Harnesk Karin, Swanberg Maria, Diez Margarita, Olsson Tomas, Piehl Fredrik, Lidman Olle
Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
J Neuroimmunol. 2009 Jul 25;212(1-2):44-52. doi: 10.1016/j.jneuroim.2009.04.019. Epub 2009 May 29.
Major histocompatibility complex (MHC) class II is of critical importance for the induction of immune responses. Levels of MHC class II in the nervous system are normally low, but expression is up-regulated in many disease conditions. In rat and human, variation in the MHC class II transactivator gene (C2ta) is associated with differential expression of MHC class II and susceptibility to autoimmune disease. Here we have characterized the response to facial nerve transection in 7 inbred mouse strains (C57BL/6J, DBA/2J, 129X1/SvJ, BALB/cJ, SJL/J, CBA/J, and NOD). The results demonstrate differences in expression of C2ta and markers for MHC class I and II expression, glial activation, and T cell infiltration. Expression levels of C2ta and Cd74 followed similar patterns, in contrast to MHC class I and markers of glial activation. The regulatory region of the C2ta gene was subsequently sequenced in the four strains (C57BL/6/J, DBA/2J, SJL/J and 129X1/SvJ) that represented the phenotypical extremes with regard to C2ta/Cd74 expression. We found 3 single nucleotide polymorphisms in the type I (pI) and type III (pIII) promoters of C2ta, respectively. Higher expression of pI in 129X1/SvJ correlated with the pI haplotype specific for this strain. Furthermore, congenic strains carrying the 129X1/SvJ C2ta allele on B6 background displayed significantly higher C2ta and Cd74 expression compared to parental controls. We conclude that genetic polymorphisms in the type I promoter of C2ta regulates differential expression of MHC class II, but not MHC class I, Cd3 and other markers of glial activation.
主要组织相容性复合体(MHC)II类分子对于诱导免疫反应至关重要。神经系统中MHC II类分子的水平通常较低,但在许多疾病状态下其表达会上调。在大鼠和人类中,MHC II类反式激活因子基因(C2ta)的变异与MHC II类分子的差异表达以及自身免疫性疾病易感性相关。在此,我们对7个近交系小鼠品系(C57BL/6J、DBA/2J、129X1/SvJ、BALB/cJ、SJL/J、CBA/J和NOD)对面神经横断的反应进行了特征分析。结果显示,C2ta以及MHC I类和II类表达、胶质细胞活化和T细胞浸润标志物的表达存在差异。与MHC I类分子和胶质细胞活化标志物不同,C2ta和Cd74的表达水平呈现相似模式。随后,我们对代表C2ta/Cd74表达表型极端情况的四个品系(C57BL/6/J、DBA/2J、SJL/J和129X1/SvJ)的C2ta基因调控区进行了测序。我们分别在C2ta的I型(pI)和III型(pIII)启动子中发现了3个单核苷酸多态性。129X1/SvJ品系中pI的较高表达与该品系特有的pI单倍型相关。此外,在B6背景上携带129X1/SvJ C2ta等位基因的同源近交系与亲本对照相比,C2ta和Cd74表达显著更高。我们得出结论,C2ta的I型启动子中的基因多态性调节MHC II类分子的差异表达,但不调节MHC I类分子、Cd3和其他胶质细胞活化标志物的表达。