TY - JOUR
T1 - Defining the Celiac Disease Transcriptome using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis
AU - Loberman-Nachum, Nurit
AU - Sosnovski, Katya
AU - Di Segni, Ayelet
AU - Efroni, Gilat
AU - Braun, Tzipi
AU - BenShoshan, Marina
AU - Anafi, Lait
AU - Avivi, Camila
AU - Barshack, Iris
AU - Shouval, Dror S.
AU - Denson, Lee A.
AU - Amir, Amnon
AU - Unger, Ron
AU - Weiss, Batia
AU - Haberman, Yael
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Celiac disease is provoked by gluten exposure, but the complete pathogenic process in the duodenum and the loss of tolerance to gluten is not well understood. We aimed to define the core celiac transcriptomic signature and pathologic pathways in pre-treatment formalin-fixed paraffin-embedded (FFPE) duodenum biopsies used for clinical diagnosis. We use mRNAseq to define pre-treatment diagnostic duodenum gene expression in 54 pediatric celiac patients and non-celiac controls, and we validate our key findings in two independent cohorts of 67 adults and pediatric participants that used fresh frozen biopsies. We further define similar and divergent genes and pathways in 177 small bowel Crohn disease patients and controls. We observe a marked suppression of mature epithelial metabolic functions in celiac patients, overlapping substantially with the Crohn disease signature. A marked adaptive immune response was noted for the up-regulated signature including interferon response, alpha-beta, and gamma-delta T-cells that overlapped to some extent with the Crohn disease signature. However, we also identified a celiac disease specific signature linked to increased cell proliferation, nuclear division, and cell cycle activity that was localized primarily to the epithelia as noted by CCNB1 and Ki67 staining. Lastly, we demonstrate the utility of the transcriptomic date to correctly classify disease or healthy states in the discovery and validation cohorts. Our data supplement recently published datasets providing insights into celiac pathogenesis using clinical pathology FFPE samples, and can stimulate new approaches to address this highly prevalent condition.
AB - Celiac disease is provoked by gluten exposure, but the complete pathogenic process in the duodenum and the loss of tolerance to gluten is not well understood. We aimed to define the core celiac transcriptomic signature and pathologic pathways in pre-treatment formalin-fixed paraffin-embedded (FFPE) duodenum biopsies used for clinical diagnosis. We use mRNAseq to define pre-treatment diagnostic duodenum gene expression in 54 pediatric celiac patients and non-celiac controls, and we validate our key findings in two independent cohorts of 67 adults and pediatric participants that used fresh frozen biopsies. We further define similar and divergent genes and pathways in 177 small bowel Crohn disease patients and controls. We observe a marked suppression of mature epithelial metabolic functions in celiac patients, overlapping substantially with the Crohn disease signature. A marked adaptive immune response was noted for the up-regulated signature including interferon response, alpha-beta, and gamma-delta T-cells that overlapped to some extent with the Crohn disease signature. However, we also identified a celiac disease specific signature linked to increased cell proliferation, nuclear division, and cell cycle activity that was localized primarily to the epithelia as noted by CCNB1 and Ki67 staining. Lastly, we demonstrate the utility of the transcriptomic date to correctly classify disease or healthy states in the discovery and validation cohorts. Our data supplement recently published datasets providing insights into celiac pathogenesis using clinical pathology FFPE samples, and can stimulate new approaches to address this highly prevalent condition.
UR - http://www.scopus.com/inward/record.url?scp=85074705596&partnerID=8YFLogxK
U2 - 10.1038/s41598-019-52733-1
DO - 10.1038/s41598-019-52733-1
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C2 - 31700112
AN - SCOPUS:85074705596
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 16163
ER -