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

BackgroundAn 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.ObjectiveTo rescue the B6-Dsg3−/− mice and to produce syngeneic PV model mice.MethodsTransgenic 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.ResultsDsg1tg/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.ConclusionTransgenic 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.