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Ta-Chiang Liu, M.D., Ph.D. Assistant Professor Department of Pathology and Immunology

Paneth Cell Phenotype Correlates with Genetics, Transcriptome Profile, Pathologic Hallmark and Predicts Clinical Outcome in Patients with Crohn's Disease. Ta-Chiang Liu, M.D., Ph.D. Assistant Professor Department of Pathology and Immunology Washington University in St. Louis.

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Ta-Chiang Liu, M.D., Ph.D. Assistant Professor Department of Pathology and Immunology

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  1. PanethCell Phenotype Correlates with Genetics, Transcriptome Profile, Pathologic Hallmark and Predicts Clinical Outcome in Patients with Crohn's Disease Ta-Chiang Liu, M.D., Ph.D. Assistant Professor Department of Pathology and Immunology Washington University in St. Louis

  2. Disclosures Nothing to disclose

  3. Goal: Identification of a cellular readout that synthesizes genetic and environmental factors and subclassifiesCrohn’s Disease Genetic Susceptibility Environment Cellular readout Disease subclassification

  4. Paneth Cells: Critical Roles in Innate Immunity Antimicrobials Lysozyme α-Defensins Risk Loci Predicted to Affect Paneth Cell Function ATG16L1 NOD2 XBP1 ITLN1

  5. Secretion defect in Atg16L1-deficient Paneth cells WT Atg16l1 deficient Cadwell et al., Nature2008.

  6. NOD2 Variants and Disease Susceptibility Allele carriage rate: <1% Rare CD-associated variants (6 known) Relative risk for development of CD: NOD2 Heterozygous = 2-3 NOD2 Homozygous = ~20 Common CD-associated variants Allele carriage rate: <5%

  7. Hypothesis NOD2 risk variants may be associated with an abnormal granule phenotype in the Paneth cells of CD patients Materials and Methods • De-identified ileocolectomy tissue from CD patients • Inclusion criteria: • Access to proximal margin of ileocolic resection • Minimum of 100 well-oriented crypts • No active or chronic inflammatory disease in the ileal sections used for lysozyme stain

  8. NOD2 Risk Variants are Associated with Abnormal Paneth cell Phenotype Scale bars: 10 µM Immunofluorescence Lysozyme Hoescht Gastroenterology, in press

  9. diminished

  10. NOD2 Risk Variants are Associated with Abnormal Paneth cell Phenotype *p<0.05 compared to 0 risk variants Gastroenterology, in press

  11. NOD2 and ATG16L1 Risk Alleles are Additive for Abnormal Paneth Cell Phenotypes

  12. Activated Immune Response Profile is Associated with Abnormal Paneth Cells Phenotype GO term analysis performed using DAVID Gastroenterology, in press

  13. Paneth cell phenotype is associated with clinical outcome CD patients from WU and CSMC (n=143) underwent resection and received post-op prophylactic therapy End point: endoscopic evidence of disease recurrence after surgery Gastroenterology, in press

  14. Paneth cell phenotype as predictive cellular biomarker for CD – practical issues

  15. Paneth cell phenotypes in involved areas correlate with that of the uninvolved areas P<0.0001

  16. Paneth cell phenotype remains stable over the years (n=30) P<0.0001

  17. Paneth cell defects may be patchy: how many crypts are needed to generate readout equivalent to resection specimens? “Virtual biopsy” At least 40-50 crypts are needed to generate equivalent results as with resection specimens.

  18. Paneth cell phenotypes in matched biopsy and resection specimens are consistent (n=20) P=0.0004

  19. Bad Paneth cell phenotype is more prevalent in pediatric CD Adult (n=124) Pediatric (n=77) (Collaboration with Nita Salzman) 15% 47% P< 0.0001

  20. Significant increase in bad Paneth cell phenotype over the past 30 years 1980-1982 (n=52) 2011-2013 (n=124) 3% 15% P=0.0328

  21. Summary • Bad Paneth cell phenotype is associated with CD-associated risk alleles, distinct gene expression profile, pathology hallmark, and clinical outcome. • Paneth cell phenotype is spatially and temporally stable. • Paneth cell phenotype analysis can be performed using routine biopsy material. • Bad Paneth cell phenotype is commonly seen in pediatric patients, and appears to be a new form of disease that have emerged over the last 30 years.

  22. Acknowledgement Washington University Kelli VanDussen Robi D. Mitra Rich Head Rodney D. Newberry FengGao Thaddeus S. Stappenbeck Cedars-Sinai Dalin Li FadiTowfic NirModiano Rachel Winter TalinHaritunains DeeptiDhall Stephan Targan Dermot P. B. McGovern Medical College of Wisconsin Nita Salzman Harvard/MGH Ramnik Xavier

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