MyD88 signaling controls autoimmune myocarditis induction
MyD88 signaling controls autoimmune myocarditis induction
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DOI：
10.1161/circulationaha.105.564294
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发表时间：
2006-01-17
期刊：
影响因子：
37.8
通讯作者：
Eriksson, U
中科院分区：
文献类型：
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作者：
Marty, RR;Dirnhofer, S;Eriksson, U
背景-实验性自身免疫性心肌炎(EAM)是一种由CD4(+)T细胞介导的病毒后心肌病小鼠模型。白介素1型和Toll样受体的激活是疾病诱导所必需的，它们共享共同的下游适配器分子MyD88。然而，MyD88在心肌炎中的具体作用尚不清楚。方法和结果-与对照仔鼠相比，MyD88(-/-)小鼠在α-肌球蛋白重链衍生肽(MyHC-α)和完全弗氏佐剂免疫后，对心肌炎具有保护作用。MyD88(-/-)小鼠的抗病能力是由于免疫后心脏特异性CD4(+)T细胞的增殖受损所致。排除MyD88(-/-)CD4(+)T细胞固有缺陷。相反，MyD88(-/-)而不是MyD88(+/+)初级抗原提呈树突状细胞(DC)在启动CD4(+)T细胞的能力方面存在缺陷。这种缺陷主要是由于MyD88(-/-)DC不能释放肿瘤坏死因子-α所致。在MyD88(-/-)小鼠中，通过重复注射活化的、MyHC-α负载的MyD88(+/+)树突状细胞，完全恢复了T细胞的增殖和心肌炎，最终证实了MyD88信号在外周淋巴室树突状细胞中的关键作用。我们认为，MyD88可能成为预防心脏特异性自身免疫和心肌病的靶点。
Background - Experimental autoimmune myocarditis (EAM) is a CD4(+) T-cell - mediated mouse model of postviral cardiomyopathy. Activation of interleukin-1 type 1 and Toll-like receptors that share the common downstream adaptor molecule MyD88 is required for disease induction. The specific role of MyD88 in myocarditis, however, is not known.Methods and Results - In contrast to control littermates, MyD88(-/-) mice were protected from myocarditis after immunization with alpha-myosin heavy chain - derived peptide (MyHC-alpha) and complete Freund's adjuvant. Disease resistance of MyD88(-/-) mice resulted from impaired expansion of heart-specific CD4(+) T cells after immunization. Intrinsic defects of MyD88(-/-) CD4(+) T cells were excluded. In contrast, MyD88(-/-) but not MyD88(+/+) primary antigen presenting dendritic cells (DCs) were defective in their capacity to prime CD4(+) T cells. This defect mainly resulted from the inability of MyD88(-/-) DCs to release tumor necrosis factor-alpha. The critical role of MyD88 signaling in DCs in the peripheral lymphatic compartments was finally proven by repetitive injection of activated, MyHC-alpha-loaded MyD88(+/+) DCs that fully restored T-cell expansion and myocarditis in MyD88(-/-) mice.Conclusions - Autoimmune myocarditis induction depends on MyD88 signaling in self-antigen presenting cells in the peripheral compartments. We conclude that MyD88 might become a target for prevention of heart-specific autoimmunity and cardiomyopathy.