Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of Crohn's disease.
Genetic variants synthesize to produce paneth cell phenotypes that define subtypes of Crohn's disease.
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DOI：
10.1053/j.gastro.2013.09.048
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发表时间：
2014-01
期刊：
影响因子：
29.4
通讯作者：
Stappenbeck TS
中科院分区：
文献类型：
--
作者：
VanDussen KL;Liu TC;Li D;Towfic F;Modiano N;Winter R;Haritunians T;Taylor KD;Dhall D;Targan SR;Xavier RJ;McGovern DP;Stappenbeck TS
克罗恩病 (CD) 的遗传易感位点数量众多、复杂，并且可能与环境中未定义的成分相互作用。将特定位点的影响与 CD 发病机制相关的细胞（例如潘氏细胞）的表型联系起来一直是一个挑战。我们研究了与特定遗传易感性位点相关的潘氏细胞的特定表型是否可用于定义 CD 的特定亚型。我们对从 2 个不同医疗中心的 CD 患者采集的 119 份切除标本进行了回顾性分析。根据溶菌酶阳性分泌颗粒形态，将潘氏细胞表型分为正常或异常（颗粒表型紊乱、减少、弥漫或排除）。为了揭示潘氏细胞表型的分子基础，我们开发了从全层和激光捕获显微解剖、福尔马林固定、石蜡包埋的组织切片中确定转录谱的方法。异常潘氏细胞的比例与 CD 相关 NOD2 风险等位基因的数量相关。 NOD2和ATG16L1风险等位基因的累积数量对异常潘氏细胞的比例具有累加效应。对人口统计和潘氏细胞数据进行无监督聚类分析，将患者分为 2 个主要亚组，根据异常潘氏细胞比例的高低比例进行定义。紊乱和弥漫性异常潘氏细胞表型与免疫系统激活的转录特征改变有关。我们观察到异常潘氏细胞与肉芽肿的存在之间呈负相关。此外，高比例的异常潘氏细胞与手术后疾病复发的时间较短有关。潘氏细胞表型的组织学分析可用于将 CD 患者分为具有不同病理和临床特征的亚组。
Genetic susceptibility loci for Crohn’s disease (CD) are numerous, complex, and likely interact with undefined components of the environment. It has been a challenge to link the effects of particular loci to phenotypes of cells associated with pathogenesis of CD, such as Paneth cells. We investigated whether specific phenotypes of Paneth cells associated with particular genetic susceptibility loci can be used to define specific subtypes of CD. We performed a retrospective analysis of 119 resection specimens collected from patients with CD at 2 separate medical centers. Paneth cell phenotypes were classified as normal or abnormal (with disordered, diminished, diffuse, or excluded granule phenotypes) based on lysozyme-positive secretory granule morphology. To uncover the molecular basis of the Paneth cell phenotypes, we developed methods to determine transcriptional profiles from whole-thickness and laser-capture microdissected, formalin-fixed, paraffin-embedded tissue sections. The proportion of abnormal Paneth cells was associated with the number of CD-associated NOD2 risk alleles. The cumulative number of NOD2 and ATG16L1 risk alleles had an additive effect on the proportion of abnormal Paneth cells. Unsupervised clustering analysis of demographic and Paneth cell data divided patients into 2 principal subgroups, defined by high and low proportions of abnormal Paneth cells. The disordered and diffuse abnormal Paneth cell phenotypes were associated with an altered transcriptional signature of immune system activation. We observed an inverse correlation between abnormal Paneth cells and the presence of granuloma. Moreover, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. Histologic analysis of Paneth cell phenotypes can be used to divide patients with CD into subgroups with distinct pathognomonic and clinical features.
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