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Humanization of autoantigen


Transmissibility of characteristic lesions to experimental animals may help us understand the pathomechanism of human autoimmune disease. Here we show that human autoimmune disease can be reproduced using genetically engineered model mice. Bullous pemphigoid (BP) is the most common serious autoimmune blistering skin disease, with a considerable body of indirect evidence indicating that the underlying autoantigen is collagen XVII (COL17). Passive transfer of human BP autoantibodies into mice does not induce skin lesions, probably because of differences between humans and mice in the amino acid sequence of the COL17 pathogenic epitope. We injected human BP autoantibody into Col17-knockout mice rescued by the human ortholog. This resulted in BP-like skin lesions and a human disease phenotype. Humanization of autoantigens is a new approach to the study of human autoimmune diseases.

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Figure 1: Generation of COL17m−/− mice.
Figure 2: Phenotype, immunohistochemistry and histology of the humanized model mice.
Figure 3: BP disease response to therapeutic decoy peptides.

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We thank M. Sato, A. Honda, A. Nagasaki and E. Nishizono for technical assistance. This work was supported in part by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (15390336, 17209038 and 18013002 to H.S.; 17659331, 18390309 and 18659315 to D.S.); by the Project for Realization of Regenerative Medicine from the Ministry of Education, Science, Sports and Culture of Japan (2003–2007 to H.S.); by a grant from the US National Institutes of Health (RO1 AR048982 to K.B.Y.); by a grant from Nu Skin Japan; and by Health and Labour Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan (2004–2006 to H.S.)

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Correspondence to Hiroshi Shimizu.

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Supplementary information

Supplementary Fig. 1

Growth and Kaplan-Meier survival curves of wild-type, COL17m− /−, and rescued COL17-humanized mice. (PDF 222 kb)

Supplementary Methods (PDF 133 kb)

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Nishie, W., Sawamura, D., Goto, M. et al. Humanization of autoantigen. Nat Med 13, 378–383 (2007).

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