Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling.
Pharmacological prion protein silencing accelerates central nervous system autoimmune disease via T cell receptor signalling.
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DOI：
10.1093/brain/awp298
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Stüve O
中科院分区：
文献类型：
--
作者：
Hu W;Nessler S;Hemmer B;Eagar TN;Kane LP;Leliveld SR;Müller-Schiffmann A;Gocke AR;Lovett-Racke A;Ben LH;Hussain RZ;Breil A;Elliott JL;Puttaparthi K;Cravens PD;Singh MP;Petsch B;Stitz L;Racke MK;Korth C;Stüve O
内源性细胞朊病毒蛋白的主要生物学功能仍不清楚。我们在体内和体外使用细胞朊蛋白基因特异性小干扰核糖核酸研究其在细胞免疫应答产生中的生物学功能。我们的研究结果得到证实，通过阻断细胞朊蛋白与单价抗体，并通过使用细胞朊蛋白缺陷和转基因小鼠。体内朊病毒蛋白基因-小干扰核糖核酸治疗效应持续时间有限，仅限于次级淋巴器官，导致白细胞中细胞朊病毒蛋白表达减少70%。细胞朊病毒蛋白信号传导的破坏增强了抗原特异性活化和增殖，并增强了T细胞受体信号传导，导致zeta链相关蛋白-70磷酸化和活化T细胞核因子/激活蛋白1转录活性。体内朊病毒蛋白基因-小干扰核糖核酸处理促进T细胞向促炎表型分化，并增加抗原特异性T细胞的存活。细胞朊病毒蛋白沉默与小干扰核糖核酸也导致积极诱导和过继转移的实验性自身免疫性脑脊髓炎的恶化。最后，用朊蛋白基因-小干扰核糖核酸治疗髓鞘碱性蛋白1 -11 T细胞受体转基因小鼠，导致自发性实验性自身免疫性脑脊髓炎。因此，中枢神经系统自身免疫性疾病在疾病的所有阶段都受到调节：T细胞效应子应答的产生、T效应子功能的激发和细胞免疫应答的持续。我们的研究结果表明，细胞朊病毒蛋白调节T细胞受体介导的T细胞活化，分化和存活。自身免疫缺陷仅限于免疫系统，而不是中枢神经系统。我们的数据确定细胞朊病毒蛋白作为细胞免疫稳态的调节剂，并建议细胞朊病毒蛋白作为一种新的潜在的治疗免疫调节的目标。
The primary biological function of the endogenous cellular prion protein has remained unclear. We investigated its biological function in the generation of cellular immune responses using cellular prion protein gene-specific small interfering ribonucleic acid in vivo and in vitro. Our results were confirmed by blocking cellular prion protein with monovalent antibodies and by using cellular prion protein-deficient and -transgenic mice. In vivo prion protein gene-small interfering ribonucleic acid treatment effects were of limited duration, restricted to secondary lymphoid organs and resulted in a 70% reduction of cellular prion protein expression in leukocytes. Disruption of cellular prion protein signalling augmented antigen-specific activation and proliferation, and enhanced T cell receptor signalling, resulting in zeta-chain-associated protein-70 phosphorylation and nuclear factor of activated T cells/activator protein 1 transcriptional activity. In vivo prion protein gene-small interfering ribonucleic acid treatment promoted T cell differentiation towards pro-inflammatory phenotypes and increased survival of antigen-specific T cells. Cellular prion protein silencing with small interfering ribonucleic acid also resulted in the worsening of actively induced and adoptively transferred experimental autoimmune encephalomyelitis. Finally, treatment of myelin basic protein1–11 T cell receptor transgenic mice with prion protein gene-small interfering ribonucleic acid resulted in spontaneous experimental autoimmune encephalomyelitis. Thus, central nervous system autoimmune disease was modulated at all stages of disease: the generation of the T cell effector response, the elicitation of T effector function and the perpetuation of cellular immune responses. Our findings indicate that cellular prion protein regulates T cell receptor-mediated T cell activation, differentiation and survival. Defects in autoimmunity are restricted to the immune system and not the central nervous system. Our data identify cellular prion protein as a regulator of cellular immunological homoeostasis and suggest cellular prion protein as a novel potential target for therapeutic immunomodulation.
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影响因子：
64.5
作者：
LAFAILLE, JJ;NAGASHIMA, K;TONEGAWA, S
通讯作者：
TONEGAWA, S
影响因子：
6
作者：
Tsutsui, Shigeki;Hahn, Jennifer N.;Jirik, Frank R.
通讯作者：
Jirik, Frank R.
影响因子：
4.4
作者：
Stüve, O;Youssef, S;Zamvil, SS
通讯作者：
Zamvil, SS
影响因子：
3.6
作者：
Mueller-Schiffmann, Andreas;Petsch, Benjamin;Korth, Carsten
通讯作者：
Korth, Carsten
影响因子：
4.3
作者：
Li, RL;Liu, DC;Sy, MS
通讯作者：
Sy, MS