The primary defect in experimental ileitis originates from a nonhematopoietic source.
The primary defect in experimental ileitis originates from a nonhematopoietic source.
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DOI：
10.1084/jem.20050407
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发表时间：
2006-03-20
期刊：
影响因子：
--
通讯作者：
Pizarro TT
中科院分区：
文献类型：
--
作者：
Olson TS;Reuter BK;Scott KG;Morris MA;Wang XM;Hancock LN;Burcin TL;Cohn SM;Ernst PB;Cominelli F;Meddings JB;Ley K;Pizarro TT
克罗恩病（CD）的起始病因仍不清楚。SAMP1/YitFc（SAMP）小鼠会发生类似于人类CD的慢性回肠炎。我们利用骨髓嵌合体来确定SAMP回肠炎是由原发性免疫缺陷引起，还是由内在的非造血（例如上皮）功能障碍继发的黏膜免疫失调所致。接受野生型（AKR）骨髓的SAMP小鼠发生了严重的回肠炎，而SAMP骨髓不会使野生型受体小鼠发生回肠炎。来自重组SAMP小鼠的野生型淋巴细胞在表面表型和细胞因子产生方面与天然SAMP群体相似。与天然野生型小鼠和接受SAMP骨髓的AKR小鼠相比，天然SAMP小鼠和接受野生型骨髓的SAMP小鼠的回肠在体外显示上皮屏障阻力降低，在体内显示上皮通透性增加。这种通透性缺陷在回肠炎症发生之前就已存在，在没有共生细菌的情况下也存在，并且伴有紧密连接蛋白克劳丁 - 2和闭合蛋白的回肠mRNA表达改变。我们的研究结果提供了证据，表明SAMP小鼠发生回肠炎的原发性缺陷源自非造血来源。致病性淋巴细胞的产生是这种缺陷的结果，并不反映白细胞固有的促炎特性。屏障功能降低表明上皮缺陷可能是SAMP回肠炎易感性的主要根源。
The initiating etiologic factor in Crohn's disease (CD) remains unclear. SAMP1/YitFc (SAMP) mice develop chronic ileitis similar to human CD. We used bone marrow chimeras to determine if SAMP ileitis results from a primary immunological defect or from dysregulated mucosal immunity secondary to intrinsic, nonhematopoietic (e.g., epithelial) dysfunction. SAMP mice receiving wild-type (AKR) BM developed severe ileitis, whereas SAMP BM did not confer ileitis to WT recipients. WT lymphocytes from reconstituted SAMP mice resembled native SAMP populations in regard to surface phenotype and cytokine production. Ilea from native SAMP mice and SAMP recipients of wild-type BM displayed decreased epithelial barrier resistance ex vivo and increased epithelial permeability in vivo compared to native WT mice and AKR recipients of SAMP BM. This permeability defect preceded the development of ileal inflammation, was present in the absence of commensal bacteria, and was accompanied by altered ileal mRNA expression of the tight junction proteins claudin-2 and occludin. Our results provide evidence that the primary defect conferring ileitis in SAMP mice originates from a nonhematopoietic source. Generation of pathogenic lymphocytes is a consequence of this defect and does not reflect intrinsic proinflammatory leukocyte properties. Decreased barrier function suggests that defects in the epithelium may represent the primary source of SAMP ileitis susceptibility.
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