Allograft Inflammatory Factor-1 Links T-Cell Activation, Interferon Response, and Macrophage Activation in Chronic Kawasaki Disease Arteritis
Allograft Inflammatory Factor-1 Links T-Cell Activation, Interferon Response, and Macrophage Activation in Chronic Kawasaki Disease Arteritis
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DOI：
10.1093/jpids/pix025
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发表时间：
2017-09
影响因子：
3.2
通讯作者：
A. Rowley;S. Baker;Kwang-Youn A. Kim;S. Shulman;A. Yang;D. Arrollo;Matthew DeBerge;Shuling Han;N. Sibinga;Adam J. Pink;E. Thorp
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文献类型：
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作者：
A. Rowley;S. Baker;Kwang-Youn A. Kim;S. Shulman;A. Yang;D. Arrollo;Matthew DeBerge;Shuling Han;N. Sibinga;Adam J. Pink;E. Thorp
背景川崎病(KD)被广泛认为是一种急性动脉炎。然而，我们的病理研究表明，慢性冠脉炎可以在发病后很长一段时间内持续存在，并与动脉狭窄密切相关。急性KD动脉炎组织的转录组图谱显示T淋巴细胞、I型干扰素和同种异体移植物炎症因子-1(AIF1)基因上调。我们确定了这些免疫反应在慢性KD动脉炎中是否持续存在，并研究了AIF1在这些反应中的作用。方法用实时定量逆转录聚合酶链式反应检测慢性KD和儿童对照动脉组织中基因的表达，用免疫组织化学和免疫荧光法检测动脉蛋白的表达。采用同种异体移植炎性因子-1小分子干扰核糖核酸巨噬细胞处理，研究AIF1在巨噬细胞和T淋巴细胞活化中的作用。结果同种异体移植物炎症因子-1蛋白在狭窄的KD动脉中高表达，并与巨噬细胞标志物CD68共定位。慢性KD冠脉组织中T淋巴细胞和干扰素途径基因表达显著上调。α干扰素诱导巨噬细胞表达CD80和主要组织相容性复合体II类依赖于AIF1，而巨噬细胞表达AIF1是抗原特异性T淋巴细胞活化所必需的。结论移植后动脉狭窄中发现的同种异体移植物炎性因子-1在KD狭窄的动脉组织中显著上调。T淋巴细胞和I型干扰素反应在慢性KD动脉炎中持续存在。同种异体移植物炎症因子-1可能在I型干扰素反应、巨噬细胞激活和抗原特异性T淋巴细胞激活之间发挥多重作用。这些结果提示淋巴细胞-髓系细胞的相互作用在KD动脉炎的发病机制中可能很重要，并可为选择新的免疫疗法用于高危KD儿童的临床试验提供信息。
Background Kawasaki disease (KD) is widely viewed as an acute arteritis. However, our pathologic studies show that chronic coronary arteritis can persist long after disease onset and is closely linked with arterial stenosis. Transcriptome profiling of acute KD arteritis tissues revealed upregulation of T lymphocyte, type I interferon, and allograft inflammatory factor-1 (AIF1) genes. We determined whether these immune responses persist in chronic KD arteritis, and we investigated the role of AIF1 in these responses. Methods Gene expression in chronic KD and childhood control arteries was determined by real-time reverse-transcriptase polymerase chain reaction, and arterial protein expression was determined by immunohistochemistry and immunofluorescence. Allograft inflammatory factor-1 small-interfering ribonucleic acid macrophage treatment was performed to investigate the role of AIF1 in macrophage and T lymphocyte activation. Results Allograft inflammatory factor-1 protein was highly expressed in stenotic KD arteries and colocalized with the macrophage marker CD68. T lymphocyte and interferon pathway genes were significantly upregulated in chronic KD coronary artery tissues. Alpha interferon-induced macrophage expression of CD80 and major histocompatibility complex class II was dependent on AIF1, and macrophage expression of AIF1 was required for antigen-specific T lymphocyte activation. Conclusions Allograft inflammatory factor-1, originally identified in posttransplant arterial stenosis, is markedly upregulated in KD stenotic arterial tissues. T lymphocyte and type I interferon responses persist in chronic KD arteritis. Allograft inflammatory factor-1 may play multiple roles linking type I interferon response, macrophage activation, and antigen-specific T lymphocyte activation. These results suggest the likely importance of lymphocyte-myeloid cell cross-talk in the pathogenesis of KD arteritis and can inform selection of new immunotherapies for clinical trials in high-risk KD children.