Molecular mechanism of Sjogren's syndrome

干燥综合征的分子机制

• 批准号: 17591027
• 负责人: SUMIDA Takayuki
• 金额: $ 2.05万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591027/
• 关键词: 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

1.Regulation of SS by analogue peptide of T cell epitopesTo 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 SSTo 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.

1.为了提出利用T细胞表位类似肽调控SS的新策略，我们重点研究了毒蕈碱乙酰胆碱受体（muscarinic acetylcholine receptor, M3R）。M3R的第二个胞外结构域是细胞内信号传递最重要的区域。因此，我们分析了M3R第二细胞外结构域的T细胞表位，筛选了T细胞表位的类似肽，并利用类似肽建立了SS的抗原特异性调控。1)我们明确了VPPGECFIQFLSEPT （AA215-229）是HLA-DR B1*0901阳性SS患者M3R的T细胞表位。2)我们选择了两个候选的类似T细胞表位分别是VPPGECFKQFLSEPT和VPPGECFIAFLSEPT。3)采用M3R多肽联合cfa2免疫建立小鼠SS模型。为了阐明SS患者的易感基因，我们利用cDNA芯片分析了唇唾液腺（LSGs）中高表达的基因。我们筛选了STAT1基因作为过表达基因的候选基因。Tyr701和Ser727被磷酸化，主要在SS的LSGs上皮细胞中表达，Fas、IP-10、RF-1等凋亡基因高表达。这些结果提示STAT1的过表达可能与SS患者LSG上皮细胞的凋亡有关。

项目成果

A functional variant of Fcg receptor IIIA is associated with rheumatoid arthritis in anti-glucose-6-p-phosphate isomerase antibodies positive individuals.

Fcg 受体 IIIA 的功能变异与抗 6-β-磷酸葡萄糖异构酶抗体阳性个体的类风湿性关节炎有关。

• 发表时间: 2005
• 期刊: Arthritis Res.Ther. 7
• 作者: Matsumoto;I.;et al.
• 通讯作者: et al.

DNA microarray analysis of labial salivary glands from patients with Sjogren's syndrome.

干燥综合征患者唇唾液腺的 DNA 微阵列分析。

• 发表时间: 2007
• 期刊: Ann.Rheum.Dis. 66
• 作者: Wakamatsu;E.;Nakamura;Y;Matsumoto;I;Goto;D;lto;S;Tsutsumi;A;Sumida,T.
• 通讯作者: Sumida,T.

Characterization of Th1 type, glusoce-6-phoshate isomerase reactive T cells in the generation of rheumatoid arthritis.

类风湿性关节炎生成过程中 Th1 型、6-磷酸葡萄糖异构酶反应性 T 细胞的表征。

• 期刊: Ann.Rheum.Dis. (in press)
• 作者: Kori;Y.;et al.
• 通讯作者: et al.

Characterization of Th1/Th2 type, glusoce-6-phoshate isomerase reactive T cells in the generation of rheumatoid arthritis.

类风湿关节炎生成过程中 Th1/Th2 型、6-磷酸葡萄糖异构酶反应性 T 细胞的表征。

• 发表时间: 2006
• 期刊: Ann. Rheum. Dis. 65
• 作者: Kori;Y.;Matsumoto;I.;Zhang;H.;Yasukochi;T.;Hayashi;T.;Iwanami;K.;Goto;D.;Ito;S.;Tsutsumi;A.;Sumida;T.
• 通讯作者: T.

TCRVa14+ NKT cells function as effector T cells in collagen-induced arthritis mice.

TCRVa14 NKT 细胞在胶原诱导的关节炎小鼠中充当效应 T 细胞。

• 发表时间: 2005
• 期刊: Clin.Exp.Immunol. 141
• 作者: Ohnishi;Y.;et al.
• 通讯作者: et al.