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A Perspective of Pemphigus from Bedside and Laboratory-Bench

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Abstract

Pemphigus represents a distinct organ-specific acquired autoimmune disease characterized by intra-epidermal blistering, which is induced by autoantibodies against desmosomal cadherins, desmoglein 1 (Dsg1), and Dsg3. Pemphigus is currently divided into three distinct varieties, i.e., pemphigus vulgaris (PV), pemphigus foliaceus (PF) and other variants of pemphigus (mostly associated with inflammation), depending on clinical features, the level of separation in the epidermis, and immunologic characteristics of auto-antigens. Blistering pathomechanisms differ for each of the types of pemphigus. Pemphigus, which results from autoantibodies against desmogleins and possibly to other proteins, binds to the cell surface antigens. This binding may cause steric hindrance to homophilic adhesion of desmogleins, and may, in turn, lead to internalization of desmogleins and inhibition of desmogleins’ integration into desmosomes, resulting in the formation of Dsg3-depleted desmosomes in PV or Dsg1-depleted desmosomes in PF. Furthermore, PV-IgG activates an “outside-in” signaling pathway to induce disassembly of desmosomal components from the inside of the cells by phosphorylation of proteins, including Dsg3. On the other hand, Pemphigus-IgG-augmented signaling pathways may be linked to the secretion of cytokines such as in case of pemphigus herpetiformis and chemokines that initiate or activate inflammation. In this article, the classification of pemphigus and the characteristic pathomechanisms for acantholysis will be reviewed, with particular emphasis on the molecular and biochemical cell biology of these diseases.

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References

  1. MacGrath JA (2005) Inherited disorders of desmosomes. Aust J Dermatol 46:221–229

    Article  Google Scholar 

  2. Kitajima Y (2002) Mechanisms of desmosome assembly and disassembly. Clin Exp Dermatol 27:684–690

    Article  PubMed  CAS  Google Scholar 

  3. Stanley JR (1992) Cell adhesion molecules as targets of autoantibodies in pemphigus and pemphigoid, bullous diseases due to defective epidermal cell adhesion. Advances in immunology. Adv Immunol 53:291–325

    Google Scholar 

  4. Amagai M (1999) Autoimmunity against desmosomal cadherins in pemphigus. J Dermatol Sci 20:92–102

    Article  PubMed  CAS  Google Scholar 

  5. Kitajima Y (2003) Current and prospective understanding of clinical classification, pathomechanisms and therapy in pemphigus. Arch Dermatol Res 295:S17–S23

    PubMed  Google Scholar 

  6. Stanley JR (2003) Pemphigus. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz S (eds) Dermatology in general medicine. McGraw-Hill, New York, NY, pp 558–567

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Amagai M (1996) Pemphigus: autoimmunity to epidermal cell adhesion molecules. Adv Dermatol 11:319–352

    PubMed  CAS  Google Scholar 

  9. 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

    PubMed  CAS  Google Scholar 

  10. Amagai M, Matsuyoshi N, Wang ZH, Andl C, Stanley JR (2000) Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1. Nat Med 6:1275–1277

    Article  PubMed  CAS  Google Scholar 

  11. Amagai M, Ishii K, Hashimoto T, Gamou S, Shimizu N, Nisshikawa T (1995) Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent. J Invest Dermatol 105:243–247

    Article  PubMed  CAS  Google Scholar 

  12. Anhalt GJ, Jim SS, Stanley C Jr, Korman Nj, Jabs DA, Kory M, Izumi H, Ratrie H 3rd, Ariss-Abdo L (1990) Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Engl J Med 323:1729–1735

    Article  PubMed  CAS  Google Scholar 

  13. Wade MS, Black MM (2005) Paraneoplastic pemphigus: a brief update. Aust J Dermatol 46:1–10

    Article  Google Scholar 

  14. Jablonska S, Chorzelski TP, Beutner EH, Jarzabek-Chorzelsska M (1975) Immunologic phenomena in herpes gestations. Their pathogenic and diagnostic significance. J Dermatol 14:353–359

    CAS  Google Scholar 

  15. Ishii K, Amagai M, Kaomai A, Ebihara T, Chorzelki TP, Jabronska S (1999) Desmoglein 1 and desmoglein 3 are the target autoantigens in herpetiform pemphigus. Arch Dermatol 135:943–947

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  17. Hashimoto T, Kiyokawa C, Mori O, Miyasato M, Chidgey MA, Garrod DR (1997) Human desmocollin 1 (Dsc1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 109:127–131

    Article  PubMed  CAS  Google Scholar 

  18. Morizane S, Yamamoto T, Hisamatsu Y, Tsuji K, Oono T, Hashimoto T, Iwatsuki K (2005) Pemphigus vegetans with IgG and IgA antidesmoglein 3 antibodies. Br J Dermatol 153:1236–1237

    Article  PubMed  CAS  Google Scholar 

  19. Hisamatsu Y, Amagai M, Garrod DR, Kanzaki T, Hashimoto T (2004) 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 151:73–83

    Article  PubMed  CAS  Google Scholar 

  20. Ahmed AR, Blose DA (1984) Pemphigus vegetans. Neumann type and Hallopeau type. Int J Dermatol 23:135–141

    PubMed  CAS  Google Scholar 

  21. Tsunoda K, Oita T, Aoki M, Yamada T, Nagai T, Nakagawa T, Koyasu S, Nishikawa T, Amagai M (2003) Induction of pemphigus phenotype by a mouse monoclonal antibody against the amino-terminal adhesive interface of desmoglein 3. J Immunol 170:2170–2178

    PubMed  CAS  Google Scholar 

  22. Kricheli D, David M -Zlotkin M, Goldsmith D, Rabinov M, Sulkes J, Milner Y (2000) The distribution of pemphigus vulgaris-IgG subclasses and their reactivity with desmoglein 3 and 1 in pemphigus patients and their first-degree relatives. Br J Dermatol 143:237–238

    Article  Google Scholar 

  23. Nguyen VT, Arredondo J, Chernyavssky AI, Kitajima Y, Pittelkow M, Grando SA (2004) Pemphigus vulgaris antibody identifies pemphaxin. A novel keratinocyte annexin-like molecule binding acetylcholine. J Biol Chem 279:2135–2146

    Article  PubMed  CAS  Google Scholar 

  24. Nguyen VT, Arredondo J, Chernyavssky AI, Pittelkow M, Kitajima Y, Grando SA (2004) The pathophysiological significance of nondesmoglein targets of pemphigus autoimmunity. Development of antibodies against keratinocyte cholinergic receptors in patients with pemphigus vulgaris and pemphigus foliaceus. Arch Dermatol 140:327–334

    Article  PubMed  CAS  Google Scholar 

  25. Nguyen VT, Ndoye A, Shultz LD, Pittelkow MR, Grando S (2000) Antibodies against keratinocyte antigens other than desmogleins 1 and 3 can induce pemphigus vulgaris-like lesions. J Clin Invest 106:1467–1479

    Article  PubMed  CAS  Google Scholar 

  26. Nguyen VT, Ndoye A, Grando SA (2000) Pemphigus vulgaris antibody identifies pemphaxin. A novel keratinocyte annexin-like molecule binding acetylcholine. J Biol Chem 275:29466–29476

    Article  PubMed  CAS  Google Scholar 

  27. Grando SA (2000) Autoimmunity to keratinocyte acethylcholin receptors in pemphigus. Dermatology 201:290–295

    Article  PubMed  CAS  Google Scholar 

  28. Grando SA (2006) Cholinergic control of epidermal cohesion. Exp Dermatol 15:265–287

    Article  PubMed  CAS  Google Scholar 

  29. Payne AS, Ishii K, Kacir S, Lin C, Li H, Hanakawa Y, Tsunoda K, Amagai M, Stanley JR, Siegel DL (2005) Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display. J Clin Invest 115:889–899

    Article  CAS  Google Scholar 

  30. Kitajima Y, Aoyama Y, Seishima M (1999) Transmembrane signaling for adhesive regulation of desmosomes and hemidesmosomes, and for cell–cell detachment induced by pemphigus IgG in cultured keratinocytes: involvement of protein kinase C. J Invest Dermatol Symp Proc 4:137–144

    Article  CAS  Google Scholar 

  31. 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 137:1091–1110

    Article  PubMed  CAS  Google Scholar 

  32. Pulkkinen L, Choi YW, Simpson A, Montagutelli X, Sundberg J, Uitto J, Mahoney MG(2002) Loss of cell adhesion in Dsg3bal-Pas mice with homozygous deletion mutation (2079del14) in the desmoglein 3 gene. J Invest Dermatol 119:1237

    Article  PubMed  CAS  Google Scholar 

  33. Stanley JR (2000) The pathophysiology of pemphigus. J Dermatol Sci 24:155–157

    Article  PubMed  CAS  Google Scholar 

  34. Kitajima Y, Inoue I, Yaoita H (1987) Effects of pemphigus antibody on the regeneration of cell–cell contact in keratinocyte cultures grown in low to normal Ca2+ concentration. J Invest Dermatol 89:167–171

    Article  PubMed  CAS  Google Scholar 

  35. Kitajima Y, Tsujimura Y, Sato M, Yamaguchi F, Aoyama Y (2001) Evidence that pemphigus vulgaris IgG causes no steric hindrance in desmosome formation, but forms desmoglein 3-deficiebt desmosomes. J Invest Dermatol 117:406 (abstract)

    Google Scholar 

  36. 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  PubMed  CAS  Google Scholar 

  37. 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 carcinoma cell line, DJM-1 cells. J Invest Dermatol 112:67–71

    Article  PubMed  CAS  Google Scholar 

  38. Kawasaki Y, Aoyama Y, Tsunoda K, Amagai M, Kitajima Y (2006) Pathogenic monoclonal antibody against desmoglein 3 augments desmoglein 3 and p38 MAPK Phosphorylation in human squamous carcinoma cell line. Autoimmunity 39:587–590

    Article  PubMed  CAS  Google Scholar 

  39. Berkowitz P, Hu P, Liu Z, Diaz LA, Enghild JJ, Chua MP, Rubinstggein DS (2005) Desmosome signaling. Inhibition of p38MAPK prevents pemphigus vulgaris IgG-induced cytoskeleton reorganization. J Biol Chem 280(23):23778–23784

    Article  PubMed  CAS  Google Scholar 

  40. Aoyama Y, Kanno M, Nagai M, Yamamoto Y, Ozawa M, Kitajima Y (2006) The cytoplasmic membrane-proximal region of desmoglein 3 is critical for p120ctn binding to desmoglein 3. J Invest Dermatol 126:32 (abstract)

    Article  Google Scholar 

  41. Kawasaki Y, Aoyama Y, Tsunoda K, Amagai M, Kitajima Y (2006) Different anti-desmoglein 3 monoclonal antibodies exert epitope-specific regulation of p120 catenin phosphorylation and of p120 catenin binding to desmoglein 3 in human squamous cell carcinoma cell line, DJM-1 cells. J Invest Dermatol 126:6 (abstract)

    Article  CAS  Google Scholar 

  42. Caldelari R, de Bruin A, Boumann 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  PubMed  CAS  Google Scholar 

  43. Puviani M, Marconi A, Cozzani E, Pincelli C (2003) Fas ligand in pemphigus sera induces keratinocyte apoptosis through the activation of caspase-8. J Invest Dermatol 120:164–167

    Article  PubMed  CAS  Google Scholar 

  44. Wang X, Brégégère F, Soroka Y, Frusic-Zlotkin M, Milner Y (2004) Replicative senescence enhances apoptosis induced by pemphigus autoimmune antibodies in human keratinocytes. FEBS Lett 567:281–286

    Article  PubMed  CAS  Google Scholar 

  45. Arredondo J, Chernyavsky AI, Karaouni A, Grando SA (2005) Novel mechanisms of target cell death and survival and of therapeutic action of IVIg in pemphigus. Am J Pathol 167:1531–1544

    PubMed  CAS  Google Scholar 

  46. Willamson L, Raess N, Caldelari R, Zakher A, de Bruin A, Posthaus H, Bolli R, Hunziker T, Suter MM, Muller EJ (2006) Pemphigus vulgaris identifies plakoglobin as key suppressor of c-Myc in the skin. EMBO J 25:3298–3309

    Article  CAS  Google Scholar 

  47. Hashimoto K, Shafran KM, Webber PA, Lazarus GS, Singer KH (1983) Anti-cell surface pemphigus antibody stimulates plasminogen activator activity of human epidermal cells. A mechanism for the loss of epidermal cohesion and blister formation. J Exp Med 157:259–272

    Article  PubMed  CAS  Google Scholar 

  48. Esaki C, Seishima M, Yamada T, Osada K, Kitajima Y (1995) Pharmacologic evidence for involvement of phospholipase C in pemphigus IgG-induced inositol 1,4,5-trisphosphate generation, intracellular calcium increase, and plasminogen activator secretion in DJM-1 cells, a squamous cell carcinoma line. J Invest Dermatol 105:329–333

    Article  PubMed  CAS  Google Scholar 

  49. Hashimoto K, Wun T-C, Baird J, Lazarus GS, Jensen PJ (1989) Characterization of keratinocyte plasminogen activator inhibitors and demonstration of the prevention of pemphigus IgG-induced acantholysis by a purified plasminogen activator inhibitor. J Invest Dermatol 92:310–315

    Article  PubMed  CAS  Google Scholar 

  50. Mahoney MG, Wang ZH, Stanley JR (1999) Pemphigus vulgaris and pemphigus foliaceus antibodies are pathogenic in plasminogen activator knockout mice. J Invest Dermatol 113:22–25

    Article  PubMed  CAS  Google Scholar 

  51. Sato M, Aoyama Y, Kitajima Y (2000) Assembly pathway pf desmoglein 3 to desmosomes and its perturbation by pemphigus vulgaris-IgG in cultured keratinocytes, as revealed by time-lapsed labeling immunoelectron microscopy. Lab Invest 80:1583–1592

    PubMed  CAS  Google Scholar 

  52. Shu E, Yamamoto Y, Sato-Nagai M, Aoyama Y, Kitajima Y (2005) Pemphigus vulgaris-IgG reduces the desmoglein 3/desmocollin 3 ratio on the cell surface in cultured keratinocytes as revealed by double-staining immunoelectron microscopy. J Dermatol Sci 40:209–211

    Article  PubMed  CAS  Google Scholar 

  53. Calkins C, Setzer SV, Jennings JM, Summers S, Tsunoda K, Amagai M, Kowalczyk AP (2006) Desmoglein endocytosis and desmosome disassembly are coordinated responses to pemphigus autoantibodies. J Biol Chem 281:7623–7634

    Article  PubMed  CAS  Google Scholar 

  54. Cirillo N, Femiano F, Gombos F, Lanza A (2006) Serum from pemphigus vulgaris reduces desmoglein 3 half-life and perturbs its de novo assembly to desmosomal sites in cultured keratinocytes. FEBS Lett 580:3276–3281

    Article  PubMed  CAS  Google Scholar 

  55. Yamamoto Y, Aoyama Y, Shu E, Tsunoda K, Amagai K, Kitajima Y (2007) Anti-desmoglein 3 (Dsg3) monoclonal antibodies deplete desmosomes of Dsg3 and differ in their Dsg3-depleting activities related to pathogenicity. J Biol Chem 282:17866–17876

    Article  PubMed  CAS  Google Scholar 

  56. Shu E, Yamamoto Y, Aoyama Y, Kitajima Y (2007) Intraperitoneal injection of pemphigus vulgaris-IgG into mouse depletes epidermal keratinocytes of desmoglein 3 associated with generation of acantholysis. Arch Dermatol Res 299:165–167

    Article  PubMed  CAS  Google Scholar 

  57. 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  PubMed  CAS  Google Scholar 

  58. Nishifuji K, Anagai M, Kuwana T, Iwassaki T, Nishikawa T (2000) Detection of antigen-specific B cells in patients with pemphigus vulgaris by enzyme-linked immunospot assay: requirement of T cell collaboration for autoantibody production. J Invest Dermatol 114:88–94

    Article  PubMed  CAS  Google Scholar 

  59. Veldman CA, Stauber R, Wasssmuth W, Ulter W, Schuler G, Hertl M (2003) Dichotomy of autoreactive Th1 and Th2 cell responses to desmoglein 3 in patients with pemphigus vulgaris (PV) and healthy carriers of PV-associated HLA class II alleles. J Immunol 170:635–642

    PubMed  CAS  Google Scholar 

  60. Veldman CA, Gebhard K, Ulter W, Wasssmuth W, Goetzinger J, Hertl (2003) T cell recognition of desmoglein 3 peptides in patients with pemphigus vulgaris and healthy individuals. J Immunol 172:3883–3892

    Google Scholar 

  61. Veldman CA, Hohne D, Dieckman G, Schuler G, Hertl (2004) Type I regulatory T cells specific for desmoglein 3 are more frequently detected in healthy individuals than in patients with pemphigus vulgaris. J Immunol 172:6468–6475

    PubMed  CAS  Google Scholar 

  62. Veldman C, Pahl A, Beissert S, Hansen W, Buer J, Dieckmann D, Schuler G, Hertl M (2006) Inhibition of the transcription factor Foxp3 converts desmoglein 3-specific type 1 regulatory T cells into Th2-like cells. J Immunol 176:3215–3222

    PubMed  CAS  Google Scholar 

  63. Hertl M, Eming R, Veldman C (2006) T cell control in autoimmune bullous skin disorders. J Clin Invest 116:1159–1166 (review)

    Article  PubMed  CAS  Google Scholar 

  64. Amagai M, Ahmed RA, Kitajima Y, Brystryn JC, Milner Y, Gniadecki R, Hertle M, Pincelli C, Fridkis-Hareli M, Aoyama Y, Frsic-Zoltkin M, Muller E, David M, Mimouni D, Vind-Kezunovic D, Michel B, Mahoney M, Grando S (2006) Are desmoglein autoantibodies essential for the immunopathogenesis of pemphigus vulgaris, or just ‘witnesses of disease’? Exp Dermatol 15:815–831

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Dr. Walter M Holleran (University of California, San Francisco, San Francisco, CA) for his review of this manuscript. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan; the Health and Labor Sciences Research Grants for Research on Measures for Intractable Disease; the Ministry of Health, Labor and Welfare of Japan.

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  1. Department of Dermatology, Gifu University School of Medicine, 1-1 Yanagido, Gifu City, 501-1194, Japan

    Yasuo Kitajima & Yumi Aoyama

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  1. Yasuo Kitajima
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Correspondence to Yasuo Kitajima.

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Kitajima, Y., Aoyama, Y. A Perspective of Pemphigus from Bedside and Laboratory-Bench. Clinic Rev Allerg Immunol 33, 57–66 (2007). https://doi.org/10.1007/s12016-007-0036-5

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