BACKGROUND The role of Mycobacteria in the etiology of Crohn's disease (CD) has been a contentious subject for many years. Recently, our laboratory showed that spontaneous colitis in IL-10-/- mice is driven in part by antigens (Ags) conserved in Mycobacteria. The present study dissects some of the common cellular and molecular mechanism that drive Mycobacteria-mediated and spontaneous colitis in IL-10-/- mice. RESULTS We show that serum from inflammatory bowel disease (IBD) patients contain significantly higher levels of Mycobacterium avium paratuberculosis-specific IgG1 and IgG2 antibodies (Abs), serum amyloid A (SAA) as well as CXCR3 ligands than serum from healthy donors. To study the cellular mechanisms of Mycobacteria-associated colitis, pathogen-free IL-10-/- mice were given heat-killed or live M. avium paratuberculosis. The numbers of mucosal T cells, neutrophils, NK/NKT cells that expressed TNFalpha, IFN-gamma, and/or CXCL10 were significantly higher in mice that received live Mycobacteria than other groups. The numbers of mucosal CXCR3+, CXCL9+, CXCL11+ and/or IFN-gamma+ dendritic cells (DCs) were also significantly higher in M. avium paratuberculosis-challenged mice, than compared to control mice. CONCLUSION The present study shows that CD and UC patients mount significant Mycobacteria-specific IgG1 > IgG2 and CXCR3 ligand responses. Several cellular mechanisms that drive spontaneous colitis also mediate Mycobacteria-enhanced colitis in IL-10-/- mice. Similar to IL-10-/- mice under conventional housing, we show that Mycobacteria-challenge IL-10-/- mice housed under otherwise pathogen-free conditions develop colitis that is driven by CXCR3- and CXCR3 ligand-expressing leukocytes, which underscores another important hallmark and molecular mechanism of colitis. Together, the data show that Mycobacteria-dependent host responses, namely CXCL10+ T cells and NK cells, assist in the recruitment and activation of CXCR3+ and CXCL11+ leukocytes to enhance colitis of susceptible hosts.

中文翻译：

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在分枝杆菌增强型结肠炎期间，CXCL10+ T 细胞和 NK 细胞有助于募集和激活 CXCR3+ 和 CXCL11+ 白细胞。

背景分枝杆菌在克罗恩病（CD）的病因学中的作用多年来一直是一个有争议的主题。最近，我们的实验室表明 IL-10-/- 小鼠的自发性结肠炎部分是由分枝杆菌中保守的抗原 (Ags) 驱动的。本研究剖析了在 IL-10-/- 小鼠中驱动分枝杆菌介导和自发性结肠炎的一些常见细胞和分子机制。结果 我们表明，与健康供体的血清相比，炎症性肠病 (IBD) 患者的血清含有显着更高水平的鸟分枝杆菌副结核特异性 IgG1 和 IgG2 抗体 (Abs)、血清淀粉样蛋白 A (SAA) 以及 CXCR3 配体。为了研究分枝杆菌相关结肠炎的细胞机制，无病原体的 IL-10-/- 小鼠被给予热灭活或活的副结核分枝杆菌。在接受活分枝杆菌的小鼠中，表达 TNFalpha、IFN-γ 和/或 CXCL10 的粘膜 T 细胞、中性粒细胞、NK/NKT 细胞的数量明显高于其他组。与对照小鼠相比，副结核分枝杆菌攻击小鼠的粘膜 CXCR3+、CXCL9+、CXCL11+ 和/或 IFN-γ+ 树突细胞 (DC) 的数量也显着更高。结论 本研究表明，CD 和 UC 患者出现显着的分枝杆菌特异性 IgG1 > IgG2 和 CXCR3 配体反应。导致自发性结肠炎的几种细胞机制也介导了 IL-10-/- 小鼠中分枝杆菌增强的结肠炎。与传统饲养环境下的 IL-10-/- 小鼠相似，我们表明，分枝杆菌攻击 IL-10-/- 小鼠在其他无病原体条件下会发展为由表达 CXCR3 和 CXCR3 配体的白细胞驱动的结肠炎，这强调了结肠炎的另一个重要标志和分子机制。总之，数据显示分枝杆菌依赖性宿主反应，即 CXCL10+ T 细胞和 NK 细胞，有助于募集和激活 CXCR3+ 和 CXCL11+ 白细胞，以增强易感宿主的结肠炎。