Molecular mechanism of Sjogren's syndrome

• Project/Area Number: 17591027
• 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: University of Tsukuba
• Principal Investigator: SUMIDA Takayuki University of Tsukuba, Graduate School of Comprehensive Human Sciences, Professor, 大学院人間総合科学研究科, 教授 (00183054)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,200,000 (Direct Cost: ¥3,200,000); Fiscal Year 2006: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 2005: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: Sjogren's syndrome / autoreactive T cell / T cell epitope / analogue peptide / Muscalinic acetylcholine receptor / autoantigen / antigen specific regulation / mouse model / 自己免疫的T細胞 / ムスカリン作動性アセチルコリン受容体

Research Abstract

1.Regulation of SS by analogue peptide of T cell epitopes
To propose the new therapeutic strategies using analogue peptide of T cell epitopes, we focused on muscarinic acetylcholine receptor (M3R). The second extra-cellular domain of M3R is the most important region for intra-cellular signaling. Thus, we analyzed T cell epitopes of the second extra-cellular domain of M3R, screened the analogue peptides of T cell epitopes, and establish an antigen-specific regulation of SS using analogue peptides. 1) We clarified VPPGECFIQFLSEPT (AA215-229) was T cell epitope of M3R in HLA-DR B1*0901 positive patients with SS. 2) We selected two of candidates for analogue T cell epitopes were VPPGECFKQFLSEPT and VPPGECFIAFLSEPT. 3)We established mouse model for SS by the immunization of M3R peptides plus CFA.
2.Gene analysis of susceptibility genes in patients with SS
To elucidate susceptibility genes in patients with SS, we analyzed highly expressed genes in labial salivary glands (LSGs) using cDNA microarray. We screened STAT1 gene as a candidate for over-expressed genes. The Tyr701 and Ser727 were phosphorylated and were mainly expressed in LSGs epithelial cells of SS. Moreover, apoptotic genes such as Fas, IP-10, and RF-1 were highly expressed. These results suggest that over-expression of STAT1 might be associated to the apoptosis of LSG epithelial cells in patients with SS.

Research Products

• [Journal Article] Effects of infliximab therapy on gene expression levels of tumor necrosis factor alpha, tristetraprolin, T cell intracellular antigen 1, and Hu antigen R in patients with rheumatoid arthritis. (2007)
  • Author(s): Sugihara, M, Tsutsumi, A, Suzuki, E, Wakamatsu, E, Suzuki, T, Ogishima, H, Hayashi, T, Chino, Y, Ishii, W, Mamura, M, Goto, D, Matsumoto, I, Ito, S, Sumida, T.
  • Journal Title: Arthritis Rheum 56(7) Pages: 2160-2169
• [Journal Article] DNA microarray analysis of labial salivary glands from patients with Sjogren's syndrome. (2007)
  • Author(s): Wakamatsu, E., Nakamura, Y, Matsumoto, I, Goto, D, lto, S, Tsutsumi, A, Sumida,T.
  • Journal Title: Ann.Rheum.Dis. 66 Pages: 844-845
• [Journal Article] Overexpression of phosphorylated STAT-1α in the labial salivary glands from patients with Sjogren's syndrome. (2006)
  • Author(s): Wakamatsu, E., Matsumoto, I., Naito, Y., Goto, D., Mamura, M., Ito, S., Tsutsumi, A., Sumida.T.
  • Journal Title: Arthritis Rheum. 54 Pages: 3476-3484
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Altered peptide ligands regulate muscarinic acetylcholine receptor reactive T cells from patients with Sjogren's syndrome. (2006)
  • Author(s): Naito, Y., Matsumoto, I., Wakamatsu, E., Goto, D., Ito, S., Tsutsumi, A., Sumida, T.
  • Journal Title: Ann. Rheum. Dis. 65 Pages: 269-271
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Characterization of Th1/Th2 type, glusoce-6-phoshate isomerase reactive T cells in the generation of rheumatoid arthritis. (2006)
  • Author(s): Kori, Y., Matsumoto, I., Zhang, H., Yasukochi, T., Hayashi, T., Iwanami, K., Goto, D., Ito, S., Tsutsumi, A., Sumida, T.
  • Journal Title: Ann. Rheum. Dis. 65 Pages: 968-969
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Overexpression of phosphorylated STAT-1 α in the labial salivary glands from patients with Sjogren' s syndrome. (2006)
  • Author(s): Wakamatsu, E., Matsumoto, I., Naito, Y., Goto, D., Mamura, M., Ito, S., Tsutsumi, A., Sumida, T.
  • Journal Title: Arthritis Rheum. 54 Pages: 3476-3484
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Altered peptide ligands regulate muscarinic acetylcholine receptor reactive T cells from patients with Sjogren' s syndrome. (2006)
  • Author(s): Naito, Y., Matsumoto, I., Wakamatsu, E., Goto, D., Ito, S., Tsutsumi, A., Sumida, T.
  • Journal Title: Ann.Rheum.Dis. 65 Pages: 269-271
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Characterization of Th1/Th2 type, glusoce-6-phoshate isomerase reactive T cells in the generation of rheumatoid arthritis. (2006)
  • Author(s): Kori, Y., Matsumoto, I., Zhang, H., Yasukochi, T., Hayashi, T., Iwanami, K., Goto, D., Ito, S., Tsutsumi, A., Sumida, T.
  • Journal Title: Ann.Rheum.Dis. 65 Pages: 968-969
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Overexpression of phosphorylated STAT-1 α in the labial salivary glands from patients with Sjogren's syndrome. (2006)
  • Author(s): Wakamatsu, E, Matsumoto, I, Naito, Y, Goto, D, Mamura, M, Ito, S, Tsutsumi, A, Sumida,T.
  • Journal Title: Arthritis Rheum. 54 Pages: 3476-3484
• [Journal Article] Altered peptide ligands regulate muscarinic acetylcholine receptor reactive T cells from patients with Sjogren's syndrome. (2006)
  • Author(s): Naito, Y, Matsumoto, I, Wakamatsu, E, Goto, D, Ito, S, Tsutsumi, A, Sumida,T.
  • Journal Title: Ann.Rheum.Dis. 65 Pages: 269-271
• [Journal Article] Characterization of Th1/Th2 type, glusoce-6-phoshate isomerase reactive T cells in the generation of rheumatoid arthritis. (2006)
  • Author(s): Kori, Y, Matsumoto, I, Zhang, H, Yasukochi, T, Hayashi, T, Iwanami, K, Goto, D, Ito, S, Tsutsumi, A, Sumida,T.
  • Journal Title: Ann.Rheum.Dis. 65 Pages: 968-969
• [Journal Article] T cell receptor BV gene repertoire in lymphocytes from bronchoalveolar lavage fjuid of polymyositis/dermatomyositis patients with interstitial pneumonitis. (2006)
  • Author(s): Chino, Y., et al.
  • Journal Title: Int.J.Mol.Med. 17 Pages: 101-109
• [Journal Article] Altered peptide ligands regulate muscarinic acetylcholine receptor reactive T cells from patients with Sjogren's syndrome. (2006)
  • Author(s): Naito, Y., et al.
  • Journal Title: Ann.Rheum.Dis. 65 Pages: 269-271
• [Journal Article] Muscarinic acetylcholine receptor autoantibodies in patients with Sjogren's syndrome. (2005)
  • Author(s): Naito, Y., Matsumoto, I., Wakamatsu, E., Goto, D., Tsutsumi, A., Sumida.T.
  • Journal Title: Ann. Rheum. Dis 64 Pages: 510-511
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TCRV α 14+ NKT cells function as effector T cells in collagen-induced arthritis mice. (2005)
  • Author(s): Ohnishi, Y., Tsutsumi, A., Goto, D., Itoh, S., Matsumoto, I., Taniguchi, M., Sumida, T.
  • Journal Title: Clin. Exp. Immunol. 141 Pages: 47-53
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Muscarinic acetylcholine receptor autoantibodies in patients with Sjogren' s syndrome. (2005)
  • Author(s): Naito, Y., Matsumoto, I., Wakamatsu, E., Goto, D., Tsutsumi, A., Sumida, T.
  • Journal Title: Ann.Rheum.Dis. 64 Pages: 510-511
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TCRV α 14+ NKT cells function as effector T cells in collagen-induced arthritis mice. (2005)
  • Author(s): Ohnishi, Y., Tsutsumi, A., Goto, D., Itoh, S., Matsumoto, I., Taniguchi, M., Sumida, T.
  • Journal Title: Clin.Exp.Immunol. 141 Pages: 47-53
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A functional variant of Fcg receptor IIIA is associated with rheumatoid arthritis in anti-glucose-6-p-phosphate isomerase antibodies positive individuals. (2005)
  • Author(s): Matsumoto, I., et al.
  • Journal Title: Arthritis Res.Ther. 7 Pages: 1183-1188
• [Journal Article] TCRVa14+ NKT cells function as effector T cells in collagen-induced arthritis mice. (2005)
  • Author(s): Ohnishi, Y., et al.
  • Journal Title: Clin.Exp.Immunol. 141 Pages: 47-53
• [Journal Article] Muscarinic acetylcholine receptor autoantibodies in patients with Sjogren's syndrome. (2005)
  • Author(s): Naito, Y., et al.
  • Journal Title: Ann.Rheu.Dis. 64 Pages: 510-511
• [Journal Article] DNA microarray analysis of labial salivary glands from patients with Sjogren's syndrome.
  • Author(s): Wakamatsu, E., Nakamura, Y., Matsumoto, I., Goto, D., Ito, S., Tsutsumi, A., Sumida, T.
  • Journal Title: Ann. Rheum. Dis. (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] DNA microarray analysis of labial salivary glands from patients with Sjogren' s syndrome.
  • Author(s): Wakamatsu, E., Nakamura, Y., Matsumoto, I., Goto, D., Ito, S., Tsutsumi, A., Sumida, T.
  • Journal Title: An.Rheum.Dis. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] High prevalence of autoantibodies to muscarinic 3 acetylcholine receptor in patients with juvenile Sjogren's syndrome
  • Author(s): Nakamura, Y, Wakamatsu, E, Tomiita, M, Kohno, Y, Yokoka, J, Goto, D, Ito, S, Matsumoto, I, Tsutsumi, A, Sumida,T.
  • Journal Title: Ann.Rheum.Dis. (in press)
• [Journal Article] Characterization of Th1 type, glusoce-6-phoshate isomerase reactive T cells in the generation of rheumatoid arthritis.
  • Author(s): Kori, Y., et al.
  • Journal Title: Ann.Rheum.Dis. (in press)