A mouse model of pemphigus vulgaris by adoptive transfer of naive splenocytes from desmoglein 3 knockout mice

Background: Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by antidesmoglein3 (anti-Dsg3) IgG autoantibodies. Recently, we developed a PV mouse model by adoptive transfer of splenocytes from recombinant Dsg3-immunized Dsg3^-/- mice to Rag2^-/- immunodeficient mice that expressed Dsg3. Objectives: We determined whether the adoptive transfer of naive splenocytes from nonimmunized Dsg3^-/- mice induces the anti-Dsg3 IgG production and the PV phenoytpe in recipient mice. Methods: We adoptively transferred naive Dsg3^-/- splenocytes into Rag2 ^-/- mice and compared their PV phenoytpe with those mice receiving immunized Dsg3^-/- splenocytes. The numbers of splenocytes and their subpopulations required for anti-Dsg3 IgG production were examined. Results: Mice that received naive Dsg3^-/- splenocytes produced anti-Dsg3 IgG, which bound to keratinocyte cell surfaces in vivo, and developed the PV phenotype, including oral erosions with suprabasilar acantholysis. Antibody production and the appearance of the PV phenotype were delayed by approximately 2 weeks in mice that received naive splenocytes compared with mice that received immunized splenocytes. However, once the PV phenotypes developed, there were no apparent differences in disease severity between the two models. Interestingly, the anti-Dsg3 IgG titres were significantly lower in mice that received naive splenocytes than in mice that received immunized splenocytes, suggesting that the former antibodies were more potent than the latter. The frequency of anti-Dsg3 IgG production depended on the number of transferred naive splenocytes. Both CD4+ T cells and B220+ B cells from naive Dsg3^-/- mice were essential for the production of anti-Dsg3 IgG antibodies. Conclusions: Dsg3-specific naive lymphocytes in Dsg3^-/- mice can be primed and activated by the endogenous Dsg3 in recipient mice to produce pathogenic anti-Dsg3 IgG without active immunization. This approach using naive lymphocytes provides a unique model to dissect immunological mechanisms of tolerance against peripheral autoimmune targets.