Analysis of the function of lymphocyte adhesion molecules and its clinical significances in autoimmune diseases

淋巴细胞粘附分子在自身免疫性疾病中的功能分析及其临床意义

• 批准号: 13470107
• 负责人: MORIMOTO Chikao
• 金额: $ 10.43万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470107/
• 关键词: β1 integrin; signal molecule; Cas-L; Rheumatoid Arthritis; tax transgenic mice; Fyn; lck; tyrosine phosphorylation; T細胞; CD45RAナイーブ; CD45ROメモリー; CD9; 共刺激; アポトーシス; 自己抗原; β2GPI

It has been repeated that the expression of b1 integrins and ligands are elevated in the inflammatory lesions in rheumatoid arthritis (RA), Crk-associated substrate lymphocyte type (Cas-L) is a docking protein that is heavily tyrosine phosphorylated by the engagement of β1 integrins in T cells.In the present study, we attempted to evaluate the role of Cas-L in the pathophysiology of rheumatoid arthritis (RA). We analyzed human T-lymphotropic virus type I (HTLV-I) tax transgenic mice, since they develop polyarthritis resembling human RA. Here we show that migratory activity of spleen cells from tax transgenic mice with arthritis (Atg) was much higher than that of tax transgenic mice without arthritis (Ntg) and littermate control mice (Ct). Biochemical studies revealed that Cas-L protein and its spontaneous tyrosine phosphorylation were increased in Atg mice compared to Ntg and Ct mice, which might be caused by activated fyn and lck. Immunohistochemical analysis showed a large number of Cas-L positive lymphocytes migrating into the affected joints. Finally, in human RA, Cas-L positive lymphocytes have been shown to infiltrate to the inflammatory lesions. The above results strongly suggest that Cas-L appears to play an important role in the pathophysiology of RA.

在类风湿关节炎（RA）的炎性病变中，β 1整合素和β 1配体的表达增加，Crk相关底物淋巴细胞型（Cas-L）是一种通过β1整合素参与T细胞酪氨酸磷酸化的对接蛋白，本研究试图探讨Cas-L在RA病理生理中的作用。我们分析了人类嗜T淋巴细胞病毒I型（HTLV-I）税收转基因小鼠，因为他们开发类似人类RA的多关节炎。在这里，我们表明，从tax转基因小鼠关节炎（Atg）的脾细胞的迁移活性远远高于无关节炎（Ntg）和同窝对照小鼠（Ct）的tax转基因小鼠。生化研究表明，与Ntg和Ct小鼠相比，Atg小鼠中的Cas-L蛋白及其自发酪氨酸磷酸化增加，这可能是由激活的fyn和lck引起的。免疫组化显示大量Cas-L阳性淋巴细胞迁移到受累关节。最后，在人类RA中，已显示Cas-L阳性淋巴细胞浸润至炎性病变。上述结果有力地表明，Cas-L似乎在RA的病理生理学中发挥重要作用。

项目成果

Ouchida R, Kusuhara M, Shimizu N, Hisada T, Makino Y, Morimoto C, Handa H, Ohsuzu F, Tanaka H: "Suppression of NF-kappaB-dependent gene expression by a hexamethylene bisacetamide-inducible protein HEXIM1 in human vascular smooth muscle cells. Genes Cells"

Ouchida R、Kusuhara M、Shimizu N、Hisada T、Makino Y、Morimoto C、Handa H、Ohsuzu F、Tanaka H：“六亚甲基双乙酰胺诱导蛋白 HEXIM1 在人血管平滑肌中抑制 NF-kappaB 依赖性基因表达

Suzuki T, Nakamoto T, Ogawa S, Seo S, Matsumura T, Tachibana K, Morimoto C, Hirai H: "MICAL, a novel CasL interacting molecule, associates with vimentin"J Biol Chem. 277. 14933-14941 (2002)

Suzuki T、Nakamoto T、Okawa S、Seo S、Matsumura T、Tachibana K、Morimoto C、Hirai H：“MICAL，一种新型 CasL 相互作用分子，与波形蛋白结合”J Biol Chem。

lwata S: "Distinctive signaling pathways through CD82 and β1 integrins in human T cells"Eur.J.Immunol. 32. 1328-1337 (2002)

Iwata S：“人 T 细胞中通过 CD82 和 β1 整合素的独特信号传导途径”Eur.J.Immunol. 32. 1328-1337 (2002)

Hisakawa N, Tanaka H, Hosono O, Nishijima R, Ohashi Y, Saito S, Nishiya K, Hashimoto K, Morimoto C.: "Aberrant Responsiveness to RANTES in Synovial Fluid T cells ten Patients with Rheumatoid Arthritis"J. Rheumatol.. 29. 1124-1134 (2002)

Hisakawa N、Tanaka H、Hosono O、Nishijima R、Ohashi Y、Saito S、Nishiya K、Hashimoto K、Morimoto C.：“十名类风湿关节炎患者滑液 T 细胞对 RANTES 的异常反应”J。

Hase H, Kanno Y, Kojima H, Morimoto C, Okumura K, Kobala T: "CD27 and CD40 inhibit p53-independent mitochondrial pathways in apoptosis of B cells induced by B cell receptor ligation"J Biol Chem. 277. 46950-46958 (2002)

Hase H、Kanno Y、Kojima H、Morimoto C、Okumura K、Kobala T：“CD27 和 CD40 在 B 细胞受体连接诱导的 B 细胞凋亡中抑制 p53 独立的线粒体途径”J Biol Chem。