title: Uncontrolled IL-17 Production by Intraepithelial Lymphocytes in a Case of non-IPEX Autoimmune Enteropathy.
abstract: OBJECTIVE
  To provide a functional and phenotypic characterization of immune cells infiltrating small intestinal mucosa during non-IPEX autoimmune enteropathy (AIE), as to gain insights on the pathogenesis of this clinical condition.
  
  
  METHODS
  Duodenal biopsies from a patient with AIE at baseline and following drug-induced remission were analyzed by immunohistochemistry, immunofluorescence, and flow cytometry, and results were compared with those obtained from patients with active celiac disease, ileal Crohn's disease and healthy controls. Lamina propria (LP) and intraepithelial (IELs) lymphocytes from AIE and controls were analyzed for mechanisms regulating cytokine production. Foxp3 expression and suppressive functions of LP regulatory T cells (Tregs) were analyzed.
  
  
  RESULTS
  The quantitative deficit of Foxp3 expression in Tregs in AIE associates with unrestrained IL-17 production by IELs. Interleukin (IL)-17-producing IELs were rare in the uninflamed duodenum and in the ileum of Crohn's disease patients, and disappeared upon drug-induced AIE remission. IL-17 upregulation in CD4(+)IELs and CD4(+)LP T cells had different requirements for pro-inflammatory cytokines. Moreover, transforming growth factor-β (TGF-β) selectively enhanced IL-17 production by CD8(+)IELs. Intriguingly, although Foxp3(low)Tregs in AIE were poorly suppressive, they could upregulate GARP-LAP/TGF-β surface expression and enhanced IL-17 production selectively by CD8(+)IELs. Finally, phosphorylated Smad2/3 was detectable in duodenal CD8(+) lymphocytes in active AIE in situ, indicating that they received signals from the TGF-β receptor in vivo.
  
  
  CONCLUSIONS
  AIE is characterized by the appearance of unconventional IL-17-producing IELs, which could be generated locally by pro-inflammatory cytokines and TGF-β. These results suggest that Foxp3(+)Tregs and Treg-derived TGF-β regulate IL-17 production by IELs in the small intestine and in AIE.
authors.affiliation: Autoimmunity Program, Istituto Nazionale di Genetica Molecolare "Romeo Ed Enrica Invernizzi", Milan, Italy.
authors.forename: Moira
authors.initials: M
authors.lastname: Paroni
authors.affiliation: Postgraduate School of Gastroenterology, University of Milan, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Magarotto
authors.affiliation: Autoimmunity Program, Istituto Nazionale di Genetica Molecolare "Romeo Ed Enrica Invernizzi", Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Tartari
authors.affiliation: Autoimmunity Program, Istituto Nazionale di Genetica Molecolare "Romeo Ed Enrica Invernizzi", Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Nizzoli
authors.affiliation: Autoimmunity Program, Istituto Nazionale di Genetica Molecolare "Romeo Ed Enrica Invernizzi", Milan, Italy.|Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Larghi
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.|Pathology Unit, Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano, Milan, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Ercoli
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.|Pathology Unit, Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano, Milan, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Gianelli
authors.affiliation: Autoimmunity Program, Istituto Nazionale di Genetica Molecolare "Romeo Ed Enrica Invernizzi", Milan, Italy.|Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milan, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Pagani
authors.affiliation: Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Elli
authors.affiliation: Autoimmunity Program, Istituto Nazionale di Genetica Molecolare "Romeo Ed Enrica Invernizzi", Milan, Italy.|DISCCO, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Abrignani
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.|Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano, Milan, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Conte
authors.affiliation: Autoimmunity Program, Istituto Nazionale di Genetica Molecolare "Romeo Ed Enrica Invernizzi", Milan, Italy.
authors.forename: Jens
authors.initials: J
authors.lastname: Geginat
authors.affiliation: Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.|Gastroenterology and Endoscopy Unit, Fondazione IRCCS Cà Granda, Ospedale Policlinico di Milano, Milan, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Caprioli