Kroner Antje, Schwab Nicholas, Ip Chi Wang, Sommer Claudia, Wessig Carsten, Wiendl Heinz, Martini Rudolf
Department of Neurology, University of Wuerzburg, Wuerzburg.
Neurobiol Dis. 2009 Jan;33(1):96-103. doi: 10.1016/j.nbd.2008.09.021. Epub 2008 Oct 15.
We have previously shown that mice heterozygously deficient for P0 are characterized by a late onset myelin disorder implicating CD8+ T-lymphocytes and macrophages. We now investigated the impact of the co-inhibitory molecule "programmed death" (PD)-1 (CD279), a CD28-related receptor expressed on activated T- and B-lymphocytes on the pathogenic phenotype of CD8+ T-lymphocytes in the P0 myelin mutants. PD-1 deficiency in P0+/- mice leads to a stronger increase of CD8+ T-lymphocytes and a substantially aggravated histological phenotype in the PNS compared to P0+/- mice expressing PD-1. Correspondingly, functional down-stream features, such as electrophysiological parameters, walking coordination and mechano-sensation are more affected than in PD-1-expressing myelin mutants. Our study demonstrates that a monogenic nerve disorder can be substantially modified by immune-controlling mechanisms. Thus, understanding the implication of disease-modifiers in inherited demyelination could be of pivotal interest for limiting the detrimental impact of primarily genetically-mediated myelin disorders by fostering immuno-regulatory pathways.
我们之前已经表明，P0基因杂合缺失的小鼠具有迟发性髓鞘疾病的特征，涉及CD8 + T淋巴细胞和巨噬细胞。我们现在研究了共抑制分子“程序性死亡”（PD）-1（CD279），一种在活化的T淋巴细胞和B淋巴细胞上表达的与CD28相关的受体，对P0髓鞘突变体中CD8 + T淋巴细胞致病表型的影响。与表达PD-1的P0 +/-小鼠相比，P0 +/-小鼠中PD-1缺乏导致CD8 + T淋巴细胞更强的增加以及周围神经系统中组织学表型的显著加重。相应地，功能下游特征，如电生理参数、行走协调性和机械感觉，比表达PD-1的髓鞘突变体受到的影响更大。我们的研究表明，单基因神经疾病可以通过免疫控制机制得到实质性改变。因此，了解疾病修饰因子在遗传性脱髓鞘中的作用可能对于通过促进免疫调节途径来限制主要由基因介导的髓鞘疾病的有害影响至关重要。
