Abstract
The current knowledge on Pemphigus vulgaris (PV) pathophysiology suggests that blister formation relies on both PV IgG and non-IgG serum factors activity. PV autoimmunity seems to develop against both desmoglein 1/3 and acetylcholine receptors leading to transduction of signals to the cell mediated by phosphorilation events. Serum factors other than IgG also participate to PV acantholysis through apoptotic or cytokine-mediated mechanisms. Apart from the role played by each actor within the acantholysis, however, the current scenario arises important methodological issues. For example, the use of PV IgG or monoclonal anti-Dsg3 antibodies to experimentally reproduce the disease appears inadequate, as it does not take into account the role of non-IgG factors. On the basis of the above observations and those from our laboratories, here we propose that using whole sera from PV patients with active disease represents the most faithful manner to mimic the disease.
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Ahmed AR, Wagner R, Khatri K, Notani G, Awdeh Z, Alper CA, Yunis EJ (1991) Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with Pemphigus vulgaris. Proc Natl Acad Sci USA 88:5056–5060
Amagai M, Ahmed AR, Kitajima Y, Bystryn JC, Milner Y, Gniadecki R, Aoyama Y, Frusˇic´-Zlotkin 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
Anhalt GJ, Labib RS, Voorhees JJ, Beals TF, Diaz LA (1982) Induction of pemphigus in neonatal mice by passive transfer of IgG from patients with the disease. N Engl J Med 306:1189–1196
Anhalt GJ, Till GO, Diaz LA, Labib RS, Patel HP, Eaglstein NF (1986) Defining the role of complement in experimental Pemphigus vulgaris in mice. J Immunol 137:2835–2840
Bhol KC, Rojas AI, Khan IU, Ahmed AR (2000) Presence of interleukin 10 in the serum and blister fluid of patients with Pemphigus vulgaris and pemphigoid. Cytokine 12:1076–1083
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
Cirillo N, Gombos F, Lanza A (2006) Changes in desmoglein 1 expression and subcellular localization in cultured keratinocytes subjected to anti-desmoglein 1 pemphigus autoimmunity. J Cell Physiol 210:411–416
Cirillo N, Femiano F, Gombos F, Lanza A (2007) Metalloproteinase 9 is the outer executioner of desmoglein 3 in apoptotic keratinocytes. Oral Dis doi:10.1111/j.1601–0825.2006.01287.x
Cirillo N, Lanza A, Gombos F, Rossiello L, Lanza M (2007) Defining the involvement of proteinases in Pemphigus vulgaris: evidence of matrix metalloproteinase 9 overexpression in experimental models of disease. J Cell Physiol (in press)
Ding X, Diaz LA, Fairley JA, Giudice GJ, Liu Z (1999) The anti-desmoglein 1 autoantibodies in Pemphigus vulgaris sera are pathogenic. J Invest Dermatol 112:739–743
Dmochowski M, Hashimoto T, Garrod DR, Nishikawa T (1993) Desmocollins I and II are recognized by certain sera from patients with various types of Pemphigus particularly Brazilian Pemphigus foliaceus. J Invest Dermatol 100:380–384
Fan JL, Memar O, McCormick DJ, Prabhakar BS (1999) BALB/c mice produce blister-causing antibodies upon immunization with a recombinant human desmoglein 3. J Immunol 163:6228–6235
Farb RM, Dykes R, Lazarus GS (1978) Anti-epidermal-cell-surface Pemphigus antibody detaches viable epidermal cells from culture plates by activation of proteinase. Proc Natl Acad Sci USA 75:459–463
Feliciani C, Toto P, Amerio P, Mohammad PS, Concione G, Shivji G, Wang B, Sauder DN (2000) In vitro and in vivo expression of interleukin-1α and tumor necrosis factor-α mRNA in Pemphigus vulgaris: interleukin-1α and tumor necrosis factor-α are involved in acantholysis. J Invest Dermatol 114:71–77
Harman KE, Seed PT, Gratian MJ, Bhogal BS, Challacombe SJ, Black MM (2001) The severity of cutaneous and oral Pemphigus is related to desmoglein 1 and 3 antibody levels. Br J Dermatol 144:775–780
Korman NJ, Eyre RW, Klaus-Kovtun V, Stanley JR (1989) Demonstration of an adhering-junction molecule (plakoglobin) in the autoantigens of Pemphigus foliaceus and Pemphigus vulgaris. N Engl J Med 321:631–635
Kricheli D, David M, Frusic-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 143:337–342
Lanza A, Cirillo N, Femiano F, Gombos F (2006) How does acantholysis occur in Pemphigus vulgaris: a critical review. J Cutan Pathol 33:401–412
Lanza A, Femiano F, De Rosa A, Cammarota M, Lanza M, Cirillo N (2006) The N-terminal fraction of desmoglein 3 encompassing its immunodominant domain is present in human serum: implications for Pemphigus vulgaris autoimmunity. Int J Immunopathol Pharmacol 19:399–407
Lopez-Robles E, Avalos-Diaz E, Vega-Memije E, Hojyo-Tomoka T, Villalobos R, Fraire S, Domiguez-Soto L, Herrera-Esparza R (2001) TNF-α and IL-6 are mediators in the blistering process of Pemphigus. Int J Dermatol 40:185–188
Mimouni D, Foedinger D, Kouba DJ, Orlow SJ, Rappersberger K, Sciubba JJ, Nikolskaia OV, Cohen BA, Anhalt GJ, Nousari CH (2004) Mucosal dominant Pemphigus vulgaris with anti-desmoplakin autoantibodies. J Am Acad Dermatol 51:62–67
Nguyen VT, Ndoye A, Grando SA (2000) Novel human α9 acetylcholine receptor regulating keratinocyte adhesion is targeted by Pemphigus vulgaris autoimmunity. Am J Pathol 157:1377–1391
Nguyen VA, Ndoye A, Grando SA (2000) Pemphigus vulgaris antibody identifies pemphaxin, a novel keratinocyte annexin-like molecule binding acetylcholine. J Biol Chem 275:29466–29476
Nguyen VT, Ndoye A, Shultz LD, Pittelkow MR, Grando SA (2000) Antibodies against keratinocyte antigens other than desmogleins 1 and 3 can induce Pemphigus vulgaris-like lesions. J Clin Invest 106:1467–1479
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
Sekiguchi M, Futei Y, Fujii Y, Iwasaki T, Nishikawa T, Amagai M (2001) Dominant autoimmune epitopes recognized by Pemphigus antibodies map to the N-terminal adhesive region of desmogleins. J Immunol 167:5439–5448
Tsunoda K, Ota 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
Ueki H, Kohda M, Nobutoh T, Yamaguchi M, Omori K, Miyashita Y, Hashimoto T, Komai A, Tomokuni A, Ueki A (2001) Antidesmoglein autoantibodies in silicosis patients with no bullous diseases. Dermatology 202:16–21
Veldman CM, Gebhard KL, Uter W, Wassmuth R, Grotzinger J, Schultz E, Hertl M (2004) T cell recognition of desmoglein 3 peptides in patients with Pemphigus vulgaris and healthy individuals. J Immunol 172:3883–3892
Yeh SW, Cavacini LA, Bhol KC, Lin MS, Kumar M, Duval M, Posner MR, Ahmed AR (2006) Pathogenic human monoclonal antibody against desmoglein 3. Clin Immunol 120:68–75
Wang X, Bregegere F, Frusic-Zlotkin M, Feinmesser M, Michel B, Milner Y (2004) Possible apoptotic mechanism in epidermal cell acantholysis induced by Pemphigus vulgaris autoimmunoglobulins. Apoptosis 9:131–143
Williamson L, Raess NA, 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
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Cirillo, N., Gombos, F., Ruocco, V. et al. Searching for experimental models of Pemphigus vulgaris . Arch Dermatol Res 299, 9–12 (2007). https://doi.org/10.1007/s00403-007-0733-1
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DOI: https://doi.org/10.1007/s00403-007-0733-1