title: Increase in neuroendocrine cells in the duodenal mucosa of patients with refractory celiac disease.
abstract: OBJECTIVE
  Several immune-mediated gastrointestinal disorders, including celiac disease (CD), are associated with neuroendocrine cell hyperplasia. However, neuroendocrine cells have never been explored in refractory CD (RCD).
  
  
  METHODS
  Serial duodenal sections from 17 patients with RCD (6 type 1 and 11 type 2), 16 uncomplicated CD patients before and after gluten-free diet, 14 patients with potential CD, 27 patients with non-CD villous atrophy, i.e., common variable immunodeficiency (n=12), Whipple's disease (n=10) and giardiasis (n=5), and 16 healthy subjects were processed for the immunohistochemical detection of chromogranin A (CgA), serotonin, and somatostatin. Mucosal tryptophan hydroxylase (TpH)-1 and serotonin-selective reuptake transporter (SERT) transcripts were measured by quantitative reverse transcription-PCR. Serum CgA and 24-h urine 5-hydroxyindoleacetic acid (5-HIAA) were assessed. Biopsies from treated CD patients were cultured with serotonin or peptic tryptic digest of gliadin (PT-gliadin), and interferon (IFN)-γ was detected by ELISA in culture supernatants.
  
  
  RESULTS
  Epithelial cells positive for CgA and serotonin, but not somatostatin, were significantly increased in RCD. Raised mucosal transcripts of TpH-1, but not SERT, were found in RCD. On biopsies from treated CD patients, serotonin upregulated IFN-γ production at levels comparable to those induced by PT-gliadin. Serum CgA, but not urine 5-HIAA, was increased in RCD. No significant difference was found between RCD type 1 and type 2 in terms of neuroendocrine cells, mucosal TpH-1 transcripts, and serum CgA.
  
  
  CONCLUSIONS
  Serotonin-producing neuroendocrine cells are increased in RCD mucosa. IFN-γ upregulation induced by serotonin suggests that this monoamine may have a role in sustaining the local inflammatory response in CD.
authors.affiliation: First Department of Medicine, Celiac Centre, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Di Sabatino
authors.affiliation: First Department of Medicine, Celiac Centre, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Giuffrida
authors.affiliation: Department of Molecular Medicine, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Vanoli
authors.affiliation: Department of Molecular Medicine, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Ombretta
authors.initials: O
authors.lastname: Luinetti
authors.affiliation: Department of Molecular Medicine, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Rachele
authors.initials: R
authors.lastname: Manca
authors.affiliation: First Department of Medicine, Celiac Centre, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Biancheri
authors.affiliation: First Department of Medicine, Celiac Centre, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Bergamaschi
authors.affiliation: First Department of Medicine, Celiac Centre, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Costanza
authors.initials: C
authors.lastname: Alvisi
authors.affiliation: First Department of Medicine, Celiac Centre, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Pasini
authors.affiliation: First Department of Medicine, Celiac Centre, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Salvatore
authors.affiliation: First Department of Medicine, Celiac Centre, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Biagi
authors.affiliation: Department of Molecular Medicine, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Solcia
authors.affiliation: First Department of Medicine, Celiac Centre, St. Matteo Hospital, University of Pavia, Pavia, Italy.
authors.forename: Gino Roberto
authors.initials: GR
authors.lastname: Corazza
mesh_terms: D000328:Adult; D000368:Aged; D001707:Biopsy, Needle; D016022:Case-Control Studies; D002446:Celiac Disease / Q000473:pathology* / Q000628:therapy*; D055050:Diet, Gluten-Free; D004384:Duodenoscopy / Q000379:methods; D004386:Duodenum; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D055099:Neuroendocrine Cells / Q000166:cytology / Q000473:pathology*; D011379:Prognosis; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012016:Reference Values; D012189:Retrospective Studies; D012701:Serotonin / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism; D018709:Statistics, Nonparametric; D017211:Treatment Failure; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D012701:Serotonin; D013004:Somatostatin; D007371:Interferon-gamma