A Novel Active Mouse Model for Bullous Pemphigoid Targeting Humanized Pathogenic Antigen

Bullous pemphigoid (BP), the most common autoimmune blistering disease, is caused by autoantibodies against type XVII collagen (COL17). To establish an active stable BP animal model that demonstrates the persistent inflammatory skin lesions initiated by the anti-human COL17 Abs, we used COL17-humani...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2010-02, Vol.184 (4), p.2166-2174
Main Authors: Ujiie, Hideyuki, Shibaki, Akihiko, Nishie, Wataru, Sawamura, Daisuke, Wang, Gang, Tateishi, Yasuki, Li, Qiang, Moriuchi, Reine, Qiao, Hongjiang, Nakamura, Hideki, Akiyama, Masashi, Shimizu, Hiroshi
Format: Article
Language:English
Subjects:
Animals
Autoantibodies - biosynthesis
Autoantigens - genetics
Autoantigens - immunology
B-Lymphocyte Subsets - immunology
B-Lymphocyte Subsets - pathology
CD4-Positive T-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - pathology
Collagen Type XVII
Disease Models, Animal
Female
Gene Targeting - methods
Humans
Immunoglobulin G - biosynthesis
Immunophenotyping
Leukocyte Common Antigens - biosynthesis
Leukocyte Common Antigens - genetics
Lymphopenia - genetics
Lymphopenia - immunology
Lymphopenia - pathology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Non-Fibrillar Collagens - deficiency
Non-Fibrillar Collagens - genetics
Non-Fibrillar Collagens - immunology
Pemphigoid, Bullous - genetics
Pemphigoid, Bullous - immunology
Pemphigoid, Bullous - pathology
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Summary:Bullous pemphigoid (BP), the most common autoimmune blistering disease, is caused by autoantibodies against type XVII collagen (COL17). To establish an active stable BP animal model that demonstrates the persistent inflammatory skin lesions initiated by the anti-human COL17 Abs, we used COL17-humanized (COL17(m-/-,h+)) mice that we recently produced. First, we generated immunodeficient Rag-2(-/-)/COL17-humanized mice by crossing Rag-2(-/-) mice with COL17-humanized mice. Then, splenocytes from wild-type mice that had been immunized by grafting of human COL17-transgenic mouse skin were transferred into Rag-2(-/-)/COL17-humanized mice. The recipient mice continuously produced anti-human COL17 IgG Abs in vivo and developed blisters and erosions corresponding to clinical, histological, and immunopathological features of BP, although eosinophil infiltration, one of the characteristic histological findings observed in BP patients, was not detected in the recipients. Although the depletion of CD8(+) T cells from the immunized splenocytes was found to produce no effects in the recipients, the depletion of CD4(+) T cells as well as CD45R(+) B cells was found to inhibit the production of anti-human COL17 IgG Abs in the recipients, resulting in no apparent clinical phenotype. Furthermore, we demonstrated that cyclosporin A significantly suppressed the production of anti-human COL17 IgG Abs and prevented the development of the BP phenotype in the treated recipients. Although this model in an immunodeficient mouse does not exactly reproduce the induction mechanism of BP in human patients, this unique experimental system targeting humanized pathogenic Ag allows us to investigate ongoing autoimmune responses to human molecules in experimental animal models.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.0903101