Functional analysis of BAFF, APRIL and their receptors, and the study of their role in the pathogenesis of autoimmune disease

• Project/Area Number: 18591113
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kyushu University
• Principal Investigator: TSUKAMOTO Hiroshi Kyushu University, University Hospital, Assistant Professor (70304772)
• Co-Investigator(Kenkyū-buntansha): HORIUCHI Takahiko Kyushu University, University Hospital, Associate Professor (90219212)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥4,010,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥510,000); Fiscal Year 2007: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
• Keywords: BAFF / APRIL / autoimmune disease / BR3 / svnovial fibroblast-like cells / polymorphism / rheumatoid arthritis / Furin転換酵素 / 共刺激

Research Abstract

Objective. To investigate the role of BAFF, APRIL and their receptors in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).Results. By exon-specific PCR/SSCP, we identified a novel polymorphism, P21R, in BR3 gene. P21R is located in the cystein-rich domain of BR3, a specific receptor for BAFF, and could be functionally important. To investigate the reverse-signal through membrane BAFF, we constructed cDNA for membrane BAFF, which was not cleaved by furin convertase, by site-directed mutagenesis. Expression of membrane BAFF was observed on transfected Jurkat cells by flow cytometry. When we analyzed the expression of BR3, TACI and BCMA on each peripheral B cell subset by flow cytometry, BR3 was highly expressed on naive B cells while BCMA was highly expressed on plasmablasts. The number of plasmablasts was increased in patients with SLE. Synovial fibroblast-like cells synthesized APRIL when they were cultured in the presence of TNF-a and IFN-y. BCMA-Ig, which was common receptor for BAFF and APRIL, but not BR3-Ig, receptor for BAFF, inhibited the proliferation of synovial fibroblast-like cells in the presence of TNF-α and IFN-γ.
Conclusions. These data suggest that BCMA has important role in the survival of plasmablasts in SLE patients. APRIL is associated with the proliferation of synovial fibroblast-like cells in autocrine fashon. APRIL and BAFF could be a therapeutic target in the treatment of autoimmune disease.

Research Products

• [Journal Article] Mechanisms for cytotoxic effects of anti-tumor necrosis factor agents on transmembrane tumor necrosis factor alpha-expressing cells: Comparison among infliximab,etanercept,and adalimumab (2008)
  • Author(s): Mitoma H, Horiuchi T, Tsukamoto H, et. al.
  • Journal Title: Arthritis Rheum 58 Pages: 1248-57
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Mechanism for cytotoxic effects of anti-TNF-α agents on transmembrane TNF-expressing cells : comparison among infliximab, etanercept and adalibmab (2008)
  • Author(s): Mitoma, H, Horiuchi, T, Tsukamoto, H, Tamimoto, Y, Kimoto, Y, Uchino, A, To, K, Harashima, S, Hatta, N, Harada, M
  • Journal Title: Arthritis Rheum 58 Pages: 1248-57
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of polymorphisms in complement component C3 gene with susceptibility to systemic lupus erythematosus (2008)
  • Author(s): Miyagawa, H, Yamai, M, Kiyohara, C, Tsukamoto, H, Kimoto, Y, Nakamura, T, Lee, J-H., Tsai, C-Y., Tsai, C-Y, Chiang, B-L, Shimoda, T, Harada, M, Tahira, T, Hayashi, K, Horiuchi, T
  • Journal Title: Rheumatology 47 Pages: 158-64
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A dose-escalation study of rituximab for treatment of systemic lupus erythematosus and Evans' syndrome : Immunological analysis of B cells, T cells and cytokines (2008)
  • Author(s): Tamimoto, Y, Horiuchi, T, Tsukamoto, H, Kiyohara, C, Niro, H, Miyagawa, H, Nakasone, A, Mitoma, H, Kimoto, Y, Uchino, A, Muta, K, Abe, Y, Inoue, Y, Ueda, A, Nakashima, H, Tada, Y, Nagasawa, K, Yoshizawa, S, Shimoda, T, Harada, M
  • Journal Title: Rheumatology (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Association of polymorphisms in complement component C3 gene.with susceptibility to systemic lupus erythematosus (2008)
  • Author(s): Miyagawa H, Yamai M, Sakaeuchi D, et. al.
  • Journal Title: Rheumatology 47 Pages: 158-64
  • Peer Reviewed
• [Journal Article] Mechanism for cytotoxic effects of anti-TNF-a agents on transmembrane TNF-expressing cells:comparison among infliximab,etanercept and adalibmab (2008)
  • Author(s): Mitoma H, Horiuchi T, Tsukamoto H, et. al.
  • Journal Title: Arthritis Rheum (印刷中)
  • Peer Reviewed
• [Journal Article] A functional M196R polymorphism of tumor necrosis factor receptor type 2 is associated with systemic lupus erythematosus: A case-control study and a meta-analysis (2007)
  • Author(s): Horiuchi T, Kiyohara C, Tsukamoto H, et. al.
  • Journal Title: Ann Rheum Dis 66 Pages: 320-4
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A functional M196R polymorphism of tumor necrosis factor receptor type 2 is associated with systemic lupus erythematosus : A case-control study and a meta-analysis (2007)
  • Author(s): Horiuchi, T, Kiyohara, C, Tsukamoto, H, Sawabe, T, Furugo, I, Yoshizawa, S, Ueda, A, Nakamura, Y, Tada, Y, Kimoto, Y, Mitoma, H, Harashima, SI, Yoshizawa, S, Shimoda, T, Okamura, S, Nagasawa, K, Harada, M
  • Journal Title: Ann Rheum Dis 66 Pages: 320-324
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A functional M196R polymorphism of tumor necrosis factor receptortype 2 is associated with systemic lupus erythematosus:A case-control study and a meta-analysis (2007)
  • Author(s): Horiuchi T, Kiyohara C, Tsukamoto H, et. al.
  • Journal Title: Ann Rheum Dis 66 Pages: 320-4
  • Peer Reviewed
• [Journal Article] A functional M196R polymorphism of tumor necrosis factor receptor type 2 is associated with systemic lupus erythematosus : A case-control study and a meta-analysis. (2007)
  • Author(s): Horiuchi T, Kiyohara C, Tsukamoto H, et al.
  • Journal Title: Ann Rheum Dis 66 Pages: 320-324
• [Journal Article] A phaseI-II trial of autologous peripheral blood stem cell transplantation in the treatment of refractory autoimmune disease (2006)
  • Author(s): Tsukamoto H, Nagafuji K, Horiuchi T, et. al.
  • Journal Title: Ann Rheum Dis 65 Pages: 508-14
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] A Phase I-II trial of autologous peripheral blood stem cell transplantation in the treatment of refractory autoimmune disease (2006)
  • Author(s): Tsukamoto, H, Nagafuji, K, Horiuchi, T, Miyamoto, T, Aoki, K, Takase, K, Henzan, H, Himeji, D, Koyama, T, Miyake, K, Inoue, Y, Nakashima, H, Otsuka, T, Tanaka, Y, Nagasawa, K, Harada, M
  • Journal Title: Ann Rheum Dis 65 Pages: 508-14
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increased expression of membrane TNF-alpha on activated peripheral CD8+ T cells in systemic lupus erythematosus (2006)
  • Author(s): Horiuchi, T, Morita, C, Tsukamoto, H, Mitoma, H, Sawabe, T, Harashima, S, Kashiwagi, Y, Okamura, S
  • Journal Title: Int J Mol Med 17 Pages: 875-9
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A phase I-II trial of autologous peripheral blood stem cell transplantation in the treatment of refractory autoimmune disease. (2006)
  • Author(s): Tsukamoto H, Nagafuji K, Horiuchi T, et al.
  • Journal Title: Ann Rheum Dis 65 Pages: 508-514
• [Journal Article] Increased expression of membrane TNF-alpha on activated peripheral CD8+ T cells in systemic lupus erythematosus. (2006)
  • Author(s): Horiuchi T, Morita C, Tsukamoto H et al.
  • Journal Title: Int J Mol Med 17 Pages: 875-879
• [Journal Article] Prevention of steroid-induced osteonecrosis of femoral head in systemic lupus erythematosus by anti-coagulant. (2006)
  • Author(s): Nagasawa K, Tada Y, Koarada S, et al.
  • Journal Title: Lupus 15 Pages: 354-357
• [Journal Article] Smoking, drinking, sleeping habits, and other lifestyle factors and the risk of systemic lupus erythematosus in Japanese females : findings from the KYSS study. (2006)
  • Author(s): Washio M, Horiuchi T, Kiyohara C, et al.
  • Journal Title: Mod Rheumatol 16 Pages: 143-150
  • NAID: 10017608637
• [Presentation] 滑膜線維芽細胞におけるAPRIL発現 (2007)
  • Author(s): 高橋 美聡、塚本 浩、堀内 孝彦, 他
  • Organizer: 第51回日本リウマチ学会総会
  • Place of Presentation: 東京
  • Year and Date: 2007-04-26
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 滑膜線維芽細胞におけるAPRIL発現 (2007)
  • Author(s): 高橋 美聡, 塚本 浩, 堀内 孝彦, 他
  • Organizer: 第51回日本リウマチ学会
  • Place of Presentation: 横浜
  • Year and Date: 2007-04-26
• [Presentation] High-dose immune suppressive therapy and autologous peripheral blood stem cell transplantation in systemic sclerosis : analysis of immune reconstitution (2006)
  • Author(s): Tsukamoto, H, Nagafuji, K, Horiuchi, T, Nakashima, H, Harada, M
  • Organizer: Annual meeting of American college of rheumatology
  • Place of Presentation: Washington, DC
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Expression of APRIL in svnovial fibroblast-like cells
  • Author(s): Takahashi, M, Tsukamoto, H, Horiuchi, T, Mitoma, H, Uchino, A, Kimoto, Y, Oryoji, K, Furukawa, M, To, K, Harada, M
  • Organizer: The 51th Annual meeting of Japan college of rheumatology
  • Place of Presentation: Tokyo
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] Role of BAFF and APRIL in differentiation to plasmablast from human peripheral B cells
  • Author(s): Uchino, A, Tsukamoto, H, Horiuchi, T, Mitoma, H, Taminoto, Y, Kimoto, Y, Oryoji, K, Furukawa, M, To, K, Harada, M
  • Organizer: The 51th Annual meeting of Japan college of rheumatology
  • Place of Presentation: Tokyo
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] High-dose cyclophosphamide and autologous peripheral blood stem cell transplantation for severe scleroderma clinical results and analysis of immune reconstitution
  • Author(s): Tsukamoto, H, Nagafuji, K, Horiuchi, T, Harada, M
  • Organizer: International workshop on scleroderma
  • Place of Presentation: Tokyo
  • Description: 「研究成果報告書概要(欧文)」より