Transgenic rescue of desmoglein 3 null mice with desmoglein 1 to develop a syngeneic mouse model for pemphigus vulgaris

Tsuyoshi Hata, Koji Nishifuji, Kouji Shimoda, Takashi Sasaki, Taketo Yamada, Takeji Nishikawa, Shigeo Koyasu, Masayuki Amagai

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background: An active disease mouse model of pemphigus vulgaris (PV) was developed using the adoptive transfer of splenocytes from Dsg3-/- mice with a mixed C57BL/6J (B6) and 129/Sv genetic background into B6-Rag2-/- mice. Further immunological investigation is needed to resolve the genetic mismatch between host and recipient mice. The B6-Dsg3-/- mice did not grow old enough to provide splenocytes, probably due to severe oral erosions, with resulting inhibition of food intake. Objective: To rescue the B6-Dsg3-/- mice and to produce syngeneic PV model mice. Methods: Transgenic expression of mouse Dsg1 was attempted to compensate for the genetic loss of Dsg3 using the keratin 5 promoter. We evaluated the compensatory ability of Dsg1 in vivo by comparing Dsg1wt/wt, Dsg1tg/wt, and Dsg1tg/tg mice. We generated a PV model via the adoptive transfer of B6-Dsg1tg/tgDsg3-/- splenocytes to B6-Rag2-/- mice. Results: Dsg1tg/tg and Dsg1tg/wt mice expressed ectopic Dsg1 on keratinocyte cell surfaces in the lower layers of the epidermis, oral epithelium, and telogen hair follicles. Ectopic Dsg1 blocked the pathogenic effects of AK23 anti-Dsg3 mAb, and improved the body weight loss, telogen hair loss, and survival rate dose-dependently. While the B6-Dsg1wt/wtDsg3-/- mice died by week 2, over 80% of the B6-Dsg1tg/tgDsg3-/- mice survived at week 6. Furthermore, the syngeneic PV model mice showed the characteristic phenotype, including stable anti-Dsg3 antibody production and suprabasilar acantholysis on histology. Conclusion: Transgenic expression of Dsg1 rescued the severe B6-Dsg3-/- phenotype and provided a syngeneic mouse model of PV, which may be a valuable tool for clarifying immunological mechanisms in autoimmunity and tolerance of Dsg3.

Original languageEnglish
Pages (from-to)33-39
Number of pages7
JournalJournal of Dermatological Science
Volume63
Issue number1
DOIs
Publication statusPublished - 2011 Jul

Fingerprint

Desmoglein 3
Desmoglein 1
Pemphigus
Keratin-5
Histology
Erosion
Adoptive Transfer
Antibodies
Acantholysis
Phenotype
Hair Follicle
Alopecia

Keywords

  • Autoantibody
  • Autoimmunity
  • Cadherin
  • Mouse model

ASJC Scopus subject areas

  • Dermatology
  • Biochemistry
  • Molecular Biology

Cite this

Transgenic rescue of desmoglein 3 null mice with desmoglein 1 to develop a syngeneic mouse model for pemphigus vulgaris. / Hata, Tsuyoshi; Nishifuji, Koji; Shimoda, Kouji; Sasaki, Takashi; Yamada, Taketo; Nishikawa, Takeji; Koyasu, Shigeo; Amagai, Masayuki.

In: Journal of Dermatological Science, Vol. 63, No. 1, 07.2011, p. 33-39.

Research output: Contribution to journalArticle

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abstract = "Background: An active disease mouse model of pemphigus vulgaris (PV) was developed using the adoptive transfer of splenocytes from Dsg3-/- mice with a mixed C57BL/6J (B6) and 129/Sv genetic background into B6-Rag2-/- mice. Further immunological investigation is needed to resolve the genetic mismatch between host and recipient mice. The B6-Dsg3-/- mice did not grow old enough to provide splenocytes, probably due to severe oral erosions, with resulting inhibition of food intake. Objective: To rescue the B6-Dsg3-/- mice and to produce syngeneic PV model mice. Methods: Transgenic expression of mouse Dsg1 was attempted to compensate for the genetic loss of Dsg3 using the keratin 5 promoter. We evaluated the compensatory ability of Dsg1 in vivo by comparing Dsg1wt/wt, Dsg1tg/wt, and Dsg1tg/tg mice. We generated a PV model via the adoptive transfer of B6-Dsg1tg/tgDsg3-/- splenocytes to B6-Rag2-/- mice. Results: Dsg1tg/tg and Dsg1tg/wt mice expressed ectopic Dsg1 on keratinocyte cell surfaces in the lower layers of the epidermis, oral epithelium, and telogen hair follicles. Ectopic Dsg1 blocked the pathogenic effects of AK23 anti-Dsg3 mAb, and improved the body weight loss, telogen hair loss, and survival rate dose-dependently. While the B6-Dsg1wt/wtDsg3-/- mice died by week 2, over 80{\%} of the B6-Dsg1tg/tgDsg3-/- mice survived at week 6. Furthermore, the syngeneic PV model mice showed the characteristic phenotype, including stable anti-Dsg3 antibody production and suprabasilar acantholysis on histology. Conclusion: Transgenic expression of Dsg1 rescued the severe B6-Dsg3-/- phenotype and provided a syngeneic mouse model of PV, which may be a valuable tool for clarifying immunological mechanisms in autoimmunity and tolerance of Dsg3.",
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AU - Shimoda, Kouji

AU - Sasaki, Takashi

AU - Yamada, Taketo

AU - Nishikawa, Takeji

AU - Koyasu, Shigeo

AU - Amagai, Masayuki

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N2 - Background: An active disease mouse model of pemphigus vulgaris (PV) was developed using the adoptive transfer of splenocytes from Dsg3-/- mice with a mixed C57BL/6J (B6) and 129/Sv genetic background into B6-Rag2-/- mice. Further immunological investigation is needed to resolve the genetic mismatch between host and recipient mice. The B6-Dsg3-/- mice did not grow old enough to provide splenocytes, probably due to severe oral erosions, with resulting inhibition of food intake. Objective: To rescue the B6-Dsg3-/- mice and to produce syngeneic PV model mice. Methods: Transgenic expression of mouse Dsg1 was attempted to compensate for the genetic loss of Dsg3 using the keratin 5 promoter. We evaluated the compensatory ability of Dsg1 in vivo by comparing Dsg1wt/wt, Dsg1tg/wt, and Dsg1tg/tg mice. We generated a PV model via the adoptive transfer of B6-Dsg1tg/tgDsg3-/- splenocytes to B6-Rag2-/- mice. Results: Dsg1tg/tg and Dsg1tg/wt mice expressed ectopic Dsg1 on keratinocyte cell surfaces in the lower layers of the epidermis, oral epithelium, and telogen hair follicles. Ectopic Dsg1 blocked the pathogenic effects of AK23 anti-Dsg3 mAb, and improved the body weight loss, telogen hair loss, and survival rate dose-dependently. While the B6-Dsg1wt/wtDsg3-/- mice died by week 2, over 80% of the B6-Dsg1tg/tgDsg3-/- mice survived at week 6. Furthermore, the syngeneic PV model mice showed the characteristic phenotype, including stable anti-Dsg3 antibody production and suprabasilar acantholysis on histology. Conclusion: Transgenic expression of Dsg1 rescued the severe B6-Dsg3-/- phenotype and provided a syngeneic mouse model of PV, which may be a valuable tool for clarifying immunological mechanisms in autoimmunity and tolerance of Dsg3.

AB - Background: An active disease mouse model of pemphigus vulgaris (PV) was developed using the adoptive transfer of splenocytes from Dsg3-/- mice with a mixed C57BL/6J (B6) and 129/Sv genetic background into B6-Rag2-/- mice. Further immunological investigation is needed to resolve the genetic mismatch between host and recipient mice. The B6-Dsg3-/- mice did not grow old enough to provide splenocytes, probably due to severe oral erosions, with resulting inhibition of food intake. Objective: To rescue the B6-Dsg3-/- mice and to produce syngeneic PV model mice. Methods: Transgenic expression of mouse Dsg1 was attempted to compensate for the genetic loss of Dsg3 using the keratin 5 promoter. We evaluated the compensatory ability of Dsg1 in vivo by comparing Dsg1wt/wt, Dsg1tg/wt, and Dsg1tg/tg mice. We generated a PV model via the adoptive transfer of B6-Dsg1tg/tgDsg3-/- splenocytes to B6-Rag2-/- mice. Results: Dsg1tg/tg and Dsg1tg/wt mice expressed ectopic Dsg1 on keratinocyte cell surfaces in the lower layers of the epidermis, oral epithelium, and telogen hair follicles. Ectopic Dsg1 blocked the pathogenic effects of AK23 anti-Dsg3 mAb, and improved the body weight loss, telogen hair loss, and survival rate dose-dependently. While the B6-Dsg1wt/wtDsg3-/- mice died by week 2, over 80% of the B6-Dsg1tg/tgDsg3-/- mice survived at week 6. Furthermore, the syngeneic PV model mice showed the characteristic phenotype, including stable anti-Dsg3 antibody production and suprabasilar acantholysis on histology. Conclusion: Transgenic expression of Dsg1 rescued the severe B6-Dsg3-/- phenotype and provided a syngeneic mouse model of PV, which may be a valuable tool for clarifying immunological mechanisms in autoimmunity and tolerance of Dsg3.

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