Analysis of new biomarker for evaluation of SLE activity with autoantibody penetration to cells

分析用于评估 SLE 活性的新生物标志物以及自身抗体渗透到细胞的情况

• 批准号: 17590483
• 负责人: ISHII Tomonori
• 金额: $ 2.24万
• 依托单位: Tohoku University
• 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-17590483/
• 关键词: SLE; anti-DNA antibody; Dendritic cell; MLR; ラフト; カベオラ; MDDC; 細胞内侵入; Fc receptor

Systemic lupus erythematosus (SLE) involves a variety of autoantibodies which may be responsible for the tissue injury. Immunoglobulin G (IgG), especially anti-DNA IgG from active SLE had an ability to penetrate into peripheral blood mononuclear cells in vitro. The target cells for the penetration are CD8 (+) T cells, B cells, NK cells, monocytes, dendritic cells (DC) in circulation. Anti-Fc antibodies failed to cause the inhibition of anti-DNA IgG penetration into cells, but the coexistence of methyl beta cyclodextrin, raft/caveolae inhibitor, or DNA antigen blocked the internalization. Immunofluorescence studies revealed that anti-DNA IgG used raft/caveolae for their entry into the cells, and were distributed in lysosome, but not detected in the nuclei. The penetration caused to alter the biological function of the immunocytes. Namely, purified anti-DNA IgG induced the maturation and activation of human monocyte-derived dendritic cell as observed by CD83 up-regulation, IL12 secretion and an enhanced stimulation of allogenic or autologus T cells to DC at mixed lymphocyte reaction. Our results provide a new sight for the role of anti-DNA autoantibodies at cell function such as maturation and production of several proteins like cytokines, and may explain a novel mechanism where peripheral tolerance is broken in SLE patients.

系统性红斑狼疮 (SLE) 涉及多种可能导致组织损伤的自身抗体。免疫球蛋白 G (IgG)，特别是来自活动性 SLE 的抗 DNA IgG，能够在体外渗透到外周血单核细胞中。渗透的靶细胞是循环中的CD8(+)T细胞、B细胞、NK细胞、单核细胞、树突状细胞(DC)。抗Fc抗体未能抑制抗DNA IgG渗透入细胞，但甲基β环糊精、筏/小窝抑制剂或DNA抗原的共存阻止了内化。免疫荧光研究表明，抗 DNA IgG 使用筏/小凹进入细胞，并分布在溶酶体中，但在细胞核中未检测到。渗透导致改变免疫细胞的生物学功能。即，通过CD83上调、IL12分泌以及混合淋巴细胞反应中同种异体或自体T细胞对DC的增强刺激观察到，纯化的抗DNA IgG诱导人单核细胞衍生的树突状细胞的成熟和活化。我们的研究结果为抗 DNA 自身抗体在细胞功能（例如细胞因子等多种蛋白质的成熟和产生）中的作用提供了新的视角，并可能解释 SLE 患者外周耐受性被破坏的新机制。