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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.
Clin Immunol. 2012 Feb; 142(2):167-75.CI

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+Show Affiliations

Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22044750

Citation

Ujiie, Hideyuki, et al. "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." Clinical Immunology (Orlando, Fla.), vol. 142, no. 2, 2012, pp. 167-75.
Ujiie H, Shibaki A, Nishie W, et al. 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. Clin Immunol. 2012;142(2):167-75.
Ujiie, H., Shibaki, A., Nishie, W., Shinkuma, S., Moriuchi, R., Qiao, H., & Shimizu, H. (2012). 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. Clinical Immunology (Orlando, Fla.), 142(2), 167-75. https://doi.org/10.1016/j.clim.2011.10.002
Ujiie H, et al. 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. Clin Immunol. 2012;142(2):167-75. PubMed PMID: 22044750.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Ujiie,Hideyuki, AU - Shibaki,Akihiko, AU - Nishie,Wataru, AU - Shinkuma,Satoru, AU - Moriuchi,Reine, AU - Qiao,Hongjiang, AU - Shimizu,Hiroshi, Y1 - 2011/10/17/ PY - 2011/09/08/received PY - 2011/10/07/revised PY - 2011/10/07/accepted PY - 2011/11/3/entrez PY - 2011/11/3/pubmed PY - 2012/4/12/medline SP - 167 EP - 75 JF - Clinical immunology (Orlando, Fla.) JO - Clin Immunol VL - 142 IS - 2 N2 - 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. SN - 1521-7035 UR - https://www.unboundmedicine.com/medline/citation/22044750/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_ DB - PRIME DP - Unbound Medicine ER -