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）涉及多种自身抗体，这些抗体可能是导致组织损伤的原因。免疫球蛋白G（IgG），尤其是活动期SLE抗DNA IgG，在体外具有穿透外周血单个核细胞的能力。用于穿透的靶细胞是循环中的CD 8（+）T细胞、B细胞、NK细胞、单核细胞、树突状细胞（DC）。抗-Fc抗体不能引起抗-DNA IgG渗透到细胞中的抑制，但是甲基β环糊精、筏/小窝抑制剂或DNA抗原的共存阻断了内化。免疫荧光研究显示，抗DNA IgG以筏状/小窝状进入细胞，主要分布于溶酶体，而在细胞核内未检测到。渗透导致免疫细胞的生物学功能改变。即，纯化的抗DNA IgG诱导人单核细胞来源的树突状细胞的成熟和活化，如通过在混合淋巴细胞反应中观察到的CD 83上调、IL 12分泌和同种异体或自体T细胞对DC的增强刺激。我们的研究结果为抗DNA自身抗体在细胞功能中的作用提供了新的视角，如成熟和产生几种蛋白质如细胞因子，并可能解释SLE患者外周耐受被打破的新机制。