Departments of Pathology and of Molecular Microbiology and Immunology, The Johns Hopkins Schools of Medicine and Public Health, Baltimore, Maryland 21205, USA.
J Interferon Cytokine Res. 2011 Oct;31(10):705-10. doi: 10.1089/jir.2011.0057. Epub 2011 Aug 23.
Infectious disease is frequently cited as a precursor of subsequent autoimmune disease in genetically susceptible hosts. However, the precise mechanisms required for the transition from infection to autoimmunity have not been well defined. We have developed a mouse model of autoimmune myocarditis initiated by infection with Coxsackievirus B3 to trace the cytokine pathways involved. We found that greater production of interleukin-1β (IL-1β) and tumor necrosis factor-α during the early innate response to virus infection is necessary and sufficient to induce a later heart-specific autoimmune disease. Severity of the autoimmune myocarditis is determined by the profile of a number of T helper 1 (Th1) and Th2 cytokines. Th2 responses are especially pronounced in the most severe forms of myocarditis where eosinophils are prominent. The Th1 pathway can lead to infiltration of the heart, but may be dampened by concurrent INF-γ production. Th17 cytokines also contribute to disease, but the signature Th17 cytokine, IL-17A, is not required for cardiac inflammation. Rather, IL-17A is needed for progression to dilated cardiomyopathy. These findings may provide useful markers to identify individuals prone to develop an autoimmune sequel after infection and suggest future early interventions.
传染病常被认为是遗传易感宿主随后发生自身免疫性疾病的先兆。然而，从感染到自身免疫的转变的确切机制尚未得到很好的定义。我们已经建立了一种柯萨奇病毒 B3 感染引发自身免疫性心肌炎的小鼠模型，以追踪涉及的细胞因子途径。我们发现，在病毒感染的早期固有反应中产生更多的白细胞介素-1β（IL-1β）和肿瘤坏死因子-α，对于诱导随后的心脏特异性自身免疫性疾病是必要和充分的。自身免疫性心肌炎的严重程度取决于许多辅助性 T 细胞 1（Th1）和 Th2 细胞因子的特征。在最严重的心肌炎中，Th2 反应尤为明显，其中嗜酸性粒细胞突出。Th1 途径可导致心脏浸润，但可能被同时产生的 INF-γ所抑制。Th17 细胞因子也有助于疾病，但特征性的 Th17 细胞因子 IL-17A 并不需要心脏炎症。相反，IL-17A 对于进展为扩张型心肌病是必需的。这些发现可能为识别感染后易发生自身免疫性疾病的个体提供有用的标志物，并提示未来的早期干预措施。
