Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice
Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice
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DOI：
10.1172/jci45538
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发表时间：
2011-04-01
影响因子：
15.9
通讯作者：
Xia, Lijun
中科院分区：
文献类型：
--
作者：
Fu, Jianxin;Wei, Bo;Xia, Lijun
粘蛋白-型O-连接低聚糖(O-多糖)是肠道粘蛋白的主要成分，形成覆盖在肠上皮上的粘液凝胶层。溃疡性结肠炎(UC)患者已观察到肠道O-糖链表达受损，但其在本病病因中的作用尚不清楚。在这里，我们报告了具有肠上皮细胞特异性核心1衍生O-多糖缺陷的小鼠，O-多糖的主要形式，发展成类似于人类UC的自发性结肠炎，包括大量的髓细胞浸润和隐窝脓肿。这些小鼠的结肠炎的特征也是在缺乏淋巴细胞的情况下，结肠粘膜中有产生肿瘤坏死因子的髓系细胞，支持髓系细胞在结肠炎发病中的重要作用。此外，诱导肠核心1衍生的O-糖链的缺失会引起成年小鼠的自发性结肠炎。这些数据表明，在结肠炎中，核心1-衍生O-糖链的丢失起了因果作用。最后，我们在UC患者的一组患者的结肠上皮中检测到了一种生物合成中间体，通常在缺乏核心10-葡聚糖、TN抗原的情况下暴露。在TN阳性的上皮细胞中，发现了编码核心1β1，3-半乳糖基转移酶特异性伴侣1(C1GALT1C1，又称Cosmc)的X连锁基因的体细胞突变。这些数据提示了我们认为UC发病的一种新的分子机制。
Mucin-type O-linked oligosaccharides (O-glycans) are primary components of the intestinal mucins that form the mucus gel layer overlying the gut epithelium. Impaired expression of intestinal O-glycans has been observed in patients with ulcerative colitis (UC), but its role in the etiology of this disease is unknown. Here, we report that mice with intestinal epithelial cell-specific deficiency of core 1-derived O-glycans, the predominant form of O-glycans, developed spontaneous colitis that resembled human UC, including massive myeloid infiltrates and crypt abscesses. The colitis manifested in these mice was also characterized by TNF-producing myeloid infiltrates in colon mucosa in the absence of lymphocytes, supporting an essential role for myeloid cells in colitis initiation. Furthermore, induced deletion of intestinal core 1-derived O-glycans caused spontaneous colitis in adult mice. These data indicate a causal role for the loss of core 1-derived O-glycans in colitis. Finally, we detected a biosynthetic intermediate typically exposed in the absence of core 1 O-glycan, Tn antigen, in the colon epithelium of a subset of UC patients. Somatic mutations in the X-linked gene that encodes core 1 beta 1,3-galactosyltransferase-specific chaperone 1 (C1GALT1C1, also known as Cosmc), which is essential for core 1 O-glycosylation, were found in Tn-positive epithelia. These data suggest what we believe to be a new molecular mechanism for the pathogenesis of UC.