title: A novel active mouse model for bullous pemphigoid targeting humanized pathogenic antigen.
abstract: 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.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ujiie
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shibaki
authors.forename: Wataru
authors.initials: W
authors.lastname: Nishie
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sawamura
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Yasuki
authors.initials: Y
authors.lastname: Tateishi
authors.forename: Qiang
authors.initials: Q
authors.lastname: Li
authors.forename: Reine
authors.initials: R
authors.lastname: Moriuchi
authors.forename: Hongjiang
authors.initials: H
authors.lastname: Qiao
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Masashi
authors.initials: M
authors.lastname: Akiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000235:genetics* / Q000276:immunology; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000096:biosynthesis / Q000235:genetics; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024041:Non-Fibrillar Collagens / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D010391:Pemphigoid, Bullous / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000097805:Collagen Type XVII
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007074:Immunoglobulin G; D017493:Leukocyte Common Antigens; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII