) Histologic features of paraneoplastic pemphigus. Arch Dermatol 128:1091–1095

    CAS  PubMed  Google Scholar 

  53. Oursler JR, Labib RS, Ariss-Abdo L, Burke T, O'Keefe EJ, Anhalt GJ (1992) Human autoantibodies against desmoplakins in paraneoplastic pemphigus. J Clin Invest 89:1775–1782

    CAS  PubMed  Google Scholar 

  54. Hashimoto T, Amagai M, Watanabe K, Chorzelski PT, Bhogal BS, Black MM, Stevens HP, Boosma DM, Korman NJ, Gamou S, Shimizu N, Nishikawa T (1995) Characterization of paraneoplastic pemphigus autoantigens by immunoblot analysis. J Invest Dermatol 104:829–834

    CAS  PubMed  Google Scholar 

  55. Kiyokawa C, Ruhrberg C, Karashima T, Mori O, Nishikawa T, Green KJ, Anhalt GJ, Watt FM, Hashimoto T (1998) Envoplakin and periplakin are components of the paraneoplastic pemphigus antigen complex. J Invest Dermatol 111:1236–1238

    Article  CAS  PubMed  Google Scholar 

  56. Kim S-C, Kwon YD, Lee IJ, et al (1997) cDNA cloning of the 210 kDa paraneoplastic pemphigus antigen reveals that envoplakin is a component of the antigen complex. J Invest Dermatol 109:365–369

    CAS  PubMed  Google Scholar 

  57. Mahoney MG, Aho S, Uitto J, Stanley JR (1998) The members of the plakin family of proteins recognized by paraneoplastic pemphigus antibodies include periplakin. J Invest Dermatol 111:308–313

    Article  CAS  PubMed  Google Scholar 

  58. Nagata Y, Karashima T, Watt FM, Salmhofer W, Kanzaki T, Hashimoto T (2001) Paraneoplastic pemphigus sera react strongly with multiple epitopes on the various regions of envoplakin and periplakin, except for C-terminal homologous domain of periplakin. J Invest Dermatol 116:556–563

    Article  CAS  PubMed  Google Scholar 

  59. Chan LS, Vanderlugt CJ, Cooper KD, Hashimoto T, Nishikawa T, Zone JJ, Black MM, Stevens SR, Yancey KB, Chen M, Fairley JA, Woodley DT, Miller SD, Gordon KB (1998) Epitope spreading: lessons from autoimmune skin diseases. J Invest Dermatol 110:103–109

    Article  CAS  PubMed  Google Scholar 

  60. Hashimoto T, Amagai M, Wang N, Nishikawa N, Karashima T, Mori O, Jablonskac S, Chorzelski TP (1998) Novel non-radioisotope immunoprecipitation studies indicate involvement of pemphigus vulgaris antigen in paraneoplastic pemphigus. J Dermatol Sci 17:132–139

    Article  CAS  PubMed  Google Scholar 

  61. Amagai M, Nishikawa T, Anhalt GJ, Hashimoto T (1998) 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 102:775–782

    CAS  PubMed  Google Scholar 

  62. Nousari HC, Deterding R, Wojtczack H, Aho S, Uitto J, Hashimoto T, Anhalt GJ (1999) The mechanism of respiratory failure in paraneoplastic pemphigus. N Engl J Med 340:1406–1410

    Article  CAS  PubMed  Google Scholar 

  63. Foedinger D, Anhalt GJ, Boecskoer B, et al (1995) Autoantibodies to desmoplakin I and II in patients with erythema multiforme. J Exp Med 181:169–179

    CAS  PubMed  Google Scholar 

  64. Yasuda H, Kobayashi H, Hashimoto T, Itoh K, Yamane M, Nakamura J (2000) Subcorneal pustular dermatosis type of IgA pemphigus: demonstration of autoantibodies to desmocollin-1 and clinical review. Br J Dermatol 143:144–148

    Article  CAS  PubMed  Google Scholar 

  65. Hashimoto T, Inamoto N, Nakamura K, Nishikawa T (1987) Intercellular IgA dermatosis with clinical features of subcorneal pustular dermatosis. Arch Dermatol 123:1062–1065

    CAS  PubMed  Google Scholar 

  66. Tagami H, Iwatsuki K, Iwase Y, Yamada M (1983) Subcorneal pustular dermatosis with vesiculo-bullous eruption: demonstration of subcorneal IgA deposits and a leukocyte chemotactic factor. Br J Dermatol 109:581–587

    CAS  PubMed  Google Scholar 

  67. Huff JC, Golitz LE, Kunke KS (1985) Intraepidermal neutrophilic IgA dermatosis. N Engl J Med 313:1643

    CAS  PubMed  Google Scholar 

  68. Teraki Y, Amagai N, Hashimoto T, Kusunoki T, Nishikawa T (1991) Intercellular IgA dermatosis of childhood. selective deposition of monomer IgA1 in the intercellular space of the epidermis. Arch Dermatol 127:221–224

    CAS  PubMed  Google Scholar 

  69. Inazumi T, Kikuchi A, Han-Yaku H, Hashimoto T, Nishikawa T (1997) Intercellular IgA vesiculopustular dermatosis: an additional case and a review of the literature. Eur J Dermatol 7:503–507

    Google Scholar 

  70. Hashimoto T, Kiyokawa C, Mori O, Miyasato M, Chidgey MAJ, Garrod DR, Kobayashi Y, Komori K, Ishii K, Amagai M, Nishikawa T (1997) Human desmocollin 1 (Dsc1) is an autoantigen for subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 109:127–131

    CAS  PubMed  Google Scholar 

  71. Hashimoto T, Komai A, Futei Y, Nishikawa T, Amagai M (2001) Desmogleins are targeted by IgA autoantibodies of a few IgA pemphigus patients. Arch Dermatol 137:735–738

    CAS  PubMed  Google Scholar 

  72. Niizeki H, Inoko H, Narimatsu H, Takata H, Sonoda A, Tadakuma T, Ando A, Tsuji K, Hashimoto T, Nishikawa T (1991) HLA class II antigens are associated with Japanese pemphigus patients. Hum Immunol 31:246–250

    CAS  PubMed  Google Scholar 

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  1. Department of Dermatology, Kurume University School of Medicine, 67 Asahimachi, 830-0011, Kurume, Fukuoka, Japan

    Takashi Hashimoto

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Hashimoto, T. Recent advances in the study of the pathophysiology of pemphigus. Arch Dermatol Res 295 (Suppl 1), S2–S11 (2003). https://doi.org/10.1007/s00403-002-0366-3

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