Identification of organ-specific cell surface molecules on T cells and endothelial cells in patients with systemic lupus erythematosus

系统性红斑狼疮患者 T 细胞和内皮细胞上器官特异性细胞表面分子的鉴定

• 批准号: 13470109
• 负责人: TANAKA Yoshiya
• 金额: $ 8.7万
• 依托单位: University of Occupational and Environmental Health, Japan
• 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 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470109/
• 关键词: systemic lupus erythematosus; T cells; endothelial cells; integrin; co-stimulatory molecules; adhesion molecules; homing molecules; organ-tropism; 全身エリテマトーデス; リンパ球; サイトカイン

Systemic lupus erythematosus (SLE) is a representative autoimmune disease, which is involved in multiple organs such as skin, kidney, central nervous system, lung and so on, and sometimes results in severe prognosis. However, the precise pathological mechanisms of each organ involvement and specific treatments for them remain unclear. We have intensively studied the mechanism of circulating T cell migration into tissues through binding with endothelial cells. Recent progress in the field clarifies certain homing molecules on T cells and endothelial cells could define organ-specific homing of T cells. In this study, we first estimated the molecules on peripheral T cells in SLE patients with skin involvement. T cells, especially Th2 cells and Tc2 cells, of SLE with skin involvement characteristically highly expressed cutaneous lymphocyte-associated antigen (CLA), whereas T cells of SLE without skin lesion possessed marginal amounts of CLA, indicating that CLA might play a role in skin ra … More sh of SLE. Next, we assessed expression of specific gene on endothelial cells purified from skin, bone/bone marrow, lung, kidney, joint, thyroid and brain, using gene chip analyses. Each endothelial cells express very interesting genes and among them, for instance, endothelial cells from synovial membrane highly expressed CD40L, enkephalin, tetranectin, C1-inhibitor, CSF-1, IL-1R, SDF-1 and so on. Based on these chip analyses would warrant further studies in the context of organ-tropism. Finally, we assessed cell surface co-stimulatory molecules on SLE T cells. Interestingly, CD28 was reduced or decreased on active SLE T cells, whereas CD29 was highly up-regulated on them. When CD29 was crosslinked by specific antibodies, T cells were efficiently activated through FAK-tyrosine kinase and CD40L and CD69 were rapidly induced on the cells. Combined with other results, CD29 could play a potent role in SLE T cell activation, in an independent manner on CD28, resulting in organ involvement such as lupus nephritis. Taken together, to clarify the mechanisms of organ-tropic involvement in SLE, as shown in the study, could lead to more specific therapeutic approaches to SLE. Less

系统性红斑狼疮（systemic lupus erythematosus，SLE）是一种具有代表性的自身免疫性疾病，累及皮肤、肾脏、中枢神经系统、肺等多个器官，有时导致严重的预后。然而，每个器官受累的确切病理机制和具体治疗方法仍不清楚。我们深入研究了循环T细胞通过与内皮细胞结合迁移到组织中的机制。最近的研究表明T细胞和内皮细胞上的某些归巢分子可以定义T细胞的器官特异性归巢。在这项研究中，我们首先估计了SLE患者皮肤受累的外周血T细胞上的分子。SLE皮肤损害患者T细胞，尤其是Th 2细胞和Tc 2细胞高表达皮肤淋巴细胞相关抗原（CLA），而无皮肤损害的SLE患者T细胞仅少量表达CLA，提示CLA可能在SLE皮肤损害中起作用。 ...更多信息 SLE的SH。接下来，我们使用基因芯片分析来评估从皮肤、骨/骨髓、肺、肾、关节、甲状腺和脑纯化的内皮细胞上的特定基因的表达。每个内皮细胞都表达非常有趣的基因，其中滑膜内皮细胞高表达CD 40 L、脑啡肽、四连接素、C1抑制剂、CSF-1、IL-1 R、SDF-1等，这些基因的芯片分析为进一步研究内皮细胞的器官嗜性提供了依据。最后，我们评估了SLE T细胞上的细胞表面共刺激分子。有趣的是，CD 28在活动的SLE T细胞上减少或降低，而CD 29在它们上高度上调。当CD 29被特异性抗体交联时，T细胞通过FAK-酪氨酸激酶被有效地激活，并且在细胞上迅速诱导CD 40 L和CD 69。结合其他结果，CD 29可能在SLE T细胞活化中发挥有效作用，以独立于CD 28的方式，导致器官受累，如狼疮肾炎。综上所述，阐明SLE的器官嗜性参与机制，如研究所示，可能会导致更具体的治疗方法。少

项目成果

Fujii K: "CD44 is the physiological trigger of Fas up-regulation on rheumatoid synovial cells"J Immunol. 167. 1198-1203 (2001)

Fujii K：“CD44 是类风湿滑膜细胞 Fas 上调的生理触发因素”J Nutrition。

Nakayamada S, Okada Y, Saito K, Tamura M, Tanaka Y.: "β1 integrin/focal adhesion kinase-mediated signaling induces intercellular adhesion molecule 1 and receptor activator of nuclear factor κB ligand on osteoblast and osteoclast maturation."J Biol Chem. 2

Nakayamada S、Okada Y、Saito K、Tamura M、Tanaka Y.：“β1 整合素/粘着斑激酶介导的信号传导诱导成骨细胞和破骨细胞成熟过程中的细胞间粘附分子 1 和核因子 κB 配体的受体激活剂。”J Biol Chem。 2

Fujii K, Fujii Y, Hubscher S, Tanaka Y: "CD44 is the physiological trigger of Fas up-regulation on rheumatoid synovial cells."J Immunol. 167. 1198-1203 (2001)

Fujii K、Fujii Y、Hubscher S、Tanaka Y：“CD44 是类风湿滑膜细胞 Fas 上调的生理触发因素。”J 免疫学杂志。

Iida T: "Hypoxia-inducible factor-1α induces cell cycle arrest of endothelial cells"Genes to Cells. 7. 143-149 (2002)

Iida T：“缺氧诱导因子 1α 诱导内皮细胞的细胞周期停滞”《Genes to Cells》7. 143-149 (2002)。

Nakayamada S: "β1 integrin-mediated signaling induces ICAM-1 and Fas and Fas-mediated apoptosis of rheumatoid synovial cells"Arthritis Rheum. (in press).

Nakayamada S：“β1 整合素介导的信号传导诱导 ICAM-1 和 Fas 以及 Fas 介导的类风湿滑膜细胞凋亡”关节炎大黄（Arthritis Rheum）。