Pemphigus and bullous pemphigoid are autoantibody-mediated blistering skin diseases. In pemphigus, keratinocytes in epidermis and mucous membranes lose cell-cell adhesion, and in pemphigoid, the basal keratinocytes lose adhesion to the basement membrane. Pemphigus lesions are mediated directly by the autoantibodies, whereas the autoantibodies in pemphigoid fix complement and mediate inflammation. In both diseases, the autoantigens have been cloned and characterized; pemphigus antigens are desmogleins (cell adhesion molecules in desmosomes), and pemphigoid antigens are found in hemidesmosomes (which mediate adhesion to the basement membrane). This knowledge has enabled diagnostic testing for these diseases by enzyme-linked immunosorbent assays and dissection of various pathophysiological mechanisms, including direct inhibition of cell adhesion, antibody-induced internalization of antigen, and cell signaling. Understanding these mechanisms of disease has led to rational targeted therapeutic strategies.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Lott JP, Gross CP. 1.  2014. Mortality from nonneoplastic skin disease in the United States. J. Am. Acad. Dermatol. 70:47–54 [Google Scholar]
  2. Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJ, West J. 2.  2008. Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study. BMJ 337:a180 [Google Scholar]
  3. Pisanti S, Sharav Y, Kaufman E, Posner LN. 3.  1974. Pemphigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion. Oral Surg. Oral Med. Oral Pathol. 38:382–87 [Google Scholar]
  4. Aoki V, Millikan RC, Rivitti EA, Hans-Filho G, Eaton DP. 4.  et al. 2004. Environmental risk factors in endemic pemphigus foliaceus (fogo selvagem). J. Investig. Dermatol. Symp. Proc. 9:34–40 [Google Scholar]
  5. Qian Y, Jeong JS, Maldonado M, Valenzuela JG, Gomes R. 5.  et al. 2012. Cutting edge: Brazilian pemphigus foliaceus anti-desmoglein 1 autoantibodies cross-react with sand fly salivary LJM11 antigen. J. Immunol. 189:1535–39 [Google Scholar]
  6. Lever WF. 6.  1953. Pemphigus. Medicine (Baltimore) 32:1–123 [Google Scholar]
  7. Payne AS, Stanley JR. 7.  2012. Pemphigus. Fitzpatrick's Dermatology in General Medicine LA Goldsmith, SI Katz, BA Gilchrest, AS Paller, DJ Leffell, K Wolff 586–99 New York: McGraw Hill Medical [Google Scholar]
  8. Koulu L, Kusumi A, Steinberg MS, Klaus-Kovtun V, Stanley JR. 8.  1984. Human autoantibodies against a desmosomal core protein in pemphigus foliaceus. J. Exp. Med. 160:1509–18 [Google Scholar]
  9. Stanley JR, Koulu L, Klaus-Kovtun V, Steinberg MS. 9.  1986. A monoclonal antibody to the desmosomal glycoprotein desmoglein I binds the same polypeptide as human autoantibodies in pemphigus foliaceus. J. Immunol. 136:1227–30 [Google Scholar]
  10. Eyre RW, Stanley JR. 10.  1987. Human autoantibodies against a desmosomal protein complex with a calcium-sensitive epitope are characteristic of pemphigus foliaceus patients. J. Exp. Med. 165:1719–24 [Google Scholar]
  11. Korman NJ, Eyre RW, Klaus-Kovtun V, Stanley JR. 11.  1989. Demonstration of an adhering-junction molecule (plakoglobin) in the autoantigens of pemphigus foliaceus and pemphigus vulgaris. N. Engl. J. Med. 321:631–35 [Google Scholar]
  12. Amagai M, Klaus-Kovtun V, Stanley JR. 12.  1991. Autoantibodies against a novel epithelial cadherin in pemphigus vulgaris, a disease of cell adhesion. Cell 67:869–77 [Google Scholar]
  13. Amagai M, Karpati S, Prussick R, Klaus-Kovtun V, Stanley JR. 13.  1992. Autoantibodies against the amino-terminal cadherin-like binding domain of pemphigus vulgaris antigen are pathogenic. J. Clin. Investig. 90:919–26 [Google Scholar]
  14. Kowalczyk AP, Anderson JE, Borgwardt JE, Hashimoto T, Stanley JR, Green KJ. 14.  1995. Pemphigus sera recognize conformationally sensitive epitopes in the amino-terminal region of desmoglein-1 (Dsg1). J. Investig. Dermatol. 105:147–52 [Google Scholar]
  15. Koch PJ, Mahoney MG, Ishikawa H, Pulkkinen L, Uitto J. 15.  et al. 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. 137:1091–102 [Google Scholar]
  16. Amagai M, Matsuyoshi N, Wang ZH, Andl C, Stanley JR. 16.  2000. Toxin in bullous impetigo and staphylococcal scalded-skin syndrome targets desmoglein 1. Nat. Med. 6:1275–77 [Google Scholar]
  17. Ishii K, Amagai M, Hall RP, Hashimoto T, Takayanagi A. 17.  et al. 1997. Characterization of autoantibodies in pemphigus using antigen-specific enzyme-linked immunosorbent assays with baculovirus-expressed recombinant desmogleins. J. Immunol. 159:2010–17 [Google Scholar]
  18. Cheng SW, Kobayashi M, Kinoshita-Kuroda K, Tanikawa A, Amagai M, Nishikawa T. 18.  2002. Monitoring disease activity in pemphigus with enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3. Br. J. Dermatol. 147:261–65 [Google Scholar]
  19. Abasq C, Mouquet H, Gilbert D, Tron F, Grassi V. 19.  et al. 2009. ELISA testing of anti–desmoglein 1 and 3 antibodies in the management of pemphigus. Arch. Dermatol. 145:529–35 [Google Scholar]
  20. Mao X, Nagler AR, Farber SA, Choi EJ, Jackson LH. 20.  et al. 2010. Autoimmunity to desmocollin 3 in pemphigus vulgaris. Am. J. Pathol. 177:2724–30 [Google Scholar]
  21. Kozlowska A, Hashimoto T, Jarzabek-Chorzelska M, Amagai A, Nagata Y. 21.  et al. 2003. Pemphigus herpetiformis with IgA and IgG antibodies to desmoglein 1 and IgG antibodies to desmocollin 3. J. Am. Acad. Dermatol. 48:117–22 [Google Scholar]
  22. Rafei D, Muller R, Ishii N, Llamazares M, Hashimoto T. 22.  et al. 2011. IgG autoantibodies against desmocollin 3 in pemphigus sera induce loss of keratinocyte adhesion. Am. J. Pathol. 178:718–23 [Google Scholar]
  23. Flores G, Culton DA, Prisayanh P, Qaqish BF, James K. 23.  et al. 2012. IgG autoantibody response against keratinocyte cadherins in endemic pemphigus foliaceus (fogo selvagem). J. Investig. Dermatol. 132:2573–80 [Google Scholar]
  24. Hisamatsu Y, Amagai M, Garrod DR, Kanzaki T, Hashimoto T. 24.  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 [Google Scholar]
  25. Evangelista F, Dasher DA, Diaz LA, Prisayanh PS, Li N. 25.  2008. E-cadherin is an additional immunological target for pemphigus autoantibodies. J. Investig. Dermatol. 128:1710–18 [Google Scholar]
  26. Anhalt GJ, Labib RS, Voorhees JJ, Beals TF, Diaz LA. 26.  1982. Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N. Engl. J. Med. 306:1189–96 [Google Scholar]
  27. Roscoe JT, Diaz L, Sampaio SA, Castro RM, Labib RS. 27.  et al. 1985. Brazilian pemphigus foliaceus autoantibodies are pathogenic to BALB/c mice by passive transfer. J. Investig. Dermatol. 85:538–41 [Google Scholar]
  28. Rock B, Martins CR, Theofilopoulos AN, Balderas RS. 28.  et al. 1989. The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem). N. Engl. J. Med. 320:1463–69 [Google Scholar]
  29. Ding X, Aoki V, Mascaro JM Jr, Lopez-Swiderski A, Diaz LA, Fairley JA. 29.  1997. Mucosal and mucocutaneous (generalized) pemphigus vulgaris show distinct autoantibody profiles. J. Investig. Dermatol. 109:592–96 [Google Scholar]
  30. Funakoshi T, Lunardon L, Ellebrecht CT, Nagler AR, O'Leary CE, Payne AS. 30.  2012. Enrichment of total serum IgG4 in patients with pemphigus. Br. J. Dermatol. 167:1245–53 [Google Scholar]
  31. Rock B, Labib RS, Diaz LA. 31.  1990. Monovalent Fab′ immunoglobulin fragments from endemic pemphigus foliaceus autoantibodies reproduce the human disease in neonatal BALB/c mice. J. Clin. Investig. 85:296–99 [Google Scholar]
  32. Ishii K, Lin C, Siegel DL, Stanley JR. 32.  2008. Isolation of pathogenic monoclonal anti-desmoglein 1 human antibodies by phage display of pemphigus foliaceus autoantibodies. J. Investig. Dermatol. 128:939–48 [Google Scholar]
  33. Payne AS, Ishii K, Kacir S, Lin C, Li H. 33.  et al. 2005. Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display. J. Clin. Investig. 115:888–99 [Google Scholar]
  34. Yamagami J, Payne AS, Kacir S, Ishii K, Siegel DL, Stanley JR. 34.  2010. Homologous regions of autoantibody heavy chain complementarity-determining region 3 (H-CDR3) in patients with pemphigus cause pathogenicity. J. Clin. Investig. 120:4111–17 [Google Scholar]
  35. Kardos M, Levine D, Gurcan HM, Ahmed RA. 35.  2009. Pemphigus vulgaris in pregnancy: analysis of current data on the management and outcomes. Obstet. Gynecol. Surv. 64:739–49 [Google Scholar]
  36. Avalos-Diaz E, Olague-Marchan M, Lopez-Swiderski A, Herrera-Esparza R, Diaz LA. 36.  2000. Transplacental passage of maternal pemphigus foliaceus autoantibodies induces neonatal pemphigus. J. Am. Acad. Dermatol. 43:1130–34 [Google Scholar]
  37. Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T. 37.  1999. The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J. Am. Acad. Dermatol. 40:167–70 [Google Scholar]
  38. Amagai M, Koch PJ, Nishikawa T, Stanley JR. 38.  1996. Pemphigus vulgaris antigen (desmoglein 3) is localized in the lower epidermis, the site of blister formation in patients. J. Investig. Dermatol. 106:351–55 [Google Scholar]
  39. Shirakata Y, Amagai M, Hanakawa Y, Nishikawa T, Hashimoto K. 39.  1998. Lack of mucosal involvement in pemphigus foliaceus may be due to low expression of desmoglein 1. J. Investig. Dermatol. 110:76–78 [Google Scholar]
  40. Mahoney MG, Wang Z, Rothenberger K, Koch PJ, Amagai M, Stanley JR. 40.  1999. Explanation for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J. Clin. Investig. 103:461–68 [Google Scholar]
  41. Wu H, Wang ZH, Yan A, Lyle S, Fakharzadeh S. 41.  et al. 2000. Protection of neonates against pemphigus foliaceus by desmoglein 3. N. Engl. J. Med. 343:31–35 [Google Scholar]
  42. Hanakawa Y, Matsuyoshi N, Stanley JR. 42.  2002. Expression of desmoglein 1 compensates for genetic loss of desmoglein 3 in keratinocyte adhesion. J. Investig. Dermatol. 119:27–31 [Google Scholar]
  43. Heupel WM, Zillikens D, Drenckhahn D, Waschke J. 43.  2008. Pemphigus vulgaris IgG directly inhibit desmoglein 3-mediated transinteraction. J. Immunol. 181:1825–34 [Google Scholar]
  44. Saito M, Stahley SN, Caughman CY, Mao X, Tucker DK. 44.  et al. 2012. Signaling dependent and independent mechanisms in pemphigus vulgaris blister formation. PLOS ONE 7:e50696 [Google Scholar]
  45. Sekiguchi M, Futei Y, Fujii Y, Iwasaki T, Nishikawa T, Amagai M. 45.  2001. Dominant autoimmune epitopes recognized by pemphigus antibodies map to the N-terminal adhesive region of desmogleins. J. Immunol. 167:5439–48 [Google Scholar]
  46. Yokouchi M, Saleh MA, Kuroda K, Hachiya T, Stanley JR. 46.  et al. 2009. Pathogenic epitopes of autoantibodies in pemphigus reside in the amino-terminal adhesive region of desmogleins which are unmasked by proteolytic processing of prosequence. J. Investig. Dermatol. 129:2156–66 [Google Scholar]
  47. Ozawa M, Kemler R. 47.  1990. Correct proteolytic cleavage is required for the cell adhesive function of uvomorulin. J. Cell Biol. 111:1645–50 [Google Scholar]
  48. Di Zenzo G, Di Lullo G, Corti D, Calabresi V, Sinistro A. 48.  et al. 2012. Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface. J. Clin. Investig. 122:3781–90 [Google Scholar]
  49. Kamiya K, Aoyama Y, Shirafuji Y, Hamada T, Morizane S. 49.  et al. 2013. A higher correlation of the antibody activities against the calcium-dependent epitopes of desmoglein 3 quantified by ethylenediamine-tetraacetic acid-treated enzyme-linked immunosorbent assay with clinical disease activities of pemphigus vulgaris. J. Dermatol. Sci. 70:190–95 [Google Scholar]
  50. Oktarina DA, van der Wier G, Diercks GF, Jonkman MF, Pas HH. 50.  2011. IgG-induced clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with the desmoglein nonassembly depletion hypothesis. Br. J. Dermatol. 165:552–62 [Google Scholar]
  51. van der Wier G, Pas HH, Kramer D, Diercks GF, Jonkman MF. 51.  2014. Smaller desmosomes are seen in the skin of pemphigus patients with anti-desmoglein 1 antibodies but not in patients with anti-desmoglein 3 antibodies. J. Investig. Dermatol. 134:2287–90 [Google Scholar]
  52. Aoyama Y, Kitajima Y. 52.  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. Investig. Dermatol. 112:67–71 [Google Scholar]
  53. Jennings JM, Tucker DK, Kottke MD, Saito M, Delva E. 53.  et al. 2011. Desmosome disassembly in response to pemphigus vulgaris IgG occurs in distinct phases and can be reversed by expression of exogenous Dsg3. J. Investig. Dermatol. 131:706–18 [Google Scholar]
  54. Stahley SN, Saito M, Faundez V, Koval M, Mattheyses AL, Kowalczyk AP. 54.  2014. Desmosome assembly and disassembly are membrane raft-dependent. PLOS ONE 9:e87809 [Google Scholar]
  55. Mao X, Choi EJ, Payne AS. 55.  2009. Disruption of desmosome assembly by monovalent human pemphigus vulgaris monoclonal antibodies. J. Investig. Dermatol. 129:908–18 [Google Scholar]
  56. Caldelari R, de Bruin A, Baumann D, Suter MM, Bierkamp C. 56.  et al. 2001. A central role for the armadillo protein plakoglobin in the autoimmune disease pemphigus vulgaris. J. Cell Biol. 153:823–34 [Google Scholar]
  57. Williamson L, Raess NA, Caldelari R, Zakher A, de Bruin A. 57.  et al. 2006. Pemphigus vulgaris identifies plakoglobin as key suppressor of c-Myc in the skin. EMBO J. 25:3298–309 [Google Scholar]
  58. Williamson L, Hunziker T, Suter MM, Muller EJ. 58.  2007. Nuclear c-Myc: a molecular marker for early stage pemphigus vulgaris. J. Investig. Dermatol. 127:1549–55 [Google Scholar]
  59. Berkowitz P, Hu P, Liu Z, Diaz LA, Enghild JJ. 59.  et al. 2005. Desmosome signaling. Inhibition of p38MAPK prevents pemphigus vulgaris IgG-induced cytoskeleton reorganization. J. Biol. Chem. 280:23778–84 [Google Scholar]
  60. Rubenstein DS, Diaz LA. 60.  2006. Pemphigus antibody induced phosphorylation of keratinocyte proteins. Autoimmunity 39:577–86 [Google Scholar]
  61. Jolly PS, Berkowitz P, Bektas M, Lee HE, Chua M. 61.  et al. 2010. p38MAPK signaling and desmoglein-3 internalization are linked events in pemphigus acantholysis. J. Biol. Chem. 285:8936–41 [Google Scholar]
  62. Mao X, Li H, Sano Y, Gaestel M, Park JM, Payne AS. 62.  2014. MAPKAP kinase 2 (MK2)-dependent and -independent models of blister formation in pemphigus vulgaris. J. Investig. Dermatol. 134:68–76 [Google Scholar]
  63. Berkowitz P, Hu P, Warren S, Liu Z, Diaz LA, Rubenstein DS. 63.  2006. p38MAPK inhibition prevents disease in pemphigus vulgaris mice. PNAS 103:12855–60 [Google Scholar]
  64. Berkowitz P, Chua M, Liu Z, Diaz LA, Rubenstein DS. 64.  2008. Autoantibodies in the autoimmune disease pemphigus foliaceus induce blistering via p38 mitogen-activated protein kinase-dependent signaling in the skin. Am. J. Pathol. 173:1628–36 [Google Scholar]
  65. Berkowitz P, Diaz LA, Hall RP, Rubenstein DS. 65.  2008. Induction of p38MAPK and HSP27 phosphorylation in pemphigus patient skin. J. Investig. Dermatol. 128:738–40 [Google Scholar]
  66. Bektas M, Jolly PS, Berkowitz P, Amagai M, Rubenstein DS. 66.  2013. A pathophysiologic role for epidermal growth factor receptor in pemphigus acantholysis. J. Biol. Chem. 288:9447–56 [Google Scholar]
  67. Mao X, Sano Y, Park JM, Payne AS. 67.  2011. p38 MAPK activation is downstream of the loss of intercellular adhesion in pemphigus vulgaris. J. Biol. Chem. 286:1283–91 [Google Scholar]
  68. Ahmed AR, Yunis EJ, Khatri K, Wagner R, Notani G. 68.  et al. 1990. Major histocompatibility complex haplotype studies in Ashkenazi Jewish patients with pemphigus vulgaris. PNAS 87:7658–62 [Google Scholar]
  69. Ahmed AR, Wagner R, Khatri K, Notani G, Awdeh Z. 69.  et al. 1991. Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris. PNAS 88:5056–60 [Google Scholar]
  70. Sinha AA, Brautbar C, Szafer F, Friedmann A, Tzfoni E. 70.  et al. 1988. A newly characterized HLA DQ beta allele associated with pemphigus vulgaris. Science 239:1026–29 [Google Scholar]
  71. Yan L, Wang JM, Zeng K. 71.  2012. Association between HLA-DRB1 polymorphisms and pemphigus vulgaris: a meta-analysis. Br. J. Dermatol. 167:768–77 [Google Scholar]
  72. Lin MS, Swartz SJ, Lopez A, Ding X, Fernandez-Vina MA. 72.  et al. 1997. Development and characterization of desmoglein-3 specific T cells from patients with pemphigus vulgaris. J. Clin. Investig. 99:31–40 [Google Scholar]
  73. Veldman C, Stauber A, Wassmuth R, Uter W, Schuler G, Hertl M. 73.  2004. 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. 170:635–42 [Google Scholar]
  74. Veldman CM, Gebhard KL, Uter W, Wassmuth R, Grotzinger J. 74.  et al. 2004. T cell recognition of desmoglein 3 peptides in patients with pemphigus vulgaris and healthy individuals. J. Immunol. 172:3883–92 [Google Scholar]
  75. Eming R, Hennerici T, Backlund J, Feliciani C, Visconti KC. 75.  et al. 2014. Pathogenic IgG antibodies against desmoglein 3 in pemphigus vulgaris are regulated by HLA-DRB1*04:02-restricted T cells. J. Immunol. 193:4391–99 [Google Scholar]
  76. Veldman C, Höhne A, Dieckmann D, Schuler G, Hertl M. 76.  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. 172:6468–75 [Google Scholar]
  77. Yokoyama T, Matsuda S, Takae Y, Wada N, Nishikawa T. 77.  et al. 2011. Antigen-independent development of Foxp3+ regulatory T cells suppressing autoantibody production in experimental pemphigus vulgaris. Int. Immunol. 23:365–73 [Google Scholar]
  78. Wada N, Nishifuji K, Yamada T, Kudoh J, Shimizu N. 78.  et al. 2011. Aire-dependent thymic expression of desmoglein 3, the autoantigen in pemphigus vulgaris, and its role in T-cell tolerance. J. Investig. Dermatol. 131:410–17 [Google Scholar]
  79. Mouquet H, Berrih-Aknin S, Bismuth J, Joly P, Gilbert D, Tron F. 79.  2008. Expression of pemphigus-autoantigen desmoglein 1 in human thymus. Tissue Antigens 71:464–70 [Google Scholar]
  80. Yamagami J, Kacir S, Ishii K, Payne AS, Siegel DL, Stanley JR. 80.  2009. Antibodies to the desmoglein 1 precursor proprotein but not to the mature cell surface protein cloned from individuals without pemphigus. J. Immunol. 183:5615–21 [Google Scholar]
  81. Cho MJ, Lo AS, Mao X, Nagler AR, Ellebrecht CT. 81.  et al. 2014. Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients. Nat. Commun. 5:4167 [Google Scholar]
  82. Hammers CM, Chen J, Lin C, Kacir S, Siegel DL. 82.  et al. 2015. Persistence of anti-desmoglein 3 IgG(+) B-cell clones in pemphigus patients over years. J. Investig. Dermatol. 135:742–49 [Google Scholar]
  83. Qian Y, Diaz LA, Ye J, Clarke SH. 83.  2007. Dissecting the anti-desmoglein autoreactive B cell repertoire in pemphigus vulgaris patients. J. Immunol. 178:5982–90 [Google Scholar]
  84. Qian Y, Clarke SH, Aoki V, Hans-Filhio G, Rivitti EA, Diaz LA. 84.  2009. Antigen selection of anti-DSG1 autoantibodies during and before the onset of endemic pemphigus foliaceus. J. Investig. Dermatol. 129:2823–34 [Google Scholar]
  85. Colliou N, Picard D, Caillot F, Calbo S, Le Corre S. 85.  et al. 2013. Long-term remissions of severe pemphigus after rituximab therapy are associated with prolonged failure of desmoglein B cell response. Sci. Transl. Med. 5:175ra30 [Google Scholar]
  86. Mouquet H, Musette P, Gougeon ML, Jacquot S, Lemercier B. 86.  et al. 2008. B-cell depletion immunotherapy in pemphigus: effects on cellular and humoral immune responses. J. Investig. Dermatol. 128:2859–69 [Google Scholar]
  87. Nguyen VT, Arredondo J, Chernyavsky AI, Kitajima Y, Pittelkow M, Grando SA. 87.  2004. Pemphigus vulgaris IgG and methylprednisolone exhibit reciprocal effects on keratinocytes. J. Biol. Chem. 279:2135–46 [Google Scholar]
  88. Hammers CM, Lunardon L, Schmidt E, Zillikens D. 88.  2013. Contemporary management of pemphigus. Expert Opin. Orphan Drugs 1:295–314 [Google Scholar]
  89. Almugairen N, Hospital V, Bedane C, Duvert-Lehembre S, Picard D. 89.  et al. 2013. Assessment of the rate of long-term complete remission off therapy in patients with pemphigus treated with different regimens including medium- and high-dose corticosteroids. J. Am. Acad. Dermatol. 69:583–88 [Google Scholar]
  90. Turner MS, Sutton D, Sauder DN. 90.  2000. The use of plasmapheresis and immunosuppression in the treatment of pemphigus vulgaris. J. Am. Acad. Dermatol. 43:1058–64 [Google Scholar]
  91. Kasperkiewicz M, Shimanovich I, Meier M, Schumacher N, Westermann L. 91.  et al. 2012. Treatment of severe pemphigus with a combination of immunoadsorption, rituximab, pulsed dexamethasone and azathioprine/mycophenolate mofetil: a pilot study of 23 patients. Br. J. Dermatol. 166:154–60 [Google Scholar]
  92. Czernik A, Beutner EH, Bystryn JC. 92.  2008. Intravenous immunoglobulin selectively decreases circulating autoantibodies in pemphigus. J. Am. Acad. Dermatol. 58:796–801 [Google Scholar]
  93. Amagai M, Ikeda S, Shimizu H, Iizuka H, Hanada K. 93.  et al. 2009. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J. Am. Acad. Dermatol. 60:595–603 [Google Scholar]
  94. Ahmed AR, Sami N. 94.  2002. Intravenous immunoglobulin therapy for patients with pemphigus foliaceus unresponsive to conventional therapy. J. Am. Acad. Dermatol. 46:42–49 [Google Scholar]
  95. Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. 95.  2006. Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N. Engl. J. Med. 355:1772–79 [Google Scholar]
  96. Joly P, Mouquet H, Roujeau JC, D'Incan M, Gilbert D. 96.  et al. 2007. A single cycle of rituximab for the treatment of severe pemphigus. N. Engl. J. Med. 357:545–52 [Google Scholar]
  97. Heelan K, Al-Mohammedi F, Smith MJ, Knowles S, Lansang P. 97.  et al. 2014. Durable remission of pemphigus with a fixed-dose rituximab protocol. JAMA Dermatol. 150:703–8 [Google Scholar]
  98. Lunardon L, Tsai KJ, Propert KJ, Fett N, Stanley JR. 98.  et al. 2012. Adjuvant rituximab therapy of pemphigus: a single-center experience with 31 patients. Arch. Dermatol. 148:1031–36 [Google Scholar]
  99. Eming R, Nagel A, Wolff-Franke S, Podstawa E, Debus D, Hertl M. 99.  2008. Rituximab exerts a dual effect in pemphigus vulgaris. J. Investig. Dermatol. 128:2850–58 [Google Scholar]
  100. Spindler V, Rotzer V, Dehner C, Kempf B, Gliem M. 100.  et al. 2013. Peptide-mediated desmoglein 3 crosslinking prevents pemphigus vulgaris autoantibody-induced skin blistering. J. Clin. Investig. 123:800–11 [Google Scholar]
  101. Tucker DK, Stahley SN, Kowalczyk AP. 101.  2014. Plakophilin-1 protects keratinocytes from pemphigus vulgaris IgG by forming calcium-independent desmosomes. J. Investig. Dermatol. 134:1033–43 [Google Scholar]
  102. Dehner C, Rotzer V, Waschke J, Spindler V. 102.  2014. A desmoplakin point mutation with enhanced keratin association ameliorates pemphigus vulgaris autoantibody-mediated loss of cell cohesion. Am. J. Pathol. 184:2528–36 [Google Scholar]
  103. Schmidt E, Zillikens D. 103.  2013. Pemphigoid diseases. Lancet 381:320–32 [Google Scholar]
  104. Pfaltz K, Mertz K, Rose C, Scheidegger P, Pfaltz M, Kempf W. 104.  2010. C3d immunohistochemistry on formalin-fixed tissue is a valuable tool in the diagnosis of bullous pemphigoid of the skin. J. Cutan. Pathol. 37:654–58 [Google Scholar]
  105. Kwon EJ, Ntiamoah P, Shulman KJ. 105.  2013. The utility of C4d immunohistochemistry on formalin-fixed paraffin-embedded tissue in the distinction of polymorphic eruption of pregnancy from pemphigoid gestationis. Am. J. Dermatopathol. 35:787–91 [Google Scholar]
  106. Mutasim DF, Morrison LH, Takahashi Y, Labib RS, Skouge J. 106.  et al. 1989. Definition of bullous pemphigoid antibody binding to intracellular and extracellular antigen associated with hemidesmosomes. J. Investig. Dermatol. 92:225–30 [Google Scholar]
  107. Shimizu H, McDonald JN, Kennedy AR, Eady RAJ. 107.  1989. Demonstration of intra- and extracellular localization of bullous pemphigoid antigen using cryofixation and freeze substitution for postembedding immunoelectron microscopy. Arch. Dermatol. Res. 281:443–48 [Google Scholar]
  108. Stanley JR, Hawley-Nelson P, Yuspa SH, Shevach EM, Katz SI. 108.  1981. Characterization of bullous pemphigoid antigen: a unique basement membrane protein of stratified squamous epithelia. Cell 24:897–903 [Google Scholar]
  109. Stanley JR, Tanaka T, Mueller S, Klaus-Kovtun V, Roop D. 109.  1988. Isolation of cDNA for bullous pemphigoid antigen by use of patients' autoantibodies. J. Clin. Investig. 82:1864–70 [Google Scholar]
  110. Tanaka T, Parry DAD, Klaus-Kovtun V, Steinert PM, Stanley JR. 110.  1991. Comparison of molecularly cloned bullous pemphigoid antigen to desmoplakin I confirms that they define a new family of cell adhesion junction plaque proteins. J. Biol. Chem. 266:12555–59 [Google Scholar]
  111. Green KJ, Virata MLA, Elgart GW, Stanley JR, Parry DAD. 111.  1992. Comparative structural analysis of desmoplakin, bullous pemphigoid antigen and plectin: members of a new gene family involved in organization of intermediate filments. Int. J. Biol. Macrobiol. 14:145–53 [Google Scholar]
  112. Bouameur JE, Favre B, Borradori L. 112.  2014. Plakins, a versatile family of cytolinkers: roles in skin integrity and in human diseases. J. Investig. Dermatol. 134:885–94 [Google Scholar]
  113. Tanaka T, Korman NJ, Shimizu H, Eady RAJ, Klaus-Kovtun V. 113.  et al. 1990. Production of rabbit antibodies against carboxy-terminal epitopes encoded by bullous pemphigoid cDNA. J. Investig. Dermatol. 94:617–23 [Google Scholar]
  114. Yang Y, Dowling J, Yu QC, Kouklis P, Cleveland DW, Fuchs E. 114.  1996. An essential cytoskeletal linker protein connecting actin microfilaments to intermediate filaments. Cell 86:655–65 [Google Scholar]
  115. Taghipour K, Chi CC, Vincent A, Groves RW, Venning V, Wojnarowska F. 115.  2010. The association of bullous pemphigoid with cerebrovascular disease and dementia: a case-control study. Arch. Dermatol. 146:1251–54 [Google Scholar]
  116. Langan SM, Groves RW, West J. 116.  2011. The relationship between neurological disease and bullous pemphigoid: a population-based case-control study. J. Investig. Dermatol. 131:631–36 [Google Scholar]
  117. Diaz L, Ratrie H, Saunders WS, Futamura S, Squiquera HL. 117.  et al. 1990. Isolation of a human epidermal cDNA corresponding to the 180-kD autoantigen recognized by bullous pemphigoid and herpes gestationis sera. J. Clin. Investig. 86:1088–94 [Google Scholar]
  118. Giudice GJ, Emery DJ, Diaz LA. 118.  1992. Cloning and primary structural analysis of the bullous pemphigoid autoantigen BP180. J. Investig. Dermatol. 99:243–50 [Google Scholar]
  119. Zillikens D, Rose PA, Balding SD, Liu Z, Olague-Marchan M. 119.  et al. 1997. Tight clustering of extracellular BP180 epitopes recognized by bullous pemphigoid autoantibodies. J. Investig. Dermatol. 109:573–79 [Google Scholar]
  120. Schmidt E, Obe K, Brocker EB, Zillikens D. 120.  2000. Serum levels of autoantibodies to BP180 correlate with disease activity in patients with bullous pemphigoid. Arch. Dermatol. 136:174–78 [Google Scholar]
  121. Roussel A, Benichou J, Randriamanantany ZA, Gilbert D, Drenovska K. 121.  et al. 2011. Enzyme-linked immunosorbent assay for the combination of bullous pemphigoid antigens 1 and 2 in the diagnosis of bullous pemphigoid. Arch. Dermatol. 147:293–98 [Google Scholar]
  122. Thoma-Uszynski S, Uter W, Schwietzke S, Hofmann SC, Hunziker T. 122.  et al. 2004. BP230- and BP180-specific auto-antibodies in bullous pemphigoid. J. Investig. Dermatol. 122:1413–22 [Google Scholar]
  123. Sakuma-Oyama Y, Powell AM, Oyama N, Albert S, Bhogal BS, Black MM. 123.  2004. Evaluation of a BP180-NC16a enzyme-linked immunosorbent assay in the initial diagnosis of bullous pemphigoid. Br. J. Dermatol. 151:126–31 [Google Scholar]
  124. Nelson KC, Zhao M, Schroeder PR, Li N, Wetsel RA. 124.  et al. 2006. Role of different pathways of the complement cascade in experimental bullous pemphigoid. J. Clin. Investig. 116:2892–900 [Google Scholar]
  125. Heimbach L, Li Z, Berkowitz P, Zhao M, Li N. 125.  et al. 2011. The C5A receptor on mast cells is critical for the autoimmune skin-blistering disease bullous pemphigoid. J. Biol. Chem. 286:15003–9 [Google Scholar]
  126. Zhao M, Trimbeger ME, Li N, Diaz LA, Shapiro SD, Liu Z. 126.  2006. Role of FcRs in animal model of autoimmune bullous pemphigoid. J. Immunol. 177:3398–405 [Google Scholar]
  127. Olasz EB, Roh J, Yee CL, Arita K, Akiyama M. 127.  et al. 2007. Human bullous pemphigoid antigen 2 transgenic skin elicits specific IgG in wild-type mice. J. Investig. Dermatol. 127:2807–17 [Google Scholar]
  128. Nishie W, Sawamura D, Natsuga K, Shinkuma S, Goto M. 128.  et al. 2009. A novel humanized neonatal autoimmune blistering skin disease model induced by maternally transferred antibodies. J. Immunol. 183:4088–93 [Google Scholar]
  129. Wang G, Ujiie H, Shibaki A, Nishie W, Tateishi Y. 129.  et al. 2010. Blockade of autoantibody-initiated tissue damage by using recombinant fab antibody fragments against pathogenic autoantigen. Am. J. Pathol. 176:914–25 [Google Scholar]
  130. Lin L, Betsuyaku T, Heimbach L, Li N, Rubenstein D. 130.  et al. 2012. Neutrophil elastase cleaves the murine hemidesmosomal protein BP180/type XVII collagen and generates degradation products that modulate experimental bullous pemphigoid. Matrix Biol. 31:38–44 [Google Scholar]
  131. Iwata H, Kamio N, Aoyama Y, Yamamoto Y, Hirako Y. 131.  et al. 2009. IgG from patients with bullous pemphigoid depletes cultured keratinocytes of the 180-kDa bullous pemphigoid antigen (type XVII collagen) and weakens cell attachment. J. Investig. Dermatol. 129:919–26 [Google Scholar]
  132. Messingham KN, Srikantha R, DeGueme AM, Fairley JA. 132.  2011. FcR-independent effects of IgE and IgG autoantibodies in bullous pemphigoid. J. Immunol. 187:553–60 [Google Scholar]
  133. Hiroyasu S, Ozawa T, Kobayashi H, Ishii M, Aoyama Y. 133.  et al. 2013. Bullous pemphigoid IgG induces BP180 internalization via a macropinocytic pathway. Am. J. Pathol. 182:828–40 [Google Scholar]
  134. Nishie W. 134.  2014. Update on the pathogenesis of bullous pemphigoid: an autoantibody-mediated blistering disease targeting collagen XVII. J. Dermatol. Sci. 73:179–86 [Google Scholar]
  135. Ujiie H, Sasaoka T, Izumi K, Nishie W, Shinkuma S. 135.  et al. 2014. Bullous pemphigoid autoantibodies directly induce blister formation without complement activation. J. Immunol. 193:4415–28 [Google Scholar]
  136. Li Q, Ujiie H, Shibaki A, Wang G, Moriuchi R. 136.  et al. 2010. Human IgG1 monoclonal antibody against human collagen 17 noncollagenous 16A domain induces blisters via complement activation in experimental bullous pemphigoid model. J. Immunol. 185:7746–55 [Google Scholar]
  137. Natsuga K, Nishie W, Shinkuma S, Ujiie H, Nishimura M. 137.  et al. 2012. Antibodies to pathogenic epitopes on type XVII collagen cause skin fragility in a complement-dependent and -independent manner. J. Immunol. 188:5792–99 [Google Scholar]
  138. Bushkell LL, Jordon RE. 138.  1983. Bullous pemphigoid: a cause of peripheral blood eosinophilia. J. Am. Acad. Dermatol. 8:648–51 [Google Scholar]
  139. Arbesman CE, Wypych JI, Reisman RE, Beutner EH. 139.  1974. IgE levels in sera of patients with pemphigus or bullous pemphigoid. Arch. Dermatol. 110:378–81 [Google Scholar]
  140. Fairley JA, Fu CL, Giudice GJ. 140.  2005. Mapping the binding sites of anti-BP180 immunoglobulin E autoantibodies in bullous pemphigoid. J. Investig. Dermatol. 125:467–72 [Google Scholar]
  141. Dimson OG, Giudice GJ, Fu CL, Van den Bergh F, Warren SJ. 141.  et al. 2003. Identification of a potential effector function for IgE autoantibodies in the organ-specific autoimmune disease bullous pemphigoid. J. Investig. Dermatol. 120:784–88 [Google Scholar]
  142. Delaporte E, Dubost-Brama A, Ghohestani R, Nicolas JF, Neyrinck JL. 142.  et al. 1996. IgE autoantibodies directed against the major bullous pemphigoid antigen in patients with a severe form of pemphigoid. J. Immunol. 157:3642–47 [Google Scholar]
  143. Borrego L, Maynard B, Peterson EA, George T, Iglesias L. 143.  et al. 1996. Deposition of eosinophil granule proteins precedes blister formation in bullous pemphigoid. Comparison with neutrophil and mast cell granule proteins. Am. J. Pathol. 148:897–909 [Google Scholar]
  144. Dvorak AM, Mihm MC Jr, Osage JE, Kwan TH, Austen KF, Wintroub BU. 144.  1982. Bullous pemphigoid, an ultrastructural study of the inflammatory response: eosinophil, basophil and mast cell granule changes in multiple biopsies from one patient. J. Investig. Dermatol. 78:91–101 [Google Scholar]
  145. Messingham KN, Holahan HM, Frydman AS, Fullenkamp C, Srikantha R, Fairley JA. 145.  2014. Human eosinophils express the high affinity IgE receptor, FcεRI, in bullous pemphigoid. PLOS ONE 9:e107725 [Google Scholar]
  146. Fairley JA, Burnett CT, Fu CL, Larson DL, Fleming MG, Giudice GJ. 146.  2007. 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. Investig. Dermatol. 127:2605–11 [Google Scholar]
  147. Zone JJ, Taylor T, Hull C, Schmidt L, Meyer L. 147.  2007. IgE basement membrane zone antibodies induce eosinophil infiltration and histological blisters in engrafted human skin on SCID mice. J. Investig. Dermatol. 127:1167–74 [Google Scholar]
  148. Hall RP III, Streilein RD, Hannah DL, McNair PD, Fairley JA. 148.  et al. 2013. Association of serum B-cell activating factor level and proportion of memory and transitional B cells with clinical response after rituximab treatment of bullous pemphigoid patients. J. Investig. Dermatol. 133:2786–88 [Google Scholar]
  149. Yu KK, Crew AB, Messingham KA, Fairley JA, Woodley DT. 149.  2014. Omalizumab therapy for bullous pemphigoid. J. Am. Acad. Dermatol. 71:468–74 [Google Scholar]
  150. Ricklin D, Lambris JD. 150.  2007. Complement-targeted therapeutics. Nat. Biotechnol. 25:1265–75 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error