title: Noncollagenous 16A domain of type XVII collagen-reactive CD4+ T cells play a pivotal role in the development of active disease in experimental bullous pemphigoid model.
abstract: Bullous pemphigoid (BP), the most common autoimmune blistering disease, is caused by autoantibodies against type XVII collagen (COL17). We recently demonstrated that CD4+ T cells were crucial for the production of anti-COL17 IgG and for the development of the BP phenotype by using a novel active BP mouse model by adoptively transferring immunized splenocytes into immunodeficient COL17-humanized mice. Noncollagenous 16A (NC16A) domain of COL17 is considered to contain the main pathogenic epitopes of BP, however, the pathogenicity of COL17 NC16A-reactive CD4+ T cells has never been elucidated. To address this issue, we modulated the immune responses against COL17 in active BP model by using anti-CD40 ligand (CD40L) monoclonal antibody MR1, an inhibitor of the CD40-CD40L interaction, in various ways. First, we show the essential role of CD4+ T cells in the model by showing that CD4+ T cells isolated from wild-type mice immunized with human COL17 enabled naïve B cells to produce anti-COL17 NC16A IgG in vivo. Second, we show that the activation of anti-COL17 NC16A IgG-producing B cells via CD40-CD40L interaction was completed within 5 days after the adoptive transfer of immunized splenocytes. Notably, a single administration of MR1 at day 0 was enough to inhibit the production of anti-COL17 NC16A IgG and to diminish skin lesions despite the presence of restored anti-COL17 IgG at the later stage. In contrast, the delayed administration of MR1 failed to inhibit the production of anti-COL17 NC16A IgG and the development of the BP phenotype. These results strongly suggest that COL17 NC16A-reactive CD4+ T cells play a pivotal role in the production of pathogenic autoantibodies and in the development of active disease in experimental BP model.
authors: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors: Hideyuki
authors: H
authors: Ujiie
authors: Akihiko
authors: A
authors: Shibaki
authors: Wataru
authors: W
authors: Nishie
authors: Satoru
authors: S
authors: Shinkuma
authors: Reine
authors: R
authors: Moriuchi
authors: Hongjiang
authors: H
authors: Qiao
authors: Hiroshi
authors: H
authors: Shimizu
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis* / Q000097:blood; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D023201:CD40 Ligand / Q000037:antagonists & inhibitors* / Q000276:immunology; D004195:Disease Models, Animal; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D024041:Non-Fibrillar Collagens / Q000276:immunology / Q000378:metabolism; D010391:Pemphigoid, Bullous / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D013997:Time Factors; D000097805:Collagen Type XVII
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D023201:CD40 Ligand; D007074:Immunoglobulin G; D024041:Non-Fibrillar Collagens; D000097805:Collagen Type XVII