Molecular Mechanism in Sjogren's syndrome

干燥综合征的分子机制

• 批准号: 08457157
• 负责人: SUMIDA Takayuki
• 金额: $ 4.67万
• 依托单位: University of Tsukuba (1998)St. Marianna University School of Medicine (1996-1997)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08457157/
• 关键词: Sjogren's syndrome; T cell receptor; autoreactive T cell; T cell epitope; alpha-amylace; アナログペプチド; シェ-グレン症候群; 自己抗原エポトープ; 自己抗原; 自己免疫疾患

Analyses of T cell receptor (TCR) on T cells in labial salivary glands of patients with Sjogren's syndrome (SS) support the notion that infiltrating T cells were induced by antigen-driven rather than superantigen-driven stimulation. T cell epitopes recognized by T cells infiltrating in the labial salivary glands of SS patients have been clarified using different four strategies such as T cell lines, PCR-SSCP, West-Western, and TOP a/b transfectants methods. 1) Cell proliferative analysis by T cell lines from labial salivary glands showed T cell epitope (DEREQLRILG) at position AA203-21 2 of Ro/SS-A protein. 2) Analysis with SSCP and the synthetic peptides combinatorial libraries demonstrated that WAEILRIGRV (TORBV6S7) and WVNMLRRGI (HSP10/60) were suitable candidates for antigens. WAEILRIGRV (TOPBV6S7) reactive T cells could produce both IL-2 and IL-4, while WVNMLRRGI (HSP10/60) reactive T cells were able to produce only IL-2 in vitro. 3) West-Western analysis using TOR CDR3 protein from unique TOP in salivary glands clarified that human a-amylase salivary precursor (NPFRPWWERYQWPV, AA68-80 and EKMSYLKNWGEG, AA287-298) is a candidate for salivary glands-specific autoantigens in SS.In fact, 3 of 11 SS patients (27%) showed a-amylase reactive T cells in labial salivary glands. 4) A full-length cDNA encoding paired TOP a and b chains has been isolated from a single T cell in labial salivary glands of SS patient. In conclusion, a-amylase function as salivary glands-specific autoantigen, whereas Ro/SS-A 52kD, and HSP10/60 act as glands-non-specific autoantigens. Furthermore, some autoantigens such as Ro/SS-A 52kD and HSP1 0/60 are thought to be autoaggressive T cell epitopes in the generation of SS, although TCRBV6S7 might be aregulatory T cell epitope in SS.

对干燥综合征 (SS) 患者唇唾液腺 T 细胞上的 T 细胞受体 (TCR) 的分析支持这样的观点，即浸润性 T 细胞是由抗原驱动而非超抗原驱动的刺激诱导的。使用不同的四种策略（例如 T 细胞系、PCR-SSCP、West-Western 和 TOP a/b 转染子方法）阐明了 SS 患者唇唾液腺中浸润的 T 细胞识别的 T 细胞表位。 1)来自唇唾液腺的T细胞系的细胞增殖分析显示T细胞表位(DEREQLRILG)位于Ro/SS-A蛋白的AA203-21 2位点。 2) SSCP 和合成肽组合文库的分析表明 WAEILRIGRV (TORBV6S7) 和 WVNMLRRGI (HSP10/60) 是合适的抗原候选者。 WAEILRIGRV (TOPBV6S7) 反应性 T 细胞可以同时产生 IL-2 和 IL-4，而 WVNMLRRGI (HSP10/60) 反应性 T 细胞在体外只能产生 IL-2。 3) 使用来自唾液腺中独特 TOP 的 TOR CDR3 蛋白进行的 West-Western 分析阐明，人 α-淀粉酶唾液前体（NPFRPWWERYQWPV、AA68-80 和 EKMSYLKNWGEG、AA287-298）是 SS 中唾液腺特异性自身抗原的候选者。事实上，11 名 SS 患者中有 3 名 (27%) 表现出唇唾液腺中的α-淀粉酶反应性T细胞。 4) 从 SS 患者唇唾液腺中的单个 T 细胞中分离出编码配对 TOP a 和 b 链的全长 cDNA。总之，α-淀粉酶充当唾液腺特异性自身抗原，而Ro/SS-A 52kD和HSP10/60充当腺体非特异性自身抗原。此外，一些自身抗原如Ro/SS-A 52kD和HSP1 0/60被认为是SS产生中的自身攻击性T细胞表位，尽管TCRBV6S7可能是SS中的调节性T细胞表位。

项目成果

Sumida,T.,et al.: "T cell receptor in Sjogren's syndrome." Br.J.Rheumatol. 36. 622-629 (1997)

Sumida,T.,et al.：“干燥综合征中的 T 细胞受体。”

Sumida,T.,et al.: "T cell receptor in Sjogren's syndrome." Br. J. Rheumatol.(in press).

Sumida,T.,et al.：“干燥综合征中的 T 细胞受体。”

Fujisawa K., et al.: "Evidence for autoantigens of env/tax proteins in HTLV-1 tax transgenic mice." Arthritis Rheum.41. 101-109 (1998)

Fujisawa K. 等人：“HTLV-1 Tax 转基因小鼠中 env/tax 蛋白自身抗原的证据。”

Kita, Y., et al.: "T cell receptor clonotypes in skin lesions from patients with systemic lupus erythematosus." J.Invest.Dermatol.110. 41-46 (1998)

Kita, Y. 等人：“系统性红斑狼疮患者皮肤病变中的 T 细胞受体克隆型。”

Kita,Y.,et al.: "T cell receptor clonotypes in skin lesions from patients with systemic lupus erythematosus." J.Invest.Dermatol.110. 41-46 (1998)

Kita,Y.,et al.：“系统性红斑狼疮患者皮肤病变中的 T 细胞受体克隆型。”