Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis
Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis
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DOI：
10.1172/jci26078
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发表时间：
2006-02-01
影响因子：
15.9
通讯作者：
Becher, B
中科院分区：
文献类型：
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作者：
Prinz, M;Garbe, F;Becher, B
CNS的炎症性疾病（例如MS及其动物模型EA）的特征是将活化的淋巴细胞和吞噬细胞浸润到中枢神经系统中。在中枢神经系统中，居民细胞的激活引发了炎症性级联反应，从而导致组织破坏，脱髓鞘和神经系统缺陷。 TLR识别微生物，是先天免疫的关键介体。在中枢神经系统中，即使在没有任何明显的微生物受累的情况下，也观察到EAE期间的增强TLR表达。为了确定这种现象在无菌自身免疫性期间的功能相关性，我们研究了不同TLR以及它们常见的信号衔接子MyD88在EAE开发中的作用。我们发现MyD88（ - / - ）小鼠完全具有抗EAE。令人惊讶的是，这种保护部分是由于CPG受体TLR9的参与。将MYD88或TLR9突变限制为托管抗射电细胞。包括中枢神经系统中的细胞包括抗性细胞的参与调节疾病病程和组织病理学变化。我们的数据非常表明，TLR9和MYD88都是疾病效应阶段自身免疫过程的重要调节剂，并表明内源性“危险信号”调节了疾病的发病机理。
Inflammatory diseases of the CNS, such as MS and its animal model EAE, are characterized by infiltration of activated lymphocytes and phagocytes into the CNS. Within the CNS, activation of resident cells initiates an inflammatory cascade, leading to tissue destruction, demyelination, and neurologic deficit. TLRs recognize microbes and are pivotal mediators of innate immunity. Within the CNS, augmented TLR expression during EAE is observed, even in the absence of any apparent microbial involvement. To determine the functional relevance of this phenomenon during sterile autoimmunity, we studied the role of different TLRs as well as their common signaling adaptor MyD88 in the development of EAE. We found that MyD88(-/-) mice were completely EAE resistant. Surprisingly, this protection is partly due to engagement of the CpG receptor TLR9. Restricting the MyD88 or TLR9 mutation to host radio-resistant cells. including the cells within the CNS, revealed that engagement of radio-resistant cells modulated the disease course and histopathological changes. Our data dearly demonstrate that both TLR9 and MyD88 are essential modulators of the autoimmune process during the effector phase of disease and suggest that endogenous "danger signals" modulate the disease pathogenesis.