Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis.
Th Cell Diversity in Experimental Autoimmune Encephalomyelitis and Multiple Sclerosis.
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DOI：
10.4049/jimmunol.1501097
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发表时间：
2015-09-15
期刊：
影响因子：
--
通讯作者：
Segal BM
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文献类型：
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作者：
Carbajal KS;Mironova Y;Ulrich-Lewis JT;Kulkarni D;Grifka-Walk HM;Huber AK;Shrager P;Giger RJ;Segal BM
多发性硬化症（MS）被认为是由髓磷脂反应性CD 4 + Th细胞引发的。IL-12极化的Th 1细胞、IL-23极化的Th 17细胞和exTh 17细胞（获得Th 1特征的Th 17细胞）各自涉及自身免疫发病机制。目前有争议的是，Th细胞是否可以驱动脱髓鞘病变的发展是表型多样性或来自单一谱系。在当前的研究中，我们评估了IL-12或IL-23刺激以及Th可塑性对能够诱导CNS轴突损伤的T细胞分化的需求。我们发现，稳定的小鼠Th 1和Th 17细胞独立地转移实验性自身免疫性脑脊髓炎（EAE，广泛用作MS的动物模型）在IL-23和IL-12的情况下，分别。可塑性Th 17细胞是脱髓鞘和轴突病的特别有效的介质。在平行研究中，我们确定了MS患者在一年内对髓鞘碱性蛋白（MBP）的IFNγ-或IL-17-偏斜反应持续增加。脑磁共振成像显示，具有混合IFNγ和IL-17反应的患者具有相对较高的T1病变负荷，这是永久性轴突损伤的衡量标准。我们的数据挑战了IL-23和Th 17可塑性是EAE发展所普遍需要的教条。这项研究明确表明，自身免疫性脱髓鞘疾病可以由不同的Th极化因子和效应子亚群驱动，强调了定制方法对MS药物管理的重要性。
Multiple sclerosis (MS) is believed to be initiated by myelin-reactive CD4+ Th cells. IL-12 polarized Th1 cells, IL-23 polarized Th17 cells, and exTh17 cells (Th17 cells that acquire Th1 characteristics) have each been implicated in autoimmune pathogenesis. It is currently debated whether Th cells that can drive the development of demyelinating lesions are phenotypically diverse or arise from a single lineage. In the current study we assess the requirement of IL-12 or IL-23 stimulation, as well as Th plasticity, for the differentiation of T cells capable of inducing CNS axon damage. We found that stable murine Th1 and Th17 cells independently transfer experimental autoimmune encephalomyelitis (EAE, widely used as an animal model of MS) in the absence of IL-23 and IL-12, respectively. Plastic Th17 cells are particularly potent mediators of demyelination and axonopathy. In parallel studies, we identified MS patients who consistently mount either IFNγ- or IL-17- skewed responses to myelin basic protein (MBP) over the course of a year. Brain magnetic resonance imaging revealed that patients with mixed IFNγ and IL-17 responses have relatively high T1 lesion burden, a measure of permanent axon damage. Our data challenge the dogma that IL-23 and Th17 plasticity are universally required for the development of EAE. This study definitively demonstrates that autoimmune demyelinating disease can be driven by distinct Th polarizing factors and effector subsets, underscoring the importance of a customized approach to the pharmaceutical management of MS.