Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis
Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis
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DOI：
10.1073/pnas.1000082107
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发表时间：
2011-03-15
影响因子：
11.1
通讯作者：
Mazmanian, Sarkis K.
中科院分区：
文献类型：
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作者：
Lee, Yun Kyung;Menezes, Juscilene S.;Mazmanian, Sarkis K.
虽然共生菌对肠道免疫发育的影响似乎是深远的，但肠道微生物群是否影响肠外生物功能仍是推测性的。多发性硬化症（MS）是一种毁灭性的自身免疫性疾病，导致神经功能进行性恶化。虽然MS的病因不明，但微生物似乎对疾病的发生和/或进展很重要。然而，尚不清楚微生物定植（无论是共生的还是感染性的）如何影响自身免疫。在此，我们研究了微生物群在诱导实验性自身免疫性脑脊髓炎（EAE）中的作用，这是一种ms动物模型。与常规定植的小鼠相比，无菌条件下维持的小鼠EAE明显减弱。EAE诱导的无菌动物在肠道和脊髓中产生较低水平的促炎细胞因子ifn - γ和IL-17A，但CD4(+)CD25(+)Foxp（3+）调节性T细胞（Tregs）显示出相应的增加。从机制上讲，我们发现无菌动物的肠道树突状细胞刺激促炎T细胞反应的能力降低。已知分节丝状细菌（SFB）的肠道定植可促进肠道中IL-17的产生；本研究表明，SFBs还能诱导中枢神经系统中产生il - 17a的CD4(+) T细胞（Th17）。值得注意的是，单独携带SFBs的无菌动物发生了EAE，这表明肠道细菌可以影响神经炎症。这些发现表明，肠道菌群深刻影响EAE过程中促炎和抗炎免疫反应的平衡，并提示肠道菌群的调节可能为MS等肠外炎症性疾病提供治疗靶点。
Although the effects of commensal bacteria on intestinal immune development seem to be profound, it remains speculative whether the gut microbiota influences extraintestinal biological functions. Multiple sclerosis (MS) is a devastating autoimmune disease leading to progressive deterioration of neurological function. Although the cause of MS is unknown, microorganisms seem to be important for the onset and/or progression of disease. However, it is unclear how microbial colonization, either symbiotic or infectious, affects autoimmunity. Herein, we investigate a role for the microbiota during the induction of experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice maintained under germ-free conditions develop significantly attenuated EAE compared with conventionally colonized mice. Germ-free animals, induced for EAE, produce lower levels of the proinflammatory cytokines IFN-gamma and IL-17A in both the intestine and spinal cord but display a reciprocal increase in CD4(+)CD25(+)Foxp(3+) regulatory T cells (Tregs). Mechanistically, we show that gut dendritic cells from germ-free animals are reduced in the ability to stimulate proinflammatory T cell responses. Intestinal colonization with segmented filamentous bacteria (SFB) is known to promote IL-17 production in the gut; here, we show that SFBs also induced IL-17A-producing CD4(+) T cells (Th17) in the CNS. Remarkably, germ-free animals harboring SFBs alone developed EAE, showing that gut bacteria can affect neurologic inflammation. These findings reveal that the intestinal microbiota profoundly impacts the balance between pro-and antiinflammatory immune responses during EAE and suggest that modulation of gut bacteria may provide therapeutic targets for extraintestinal inflammatory diseases such as MS.