Marty René R, Dirnhofer Stephan, Mauermann Nora, Schweikert Sacha, Akira Shizuo, Hunziker Lukas, Penninger Josef M, Eriksson Urs
Division of Experimental Critical Care Medicine, Department of Research, University Hospital, Basel, Switzerland.
Circulation. 2006 Jan 17;113(2):258-65. doi: 10.1161/CIRCULATIONAHA.105.564294. Epub 2006 Jan 9.
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.
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.
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.
实验性自身免疫性心肌炎（EAM）是一种由CD4 + T细胞介导的病毒性心肌病小鼠模型。疾病诱导需要激活共同下游衔接分子MyD88的白细胞介素-1 型受体和Toll样受体。然而，MyD88在心肌炎中的具体作用尚不清楚。
与对照同窝小鼠相比，MyD88（-/-）小鼠在用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抵抗力。MyD88（-/-）小鼠的抗病性是由于免疫后心脏特异性CD4 + T细胞的扩增受损。排除了MyD88（-/-）CD4 + T细胞的内在缺陷。相反，MyD88（-/-）而非MyD88（+/ +）的原发性抗原呈递树突状细胞（DC）在启动CD4 + T细胞的能力上存在缺陷。这种缺陷主要是由于MyD88（-/-）DC无法释放肿瘤坏死因子-α。通过重复注射活化的、负载MyHC-α的MyD88（+/ +）DC最终证明了外周淋巴区室中DC中MyD88信号传导的关键作用，这些DC完全恢复了MyD88（-/-）小鼠的T细胞扩增和心肌炎。
自身免疫性心肌炎的诱导取决于外周区室中自身抗原呈递细胞中的MyD88信号传导。我们得出结论，MyD88可能成为预防心脏特异性自身免疫和心肌病的靶点。
