期刊
GASTROENTEROLOGY
卷 146, 期 1, 页码 200-209出版社
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1053/j.gastro.2013.09.048
关键词
Pathogenesis; Prognostic Factor; Diagnosis; Inflammatory Bowel Disease
资金
- National Institutes of Health [T32 AI007163]
- Washington University Institute of Clinical and Translational Sciences [CTSA308]
- National Institute of Diabetes and Digestive and Kidney Disease [P30DK052574]
- US Public Health Service [PO1DK046763]
- Cedars-Sinai F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute
- National Center for Research Resources [M01-RR00425]
- UCLA/Cedars-Sinai/Harbor/Drew Clinical and Translational Science Institute [UL1 TR000124-01]
- Southern California Diabetes and Endocrinology Research grant [DK063491]
- Helmsley Charitable Trust
- European Union
- Crohn's and Colitis Foundation of America (CCFA)
- Feintech Family Chair in IBD
- Joshua L. and Lisa Z. Greer Chair in IBD Genetics
- CCFA Genetics initiative
- [DK043351]
- [DK097485]
- [DK092405]
- [DK062413]
- [DK046763-19]
- [AI067068]
- [HS021747]
- [AI084887]
- AGENCY FOR HEALTHCARE RESEARCH AND QUALITY [R01HS021747] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000448, UL1TR000124] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000425] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [U01AI067068, R01AI084887, T32AI007163] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [U01DK062413, R01DK092405, P30DK043351, P30DK052574, R01DK097485, P30DK063491, P01DK046763] Funding Source: NIH RePORTER
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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 presence of granuloma. In addition, high proportions of abnormal Paneth cells were associated with shorter time to disease recurrence after surgery. CONCLUSIONS: 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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