Molecular mechanism and its regulation of heterophilic adhesion between α E 3 7 (CD103) and E-cadherin in autoimmune epithelial injury

自身免疫性上皮损伤中α E 3 7 (CD103)与E-cadherin异嗜粘附的分子机制及其调控

• 批准号: 18591122
• 负责人: TAKEUCHI Tsutomu
• 金额: $ 2.57万
• 依托单位: Saitama Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591122/
• 关键词: autoimmunity; epithelial injuries; adherin; integrin; CD103

It is proposed that immuno-competent cells, which play an indispensable role in host defense in normal individuals, attack self tissues in autoimmune diseases. We have demonstrated that these immune cells are involving the tissue injuries as the effector cells not only in salivary gland destruction in Sjogren's syndrome, but also in interstitial alveolar damage in dermatomyositis, raising a hypothesis of autoimmune epithelitis. Given the observation that CD8+ T lymphocytes are infiltrated around the aciner epithelial cells and the CD8+ cells are expressing aEb7 (CD 103) adhesion molecules, it is suggested that these lymphocytes adhere to the epithelial cells through aEb7 and E-cadherin on the epithelial cells. However, the detailed molecular mechanism remains to be clarified. In this study, we focus on the aEb7 and E-cadherin adhesion and attempt to explore the immunological mechanism of autoimmune epithelial injuries. In addition, we investigate the efficient intervention of the adhesion for applying to the future clinical development. Monoclonal antibodies or peptide antagonist may be useful to inhibit the adhesion, but those may also interfere to homophilic adhesion between epithelial cells. To search the inhibitory modalities specifically block heterophilic adhesion between aEb7 and E-cadherin, but not homophilic adhesion, we generated a series of deletion mutant of wild type E-cadherins and established the L-cell transfectant expressing E-cadherin without each domains. Using these L-cells and transfectants with aE chain and b7 chasin of integrins, we identified that 5th domain is responsible for the heterophilic adhesion. On the basis of the findings, we examined expression of the aEb7 on the peripheral and tissue lymphocytes and E-cadherin in the inflamed tissues.

在自身免疫性疾病中，免疫活性细胞在机体防御中起着不可缺少的作用，可攻击自身组织。我们已经证明，这些免疫细胞作为效应细胞参与了组织损伤，不仅在干燥综合征的唾液腺破坏中，而且在皮肌炎的间质肺泡损伤中，提出了自身免疫性上皮炎的假说。观察到腺泡上皮细胞周围有CD8+T细胞浸润，CD8+细胞表达a Eb7(CD103)黏附分子，提示这些淋巴细胞是通过上皮细胞上的aEb7和E-钙粘素与上皮细胞黏附的。然而，具体的分子机制仍有待阐明。在本研究中，我们以aEb7和E-钙粘附素的黏附为研究重点，试图探讨自身免疫性上皮损伤的免疫学机制。此外，我们还探讨了粘连的有效干预措施，以应用于未来的临床开发。单抗或多肽拮抗剂可能有助于抑制黏附，但也可能干扰上皮细胞间的亲和性黏附。为了寻找特异性阻断E-钙粘蛋白与aEB7之间的异亲黏附而不是同亲黏附的抑制方式，我们构建了一系列野生型E-钙粘蛋白的缺失突变体，并建立了不含每个结构域的表达E-钙粘素的L细胞株。利用这些L细胞和带有AE链和整合素的b7 Chasin的转染体，我们发现第5个结构域是导致异嗜性黏附的原因。在此基础上，我们检测了aEb7在外周和组织淋巴细胞上的表达以及炎症组织中E-钙粘附素的表达。

项目成果

Platelet-Derived Growth Factor as a Therapeutic Target for systemic autoimmunediseases.2:1-9,2007

血小板衍生生长因子作为系统性自身免疫性疾病的治疗靶点。2:1-9,2007

• 发表时间: 2007
• 期刊: Drug Target lnsight 2
• 作者: Kameda Hideto;et. al.
• 通讯作者: et. al.

Efficacy and Safety of Tacrolimus in Patients with rheumatoid arthritis in clinical practice : Significant role of blood concentration measurement for preventing severe adverse events

他克莫司在临床实践中对类风湿性关节炎患者的疗效和安全性：血药浓度测量对于预防严重不良事件的重要作用

• 发表时间: 2007
• 期刊: Arthritis Rheum S 35
• 作者: Suzuki;K;Takei;H;Kameda;H;Nagasawa;H;Sekiguchi;N;Nishi;E;Ogawa;H;Tsuzaka;K;Amano;K;Takeuchi;T
• 通讯作者: T

DNA microarray gene expression profile of T cells with splice variants of TCRz mRNA observed in SLE

SLE 中观察到的具有 TCRz mRNA 剪接变体的 T 细胞的 DNA 微阵列基因表达谱

• 发表时间: 2006
• 期刊: J Immunol 176
• 作者: Suzuki Katsuya;et. al.;Tsuzaka Kensei
• 通讯作者: Tsuzaka Kensei

14-kd protein binds to the conservative region in TCR zeta mRNA 3'UTR and regulates the production of TCR zeta and TCR/CD3 complex.

14-kd 蛋白结合 TCR zeta mRNA 3UTR 中的保守区域，并调节 TCR zeta 和 TCR/CD3 复合物的产生。

• 发表时间: 2007
• 作者: Tsuzaka;K;Itami;Y;Kumazawa;C;Setoyama;Y;Yoshimoto;K;Suzuki;K;Abe;T;Takeuchi;T;Suzuki Katsuya;Tsuzaka Kensei
• 通讯作者: Tsuzaka Kensei

Possible involvement of MMP in the production of soluble BAFF in human T cells.

MMP 可能参与人类 T 细胞中可溶性 BAFF 的产生。

• 发表时间: 2007
• 作者: Tsuzaka;K;Itami;Y;Kumazawa;C;Setoyama;Y;Yoshimoto;K;Suzuki;K;Abe;T;Takeuchi;T;Suzuki Katsuya;Tsuzaka Kensei;Yoshimoto Keiko;Tsuzaka Kensei;Kumazawa Chika;Yoshimoto Keiko
• 通讯作者: Yoshimoto Keiko