Pathogenic autoantibody production requires loss of tolerance against desmoglein 3 in both T and B cells in experimental pemphigus vulgaris

Mechanisms of tolerance break against desmoglein 3 (Dsg3) in patients with pemphigus vulgaris (PV) producing pathogenic anti-Dsg3 IgG autoantibodies are unclear. In this study, using a novel PV mouse model involving Dsg3 knockout mice, we investigated the mechanisms leading to production of autoantibodies against Dsg3. Adoptive transfer of Dsg3^-/- splenocytes immunized with recombinant mouse Dsg3 to Rag2^-/- recipient mice expressing Dsg3 resulted in the stable production of anti-Dsg3 IgG and development of PV phenotypes including oral erosions with suprabasilar acantholysis. When purified T and B cells from Dsg3^-/-, Dsg3^+/- or Dsg3^+/+ mice were mixed with various combinations and transferred to Rag2^-/- mice, pathogenic anti-Dsg3 IgG production was observed only with a combination of Dsg3^-/-T and Dsg3^-/- B cells but not with the other combinations. These results suggest that loss of tolerance against Dsg3 in both B and T cells is important for the development of auto-immune state of PV.