武汉云克隆科技股份有限公司

Abstract:

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. Absence of definitive diagnostic markers limits the accuracy of clinical evaluations of suspected KD with significant increases in morbidity. In turn, incomplete understanding of its molecular pathogenesis hinders the identification of rational targets needed to improve therapy. We used high-accuracy mass spectrometry proteomics to analyse over 2000 unique proteins in clinical urine specimens of patients with KD. We discovered that urine proteomes of patients with KD, but not those with mimicking conditions, were enriched for markers of cellular injury such as filamin and talin, immune regulators such as complement regulator CSMD3, immune pattern recognition receptor muclin, and immune cytokine protease meprin A. Significant elevations of filamin C and meprin A were detected in both the serum and urine in two independent cohorts of patients with KD, comprised of a total of 236 patients. Meprin A and filamin C exhibited superior diagnostic performance as compared to currently used markers of disease in a blinded case-control study of 107 patients with suspected KD, with receiver operating characteristic areas under the curve of 0.98 (95% confidence intervals [CI] of 0.97-1 and 0.95-1, respectively). Notably, meprin A was enriched in the coronary artery lesions of a mouse model of KD. In all, urine proteome profiles revealed novel candidate molecular markers of KD, including filamin C and meprin A that exhibit excellent diagnostic performance. These disease markers may improve the diagnostic accuracy of clinical evaluations of children with suspected KD, lead to the identification of novel therapeutic targets, and allow the development of a biological classification of Kawasaki disease.

摘要：

川崎病(KD)是一种病因不明的全身血管炎，由于缺乏明确的诊断指标，川崎病临床诊断准确性受到限制，发病率显著增加。此外由于不完全了解其分子机制，不便于确定需要治疗的靶点。我们采用高精度质谱分析法，对KD患者临床尿液标本中的2000种独特蛋白质进行分析。我们发现在KD患者尿蛋白组中富集着细胞损伤标记物，如丝素和距骨素，免疫调节剂，如补体调节剂CSMD3，免疫模式识别受体粘蛋白和免疫细胞因子蛋白酶甲脯氨酸。将236例患者分成两组，两组KD患者血清和尿液中Filamin C和Meprin A水平显著升高。在107例疑似KD患者的盲病例对照研究中发现Meprin A和filamin C的诊断性能优于目前的疾病标志物（95%置信区间[CI]分别为0.97-1和0.95-1）。此外我们发现Meprin A在KD小鼠冠状动脉病变中富集。尿液蛋白质组图谱显示了新的KD候选分子标记物，包括Filamin C和Meprin A，它们具有良好的诊断性能。这些疾病标志物可提高对疑似KD患儿临床诊断的准确性，从而确定新的治疗靶点，并对川崎病进行生物学分类。

使用试剂原文信息：Concentrations of filamin C and meprin A were measured using enzyme-linked immunosorbent assays (USCN Life Science, Wuhan,China).