Abstract
Pemphigus is a group of autoimmune bullous diseases of the skin and mucous membranes, which are characterized by IgG autoantibodies against desmogelin 3 (Dsg3) and/or Dsg1. Recent molecular biology techniques such as the phage display system allowed us to isolate monoclonal antibodies from peripheral blood of patients with pemphigus and to characterize their pathogenic activities and their epitopes on desmogleins. Through these studies, hot epitopes as well as a characteristic consensus sequence of CDR3 regions of pathogenic antibodies were identified. Concurrently, an active disease mouse model of pemphigus was developed by adoptive transfer of peripheral lymphocytes from Dsg3−/− mice. Dsg3-specific CD4+ T cells were isolated from pemphigus model mice and, subsequently, Dsg3-specific T cell receptor (TCR) transgenic mice were generated. These studies have revealed that Dsg3-specific CD4+ T cells were able to induce, not only antibody production with B cells and acantholysis, but also interface dermatitis. These studies have provided better understanding of pathophysiological mechanisms for pemphigus as well as deep insights for T-cell–mediated inflammatory skin diseases.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsReferences
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(4):888–899
Ishii K, Lin C, Siegel DL, Stanley JR (2008) Isolation of pathogenic monoclonal anti-desmoglein 1 human antibodies by phage display of pemphigus foliaceus autoantibodies. J Invest Dermatol 128(4):939–948. doi:10.1038/sj.jid.5701132
Rock B, Labib RS, Diaz LA (1990) Monovalent Fab’ immunoglobulin fragments from endemic pemphigus foliaceus autoantibodies reproduce the human disease in neonatal Balb/c mice. J Clin Invest 85(1):296–299. doi:10.1172/JCI114426
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(4):2170–2178
Di Zenzo G, Di Lullo G, Corti D, Calabresi V, Sinistro A, Vanzetta F, Didona B, Cianchini G, Hertl M, Eming R, Amagai M, Ohyama B, Hashimoto T, Sloostra J, Sallusto F, Zambruno G, Lanzavecchia A (2012) Pemphigus autoantibodies generated through somatic mutations target the desmoglein-3 cis-interface. J Clin Invest 122(10):3781–3790. doi:10.1172/JCI64413
Boggon TJ, Murray J, Chappuis-Flament S, Wong E, Gumbiner BM, Shapiro L (2002) C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science 296(5571):1308–1313. doi:10.1126/science.1071559
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(9):5439–5448
Yamagami J, Kacir S, Ishii K, Payne AS, Siegel DL, Stanley JR (2009) Antibodies to the desmoglein 1 precursor proprotein but not to the mature cell surface protein cloned from individuals without pemphigus. J Immunol 183(9):5615–5621. doi:10.4049/jimmunol.0901691
Yamagami J, Payne AS, Kacir S, Ishii K, Siegel DL, Stanley JR (2010) Homologous regions of autoantibody heavy chain complementarity-determining region 3 (H-CDR3) in patients with pemphigus cause pathogenicity. J Clin Invest 120(11):4111–4117. doi:10.1172/JCI44425
Sinha AA, Brautbar C, Szafer F, Friedmann A, Tzfoni E, Todd JA, Steinman L, McDevitt HO (1988) A newly characterized HLA DQ beta allele associated with pemphigus vulgaris. Science 239(4843):1026–1029
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 U S A 88(11):5056–5060
Ahmed AR, Mohimen A, Yunis EJ, Mirza NM, Kumar V, Beutner EH, Alper CA (1993) Linkage of pemphigus vulgaris antibody to the major histocompatibility complex in healthy relatives of patients. J Exp Med 177(2):419–424
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(4):246–250
Niizeki H, Inoko H, Mizuki N, Inamoto N, Watababe K, Hashimoto T, Nishikawa T (1994) HLA-DQA1, -DQB1 and -DRB1 genotyping in Japanese pemphigus vulgaris patients by the PCR-RFLP method. Tissue Antigens 44(4):248–251
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(5):625–631
Tsunoda K, Ota T, Suzuki H, Ohyama M, Nagai T, Nishikawa T, Amagai M, Koyasu S (2002) Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental pemphigus vulgaris. Eur J Immunol 32(3):627–633
Takahashi H, Amagai M, Nishikawa T, Fujii Y, Kawakami Y, Kuwana M (2008) Novel system evaluating in vivo pathogenicity of desmoglein 3-reactive T cell clones using murine pemphigus vulgaris. J Immunol 181(2):1526–1535
Veldman C, Stauber A, Wassmuth R, Uter 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(1):635–642
Takahashi H, Kouno M, Nagao K, Wada N, Hata T, Nishimoto S, Iwakura Y, Yoshimura A, Yamada T, Kuwana M, Fujii H, Koyasu S, Amagai M (2011) Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice. J Clin Invest 121(9):3677–3688. doi:10.1172/JCI57379, 57379 [pii]
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Japan
About this chapter
Cite this chapter
Yamagami, J., Takahashi, H., Amagai, M. (2016). Pemphigus. In: Kabashima, K. (eds) Immunology of the Skin. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55855-2_25
Download citation
DOI: https://doi.org/10.1007/978-4-431-55855-2_25
Published:
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-55853-8
Online ISBN: 978-4-431-55855-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)