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

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 Dsg1^wt/wt, Dsg1^tg/wt, and Dsg1^tg/tg mice. We generated a PV model via the adoptive transfer of B6-Dsg1^tg/tgDsg3^-/- splenocytes to B6-Rag2^-/- mice. Results: Dsg1^tg/tg and Dsg1^tg/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-Dsg1^wt/wtDsg3^-/- mice died by week 2, over 80% of the B6-Dsg1^tg/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.