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Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus
Masayuki Amagai, … , Shigeo Koyasu, Takeji Nishikawa
Masayuki Amagai, … , Shigeo Koyasu, Takeji Nishikawa
Published March 1, 2000
Citation Information: J Clin Invest. 2000;105(5):625-631. https://doi.org/10.1172/JCI8748.
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Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus

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Abstract

The development of experimental models of active autoimmune diseases can be difficult due to tolerance of autoantigens, but knockout mice, which fail to acquire tolerance to the defective gene product, provide a useful tool for this purpose. Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris (PV), we have generated an active disease model for this autoantibody-mediated disease. Dsg3–/– mice, but not Dsg3+/– littermates, produced anti-Dsg3 IgG that binds native Dsg3, when immunized with recombinant mouse Dsg3. Splenocytes from the immunized Dsg3–/– mice were then adoptively transferred into Rag-2–/– immunodeficient mice expressing Dsg3. Anti-Dsg3 IgG was stably produced in the recipient mice for more than 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–/– 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.

Authors

Masayuki Amagai, Kazuyuki Tsunoda, Harumi Suzuki, Koji Nishifuji, Shigeo Koyasu, Takeji Nishikawa

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Figure 1

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Anti-Dsg3 IgG antibodies that can bind the native Dsg3 in vivo are produ...
Anti-Dsg3 IgG antibodies that can bind the native Dsg3 in vivo are produced in Dsg3–/– mice, but not in Dsg3+/– mice. (a) Dsg3–/– mice and their Dsg3+/– littermates were immunized with mouse rDsg3, and the ELISA titers against rDsg3 were measured over time. Mice were primed by intraperitoneal injection of purified mouse rDsg3 in complete Freund’s adjuvant on day 0 (arrow). They were subsequently boosted with mouse rDsg3 in incomplete Freund’s adjuvant (solid triangles), and then injected with the mouse rDsg3 without adjuvant (open triangles). (b) A mouse keratinocyte cell line, PAM212, was incubated with mouse serum samples in culture media in a CO2 incubator for 30 minutes. After being washed and fixed with methanol, bound mouse IgG was revealed with FITC-conjugated goat anti-mouse IgG antibodies. Sera from immunized Dsg3–/– mice (left), but not from their Dsg3+/– littermates (right), stained the cell-cell contact sites of cultured keratinocytes. Bar, 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 4 patents
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