Biological Engineering Department, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
PLoS One. 2010 Oct 19;5(10):e13277. doi: 10.1371/journal.pone.0013277.
Diagnosis of chronic intestinal inflammation, which characterizes inflammatory bowel disease (IBD), along with prediction of disease state is hindered by the availability of predictive serum biomarker. Serum biomarkers predictive of disease state will improve trials for therapeutic intervention, and disease monitoring, particularly in genetically susceptible individuals. Chronic inflammation during IBD is considered distinct from infectious intestinal inflammation thereby requiring biomarkers to provide differential diagnosis. To address whether differential serum biomarkers could be identified in murine models of colitis, immunological profiles from both chronic spontaneous and acute infectious colitis were compared and predictive serum biomarkers identified via multivariate modeling.
METHODOLOGY/PRINCIPAL FINDINGS: Discriminatory multivariate modeling of 23 cytokines plus chlorotyrosine and nitrotyrosine (protein adducts from reactive nitrogen species and hypochlorite) in serum and tissue from two murine models of colitis was performed to identify disease-associated biomarkers. Acute C. rodentium-induced colitis in C57BL/6J mice and chronic spontaneous Helicobacter-dependent colitis in TLR4(-/-) x IL-10(-/-) mice were utilized for evaluation. Colon profiles of both colitis models were nearly identical with chemokines, neutrophil- and Th17-related factors highly associated with intestinal disease. In acute colitis, discriminatory disease-associated serum factors were not those identified in the colon. In contrast, the discriminatory predictive serum factors for chronic colitis were neutrophil- and Th17-related factors (KC, IL-12/23p40, IL-17, G-CSF, and chlorotyrosine) that were also elevated in colon tissue. Chronic colitis serum biomarkers were specific to chronic colitis as they were not discriminatory for acute colitis.
CONCLUSIONS/SIGNIFICANCE: Immunological profiling revealed strikingly similar colon profiles, yet distinctly different serum profiles for acute and chronic colitis. Neutrophil- and Th17-related factors were identified as predictive serum biomarkers of chronic colitis, but not acute colitis, despite their presence in colitic tissue of both diseases thereby demonstrating the utility of mathematical modeling for identifying disease-associated serum biomarkers.
慢性肠道炎症的诊断，其特征是炎症性肠病（IBD），以及疾病状态的预测，受到预测性血清生物标志物的可用性的阻碍。预测疾病状态的血清生物标志物将改善治疗干预的试验，并改善疾病监测，特别是在遗传易感个体中。IBD 期间的慢性炎症被认为与感染性肠道炎症不同，因此需要生物标志物来提供鉴别诊断。为了确定是否可以在结肠炎的小鼠模型中识别出差异血清生物标志物，比较了慢性自发性和急性感染性结肠炎的免疫谱，并通过多元建模来识别预测性血清生物标志物。
方法/主要发现：对两种结肠炎小鼠模型的血清和组织中的 23 种细胞因子加氯酪氨酸和亚硝基酪氨酸（活性氮物种和次氯酸盐的蛋白质加合物）进行了判别多元建模，以识别与疾病相关的生物标志物。利用 C57BL/6J 小鼠中 C. rodentium 诱导的急性结肠炎和 TLR4(-/-) x IL-10(-/-) 小鼠中的慢性自发性幽门螺杆菌依赖性结肠炎进行评估。两种结肠炎模型的结肠谱几乎相同，趋化因子、中性粒细胞和 Th17 相关因子与肠道疾病高度相关。在急性结肠炎中，鉴别疾病相关的血清因子不是在结肠中识别的那些。相比之下，慢性结肠炎的鉴别预测性血清因子是中性粒细胞和 Th17 相关因子（KC、IL-12/23p40、IL-17、G-CSF 和氯酪氨酸），它们在结肠组织中也升高。慢性结肠炎的血清生物标志物是慢性结肠炎特有的，因为它们不能鉴别急性结肠炎。
结论/意义：免疫分析显示，急性和慢性结肠炎的结肠谱非常相似，但血清谱明显不同。中性粒细胞和 Th17 相关因子被确定为慢性结肠炎的预测性血清生物标志物，但不是急性结肠炎的生物标志物，尽管它们存在于两种疾病的结肠炎组织中，从而证明了数学建模用于识别与疾病相关的血清生物标志物的实用性。
