Diosdado Begoña, van Bakel Harm, Strengman Eric, Franke Lude, van Oort Erica, Mulder Chris J, Wijmenga Cisca, Wapenaar Martin C
Department of Medical Genetics, Division of Biomedical Genetics, University Medical Center, Utrecht, The Netherlands.
Clin Gastroenterol Hepatol. 2007 May;5(5):574-81. doi: 10.1016/j.cgh.2006.11.014. Epub 2007 Mar 2.
BACKGROUND & AIMS: Celiac disease is an enteropathy featuring villous atrophy, crypt hyperplasia, and lymphocytosis. Tissue remodeling is driven by an inflammatory reaction to gluten in genetically susceptible individuals. The adaptive pathway is considered the major immune response but recent evidence has indicated the involvement of innate immunity as well. To assess the contribution of either immune response we performed global gene expression profiling of the regenerating mucosa.
Microarray hybridizations were performed with biopsy samples from 13 untreated patients, 31 patients on a gluten-free diet in various stages of remission, and 21 controls. Additional data were generated using low-density array and conventional quantitative reverse-transcription polymerase chain reaction, and immunohistochemistry.
A total of 108 differentially expressed immune-related genes were identified (50 innate, 43 adaptive, 9 both innate/adaptive, and 6 immunoregulatory). Expression levels showed a gradual change as opposed to the discrete histological transitions. In addition to details provided on the adaptive and innate immune pathways used, we observed a chronic recruitment of activated neutrophils. Neutrophil involvement was unabated in otherwise completely normalized remission patients.
We observed a contribution of both the innate and adaptive immune response in celiac disease pathogenesis. The discrepancy between the histological classification and the observed incremental change in immune-gene expression may have consequences for current diagnostic inclusion criteria. Enhanced neutrophil infiltration in both active and remission patients points to a genetic impairment of the intestinal barrier that may contribute to the cause rather than the consequence of celiac disease.
乳糜泻是一种以绒毛萎缩、隐窝增生和淋巴细胞增多为特征的肠病。在遗传易感性个体中，组织重塑由对麸质的炎症反应驱动。适应性途径被认为是主要的免疫反应，但最近的证据表明固有免疫也参与其中。为了评估这两种免疫反应的作用，我们对再生黏膜进行了全基因表达谱分析。
对13例未经治疗的患者、31例处于不同缓解阶段的无麸质饮食患者和21例对照的活检样本进行微阵列杂交。使用低密度阵列、传统定量逆转录聚合酶链反应和免疫组织化学生成额外数据。
共鉴定出108个差异表达的免疫相关基因（50个固有免疫相关基因、43个适应性免疫相关基因、9个固有/适应性免疫相关基因和6个免疫调节相关基因）。表达水平呈现出逐渐变化，与离散的组织学转变不同。除了提供的关于所使用的适应性和固有免疫途径的详细信息外，我们还观察到活化中性粒细胞的持续募集。在其他方面完全正常化的缓解患者中，中性粒细胞的参与并未减弱。
我们观察到固有免疫和适应性免疫反应在乳糜泻发病机制中均有作用。组织学分类与观察到的免疫基因表达的渐进变化之间的差异可能对当前的诊断纳入标准产生影响。活动期和缓解期患者中性粒细胞浸润增强表明肠道屏障的遗传损伤可能是乳糜泻的病因而非结果。
