The prototypic bullous skin diseases, pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid, are characterized by the blister formation in the skin and/or oral mucosa in combination with circulating and deposited autoantibodies reactive with (hemi)desmosomes. Koch’s postulates, adapted for autoimmune diseases, were applied on these skin diseases. It appears that all adapted Koch’s postulates are fulfilled, and, therefore, these bullous skin diseases are to be considered classical autoimmune diseases within the wide and expanding spectrum of autoimmune diseases. 1. Introduction The bullous skin diseases, including pemphigus and bullous pemphigoid, affect the skin and/or oral mucosa. Since the skin is a vital organ in the protection of the body against dehydration and infections, these skin diseases may be life threatening. The bullous skin diseases are being divided in two categories based on whether the skin is affected within the epidermis or at the epidermal-dermal interphase. The first category is referred to as pemphigus and entails 4 disease entities: pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, and IgA pemphigus. Altogether, the yearly incidence of this category is about 0.3/100,000 and the age of onset of these diseases is primarily in the fifties and sixties. The second category entails multiple disease entities. When considering dermatitis herpetiformis, a bullous skin manifestation of celiac disease, as a distinct subcategory of the pemphigoid skin diseases, the overall yearly incidence of the second category is about 1.0/100,000. These diseases typically become manifest at an age >65 years [1–3]. The diagnosis of the bullous skin diseases is based on the typical skin manifestations, which may be objectified by the Nikolsky sign and characteristic direct immunofluorescence (DIF) patterns in skin biopsies (Table 1). The presence of skin-specific autoantibodies in the circulation will further add to the diagnosis [1]. Table 1: Clinical and laboratory characteristics of bullous skin diseases. In the current paper Koch’s postulates for defining infectious diseases and adapted for autoimmune diseases are applied on both categories of bullous skin diseases [4, 5]. Since these skin diseases fulfil all criteria, they can be considered to belong to the small number of unequivocal autoimmune diseases within the ever expanding number of diseases that are supposed to be autoimmune. 2. Koch’s Postulates Adapted for Autoimmune Diseases While Koch’s postulates were originally intended to define the infectious origin of a
References
[1]
E. Schmidt and D. Zillikens, “Modern diagnosis of autoimmune blistering skin diseases,” Autoimmunity Reviews, vol. 10, no. 2, pp. 84–89, 2010.
[2]
L. Sagi, S. Baum, N. Agmon-Levin et al., “Autoimmune bullous diseases. The spectrum of infectious agent antibodies and review of the literature,” Autoimmunity Reviews, vol. 10, no. 9, pp. 527–535, 2011.
[3]
M. Sticherling and C. Erfurt-Berge, “Autoimmune blistering diseases of the skin,” Autoimmunity Reviews, vol. 11, no. 3, pp. 226–230, 2012.
[4]
N. R. Rose and C. Bona, “Defining criteria for autoimmune diseases (Witebsky's postulates revisited),” Immunology Today, vol. 14, no. 9, pp. 426–430, 1993.
[5]
J. G. M. C. Damoiseaux and J. W. Cohen Tervaert, “The definition of autoimmune disease: are Koch's postulates applicable?” Netherlands Journal of Medicine, vol. 60, no. 7, pp. 266–268, 2002.
[6]
J. Damoiseaux and J. W. Cohen Tervaert, “Tests for autoantibodies,” in Encyclopedic Reference of Immunotoxicology, H. Vohr, Ed., pp. 68–72, Spinger, Heidelberg, Germany.
[7]
E. Fuchs and S. Raghavan, “Getting under the skin of epidermal morphogenesis,” Nature Reviews Genetics, vol. 3, no. 3, pp. 199–209, 2002.
[8]
P. Martel and P. Joly, “Pemphigus: autoimmune diseases of keratinocyte's adhesion molecules,” Clinics in Dermatology, vol. 19, no. 6, pp. 662–674, 2001.
[9]
M. Amagai, A. Komai, T. Hashimoto et al., “Usefulness of enzyme-linked immunosorbent assay using recombinant desmogleins 1 and 3 for serodiagnosis of pemphigus,” British Journal of Dermatology, vol. 140, no. 2, pp. 351–357, 1999.
[10]
M. Itsukaichi, K. Takakuwa, M. Yamaguchi, et al., “Twins with neonatal pemphigus vulgaris born to a mother with pemphigus vulgaris: a case report,” Pediatric Dermatology. In press.
[11]
A. I. Lorente Lavirgen, J. Bernabeu-Wittel, J. Dominguez-Cruz, and J. Conejo-Mir, “Neonatal pemphigus foliaceus,” Journal of Pediatrics, vol. 161, no. 4, p. 768, 2012.
[12]
G. J. Anhalt, R. S. Labib, and J. J. Voorhees, “Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease,” The New England Journal of Medicine, vol. 306, no. 20, pp. 1189–1196, 1982.
[13]
I. Juhasz, G. S. Lazarus, G. F. Murphy, L. M. Shih, and M. Herlyn, “Development of pemphigus vulgaris-like lesions in severe combined immunodeficiency disease mice reconstituted with lymphocytes from patients,” Journal of Clinical Investigation, vol. 92, no. 5, pp. 2401–2407, 1993.
[14]
M. Amagai, K. Tsunoda, H. Suzuki, K. Nishifuji, S. Koyasu, and T. Nishikawa, “Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus,” Journal of Clinical Investigation, vol. 105, no. 5, pp. 625–631, 2000.
[15]
S. Johnston and C. Kennedy, “Images in clinical medicine. Pemphigus foliaceus,” The New England journal of medicine., vol. 353, no. 24, p. 2589, 2005.
[16]
Y. Aoyama, Y. Tsujimura, M. Funabashi, M. Sato, H. Kamiya, and Y. Kitajima, “An experience for ELISA for desmoglein 1, suggesting a possible diagnostic help to determine the initial therapy for pemphigus foliaceus,” European Journal of Dermatology, vol. 10, no. 1, pp. 18–21, 2000.
[17]
D. T. Woodley, C. Chang, P. Saadat, R. Ram, Z. Liu, and M. Chen, “Evidence that anti-type VII collagen antibodies are pathogenic and responsible for the clinical, histological, and immunological features of epidermolysis bullosa acquisita,” Journal of Investigative Dermatology, vol. 124, no. 5, pp. 958–964, 2005.
[18]
S. E. Kelly and F. Wojnarowska, “The use of chemically split tissue in the detection of circulating anti-basement membrane zone antibodies in bullous pemphigoid and cicatricial pemphigoid,” British Journal of Dermatology, vol. 118, no. 1, pp. 31–40, 1988.
[19]
J. Damoiseaux, M. Van Rijsingen, N. Warnemünde, et al., “Autoantibody detection in bullous pemphigoid: clinical evaluation of the EUROPLUS dermatology mosaic,” Journal of Immunological Methods, vol. 382, pp. 76–80, 2012.
[20]
J. D. Fine, “Prevalence of autoantibodies to bullous pemphigoid antigens within the normal population,” Archives of Dermatology, vol. 146, no. 1, pp. 74–75, 2010.
[21]
C. N. Wieland, N. I. Comfere, L. E. Gibson, A. L. Weaver, P. K. Krause, and J. A. Murray, “Anti-bullous pemphigoid 180 and 230 antibodies in a sample of unaffected subjects,” Archives of Dermatology, vol. 146, no. 1, pp. 21–25, 2010.
[22]
N. Al-Mutairi, A. K. Sharma, A. Zaki, E. El-Adawy, M. Al-Sheltawy, and O. Nour-Eldin, “Maternal and neonatal pemphigoid gestationis,” Clinical and Experimental Dermatology, vol. 29, no. 2, pp. 202–204, 2004.
[23]
W. Nishie, D. Sawamura, M. Goto et al., “Humanization of autoantigen,” Nature Medicine, vol. 13, no. 3, pp. 378–383, 2007.
[24]
H. Ujiie, A. Shibaki, W. Nishie et al., “A novel active mouse model for bullous pemphigoid targeting humanized pathogenic antigen,” Journal of Immunology, vol. 184, no. 4, pp. 2166–2174, 2010.
[25]
Y. Tsuji-Abe, M. Akiyama, Y. Yamanaka, T. Kikuchi, K. C. Sato-Matsumura, and H. Shimizu, “Correlation of clinical severity and ELISA indices for the NC16A domain of BP180 measured using BP180 ELISA kit in bullous pemphigoid,” Journal of Dermatological Science, vol. 37, no. 3, pp. 145–149, 2005.
