Mass General Hospital for Children and Division of Pediatric Gastroenterology and Nutrition, Harvard Medical School, Boston, Massachusetts, United States of America.
Center for Celiac Research and Treatment, Mucosal Immunology and Biology Research Center, Boston, Massachusetts, United States of America.
PLoS One. 2019 Apr 18;14(4):e0215132. doi: 10.1371/journal.pone.0215132. eCollection 2019.
BACKGROUND & AIMS: The early steps in the pathophysiology of celiac disease (CD) leading to loss of tolerance to gluten are poorly described. Our aim was to use RNA sequencing of duodenal biopsies in patients with active CD, CD in remission, and non-CD controls to gain insight into CD pathophysiology, identify additional genetic signatures linked to CD, and possibly uncover targets for future therapeutic agents.
We performed whole transcriptome shotgun sequencing of intestinal biopsies in subjects with active and remission CD and non-CD controls. We also performed functional pathway analysis of differentially expressed genes to identify statistically significant pathways that are up or down regulated in subjects with active CD compared to remission CD.
We identified the upregulation of novel genes including IL12R, ITGAM and IGSF4 involved in the immune response machinery and cell adhesion process in the mucosa of subjects with active CD compared to those in remission. We identified a unique signature of genes, related to innate immunity, perturbed exclusively in CD irrespective of disease status. Finally, we highlight novel pathways of interest that may contribute to the early steps of CD pathogenesis and its comorbidities such as the spliceosome, pathways related to the innate immune response, and pathways related to autoimmunity.
Our study confirmed previous findings based on GWAS and immunological studies pertinent to CD pathogenesis and describes novel genes and pathways that with further validation may be found to contribute to the early steps in the pathogenesis of CD, ongoing inflammation, and comorbidities associated with CD.
乳糜泻（CD）发病机制的早期步骤导致对麸质不耐受的机制尚未完全阐明。本研究旨在通过对活动性 CD、缓解期 CD 和非 CD 对照患者的十二指肠活检进行 RNA 测序，深入了解 CD 的发病机制，鉴定与 CD 相关的其他遗传特征，并可能发现未来治疗药物的靶点。
我们对活动性 CD、缓解期 CD 和非 CD 对照患者的肠道活检标本进行全转录组鸟枪法测序。我们还对差异表达基因进行了功能途径分析，以鉴定在活动性 CD 患者中与缓解期 CD 相比上调或下调的具有统计学意义的途径。
与缓解期 CD 相比，我们发现活动性 CD 患者黏膜中包括 IL12R、ITGAM 和 IGSF4 在内的新基因上调，这些基因参与免疫反应机制和细胞黏附过程。我们鉴定了一个独特的与固有免疫相关的基因特征，该特征仅在 CD 中受到干扰，而与疾病状态无关。最后，我们强调了可能有助于 CD 发病机制及其并发症（如剪接体、固有免疫反应相关途径和自身免疫相关途径）早期步骤的新途径。
本研究证实了先前基于 GWAS 和免疫研究的与 CD 发病机制相关的发现，并描述了新的基因和途径，这些基因和途径可能有助于 CD 发病机制的早期步骤、持续的炎症以及与 CD 相关的并发症。
