Nature Immunol：关闭基因Arih2或可治疗肝炎

cwy121

2012年11月26日 讯 / --一项新研究发现基因Arih2是免疫系统功能的基础，能对免疫反应是否的开启起决定性作用。它的发现能对治疗慢性感染如HIV，免疫系统疾病以及慢性炎症疾病如类风湿关节炎和败血症的治疗带来新思路。

研究结果发表在Nature Immunology杂志上。Arih2被发现存在于免疫系统哨兵树突状细胞中，其在抵抗外来入侵者发挥了至关重要的作用。

Arih2是免疫反应是否应启动或关闭最根本，最重要的决定因子。如果作出错误的决定，机体将屈服于感染，或发生自身免疫性疾病。我们的免疫系统运作良好，对许多感染已经建立了精确生物机制以逃避或对抗感染。

但在进化过程中，一些生物已经进化耗尽我们的免疫系统，这也是我们罹患HIV，乙肝和结核病的原因。Ebert博士说，研究小组正在分析短的时间内关闭Arih2对慢性感染免疫反应的影响。Arih2具有独特的结构，我们认为这是一个很好的药物靶标，但开发出以此为靶点的药物还需数年的研究）


doi:10.1038/ni.2478
PMC:
PMID:
ARIH2 is essential for embryogenesis, and its hematopoietic deficiency causes lethal activation of the immune system

Amy E Lin,Gregor Ebert,Yongkai Ow,et al.

The E3 ligase ARIH2 has an unusual structure and mechanism of elongating ubiquitin chains. To understand its physiological role, we generated gene-targeted mice deficient in ARIH2. ARIH2 deficiency resulted in the embryonic death of C57BL/6 mice. On a mixed genetic background, the lethality was attenuated, with some mice surviving beyond weaning and then succumbing to an aggressive multiorgan inflammatory response. We found that in dendritic cells (DCs), ARIH2 caused degradation of the inhibitor IκBβ in the nucleus, which abrogated its ability to sequester, protect and transcriptionally coactivate the transcription factor subunit p65 in the nucleus. Loss of ARIH2 caused dysregulated activation of the transcription factor NF-κB in DCs, which led to lethal activation of the immune system in ARIH2-sufficent mice reconstituted with ARIH2-deficient hematopoietic stem cells. Our data have therapeutic implications for targeting ARIH2 function.

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