Development of novel mouse model for autoimmune diseases using autoantigen knockout mice

The development of experimental models of active autoimmune diseases can be difficult due totolerance of autoantigens. Knockout mice do not acquire tolerance of the defective gene product.Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris，我们established a method to generate an active disease model for this autoantibody-mediated disease.Dsg3 -/- D1 mice, but not Dsg3 - D1+/- D1 littermates，produced anti-Dsg3 IgG that was able to bind the native Dsg3 when immunized with recombinant mouseDsg3. Splenocytes from the immunized Dsg3 mice were then adoptively transferred intoRag-2 - immunodeficient mice expressing Dsg3. Anti-Dsg3 IgG was stably produced in therecipient mice for over 6 months without further boosting. This IgG bound to Dsg3 in vivo anddisrupted the cell-cell adhesion of keratinocytes. Consequently，the recipient mice developed erosions in their oral mucous membranes with typical histologicfindings of PV. In addition, the recipient mice showed telogen hair lossas found in Dsg3关于D1-/- mice. Collectively，the recipient mice developed the phenotype of PV due to the pathogenic anti-Dsg3 IgG. This modelwill be valuable for developing novel therapeutic strategies. Furthermoreour approach可以应用的broadly for the development of various autoimmune disease models。

The development of experimental models of active autoimmune diseases can be difficult due to tolerance of autoantigens. Knockout mice do not acquire tolerance of the defective gene product. Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris (PV), we established a method to generate an active disease model for this autoantibody-mediated disease. Dsg3ィイD1-/-ィエD1 mice, but not Dsg3ィイD1+/-ィエD1 littermates, produced anti-Dsg3 IgG that was able to bind the native Dsg3 when immunized with recombinant mouse Dsg3. Splenocytes from the immunized Dsg3ィイD1-/-ィエD1 mice were then adoptively transferred into Rag-2ィイD1-/-ィエD1 immunodeficient mice expressing Dsg3. Anti-Dsg3 IgG was stably produced in the recipient mice for over 6 months without further boosting. This IgG bound to Dsg3 in vivo and disrupted the cell-cell adhesion of keratinocytes. Consequently, the recipient mice developed erosions in their oral mucous membranes with typical histologic findings of PV. In addition, the recipient mice showed telogen hair loss, as found in Dsg3ィイD1-/-ィエD1 mice. Collectively, the recipient mice developed the phenotype of PV due to the pathogenic anti-Dsg3 IgG. This model will be valuable for developing novel therapeutic strategies. Furthermore, our approach can be applied broadly for the development of various autoimmune disease models.