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Defining the Celiac Disease Transcriptome using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis.
Sci Rep 2019; 9(1):16163SR

Abstract

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.

Authors+Show Affiliations

The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Ramat Gan, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel.The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel.Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel.Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Institute of Pathology, Sheba Medical Center, Tel Hashomer, Israel.The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.Mina and Everard Goodman Faculty of Life Science, Bar-Ilan University, Ramat Gan, Israel.The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.The Pediatric Gastroenterology Unit, The Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel-Hashomer, Israel. Yael.Haberman@sheba.health.gov.il. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Yael.Haberman@sheba.health.gov.il. Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Yael.Haberman@sheba.health.gov.il.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31700112

Citation

Loberman-Nachum, Nurit, et al. "Defining the Celiac Disease Transcriptome Using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis." Scientific Reports, vol. 9, no. 1, 2019, p. 16163.
Loberman-Nachum N, Sosnovski K, Di Segni A, et al. Defining the Celiac Disease Transcriptome using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis. Sci Rep. 2019;9(1):16163.
Loberman-Nachum, N., Sosnovski, K., Di Segni, A., Efroni, G., Braun, T., BenShoshan, M., ... Haberman, Y. (2019). Defining the Celiac Disease Transcriptome using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis. Scientific Reports, 9(1), p. 16163. doi:10.1038/s41598-019-52733-1.
Loberman-Nachum N, et al. Defining the Celiac Disease Transcriptome Using Clinical Pathology Specimens Reveals Biologic Pathways and Supports Diagnosis. Sci Rep. 2019 Nov 7;9(1):16163. PubMed PMID: 31700112.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2019/11/07/ PY - 2019/08/15/received PY - 2019/10/21/accepted PY - 2019/11/9/entrez PY - 2019/11/9/pubmed PY - 2019/11/9/medline SP - 16163 EP - 16163 JF - Scientific reports JO - Sci Rep VL - 9 IS - 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. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/31700112/Defining_the_Celiac_Disease_Transcriptome_using_Clinical_Pathology_Specimens_Reveals_Biologic_Pathways_and_Supports_Diagnosis L2 - http://dx.doi.org/10.1038/s41598-019-52733-1 DB - PRIME DP - Unbound Medicine ER -