ERK1-/- mice exhibit Th1 cell polarization and increased susceptibility to experimental autoimmune encephalomyelitis
ERK1-/- mice exhibit Th1 cell polarization and increased susceptibility to experimental autoimmune encephalomyelitis
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DOI：
10.4049/jimmunol.176.10.5788
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发表时间：
2006-05-15
影响因子：
4.4
通讯作者：
Pulendran, Bali
中科院分区：
文献类型：
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作者：
Agrawal, Anshu;Dillon, Stephanie;Pulendran, Bali
MAPK/ERK 1/2的激活在Th 1/Th 2极化和调节APC产生细胞因子中起重要作用。ERK家族由两个成员ERK 1和ERK 2组成，它们在氨基酸水平上具有相似的84%的同源性，并且可以在大多数功能上相互补偿。尽管有这些特征，ERK 1和ERK 2确实具有不同的功能，但关于ERK个体形式对先天性和适应性免疫应答的贡献的信息很少。在这项研究中，我们描述了ERKI-/-小鼠显示偏向Th 1型免疫应答。与该观察结果一致，来自ERK 1（-/-）小鼠的树突状细胞显示响应TLR刺激的IL-12 p70分泌增强和IL-10分泌减少。此外，与野生型小鼠相比，来自ERK 1（-/-）小鼠的血清具有高100倍的总IgG 2b和高10倍的总IgG 2a和IgG 1 Ab同种型滴度，以及增强的Ag特异性IgG 2b Ab滴度水平。与这种增强的Th 1偏倚一致，ERK 1-/-小鼠表现出对髓鞘少突胶质细胞糖蛋白（MOG）35-55肽诱导的实验性自身免疫性脑脊髓炎（EAE）的易感性增强，与野生型小鼠相比，EAE发生更早，严重程度增加。重要的是，在ERK 1（-/-）小鼠中存在向Th 1应答的显著倾斜，在MOG 35 -55致敏的T细胞中具有较高的IFN-γ产生和较低的IL-5产生，以及MOG特异性IgG 2a和IgG 2b Th 1 Ab同种型的增加。最后，在ERK 1-/-小鼠的脊髓中观察到浸润细胞增加和髓鞘破坏。综上所述，我们的数据表明，ERK 1的缺陷偏向Th 1的免疫反应，导致EAE的易感性增加。
Activation of MAPK ERK1/2 has been shown to play an important role in Th1/Th2 polarization and in regulating cytokine production from APCs. The ERK family consists of two members ERK1 and ERK2, which share similar to 84% identity at the amino acid level and can compensate for each other for most functions. Despite these features, ERK1 and ERK2 do serve different functions, but there is very little information on the contribution of individual forms of ERK on innate and adaptive immune responses. In this study, we describe that ERKI-/- mice display a bias toward Th1 type immune response. Consistent with this observation, dendritic cells from ERK1(-/-) mice show enhanced IL-12p70 and reduced IL-10 secretion in response to TLR stimulation. Furthermore, serum from ERK1(-/-) mice had 100-fold higher total IgG2b and 10-fold higher total IgG2a and IgG1 Ab isotype titers, and enhanced levels of Ag-specific IgG2b Ab titers, compared with wild-type mice. Consistent with this enhanced Th1 bias, ERK1-/- mice showed enhanced susceptibility to myelin oligodendrocyte glycoprotein (MOG)35-55 peptide-induced experimental autoimmune encephalomyelitis (EAE) and developed EAE earlier, and with increased severity, compared with wild-type mice. Importantly, there was a profound skewing toward Th1 responses in ERK1(-/-) mice, with higher IFN-gamma production and lower IL-5 production in MOG35-55-primed T cells, as well as an augmentation in the MOG-specific IgG2a and IgG2b Th1 Ab isotypes. Finally, increased infiltrating cells and myelin destruction was observed in the spinal cord of ERK1-/- mice. Taken together, our data suggest that deficiency of ERK1 biases the immune response toward Th1 resulting in increased susceptibility to EAE.