title: Increased Intraepithelial Vα24 Invariant NKT Cells in the Celiac Duodenum.
abstract: Celiac Disease (CD) is an interferon (IFN)γ-mediated duodenal hypersensitivity to wheat gluten occurring in genetically predisposed individuals. Gluten-free diet (GFD) leads to a complete remission of the disease. Vα24-restricted invariant NKT (iNKT) cells are important to maintain immune homeostasis in the gut mucosa because of their unique capacity to rapidly produce large quantities of both T-helper (Th)1 and Th2 cytokines upon stimulation. We studied the presence of these cells in the CD duodenum. Duodenal biopsies were obtained from 45 untreated-CD patients (uCD), 15 Gluten Free Diet-CD patients (GFD-CD), 44 non-inflamed non-CD controls (C-controls) and 15 inflamed non-CD controls (I-controls). Two populations from Spain and Argentina were recruited. Messenger RNA (mRNA) expression of Vα24-Jα18 (invariant TCRα chain of human iNKT cells), IFNγ and intracellular transcription factor Forkhead Box P3 (Foxp3), and flow cytometry intraepithelial lymphocyte (IEL) profile were determined. Both uCD and GFD-CD patients had higher Vα24-Jα18 mRNA levels than non-CD controls (I and C-controls). The expression of Vα24-Jα18 correlated with Marsh score for the severity of mucosal lesion and also with increased mRNA IFNγ levels. uCD and GFD-CD patients had decreased mRNA expression of FoxP3 but increased expression of Vα24-Jα18, which revealed a CD-like molecular profile. Increased numbers of iNKT cells were confirmed by flow cytometry within the intraepithelial lymphocyte compartment of uCD and GFD-CD patients and correlated with Vα24-Jα18 mRNA expression. In conclusion, we have found an increased number of iNKT cells in the duodenum from both uCD and GFD-CD patients, irrespective of the mucosal status. A CD-like molecular profile, defined by an increased mRNA expression of Vα24-Jα18 together with a decreased expression of FoxP3, may represent a pro-inflammatory signature of the CD duodenum.
authors.affiliation: Mucosal Immunology Lab, IBGM, University of Valladolid-CSIC, Sanz y Forés 3, 47003 Valladolid, Spain. emontalvillo@gmail.com.
authors.forename: Enrique
authors.initials: E
authors.lastname: Montalvillo
authors.affiliation: Antigen Presentation Research Group, Imperial College London, Northwick Park & St Mark's Campus, Level 7W, St Mark's Building Watford Road Harrow HA1 3UJ, UK. d.bernardo.ordiz@gmail.com.|Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid 28006, Spain. d.bernardo.ordiz@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Bernardo
authors.affiliation: Mucosal Immunology Lab, IBGM, University of Valladolid-CSIC, Sanz y Forés 3, 47003 Valladolid, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Martínez-Abad
authors.affiliation: Laboratorio de Investigación en el Sistema Inmune -LISIN, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 115, La Plata 1900, Buenos Aires, Argentina. yallegretti@gmail.com.
authors.forename: Yessica
authors.initials: Y
authors.lastname: Allegretti
authors.affiliation: Gastroenterology Unit, Hospital Clínico Universitario. luisfernsal@gmail.com.
authors.forename: Luis
authors.initials: L
authors.lastname: Fernández-Salazar
authors.affiliation: Paediatric Unit, Hospital Clínico Universitario. carmencalvoromero@gmail.com.
authors.forename: Carmen
authors.initials: C
authors.lastname: Calvo
authors.affiliation: Laboratorio de Investigación en el Sistema Inmune -LISIN, Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 115, La Plata 1900, Buenos Aires, Argentina. fchirdo@biol.unlp.edu.ar.
authors.forename: Fernando G
authors.initials: FG
authors.lastname: Chirdo
authors.affiliation: Mucosal Immunology Lab, IBGM, University of Valladolid-CSIC, Sanz y Forés 3, 47003 Valladolid, Spain. jagarrote@saludcastillayleon.es.|Medical Laboratory Service, Hospital Universitario Rio Hortega. jagarrote@saludcastillayleon.es.
authors.forename: José A
authors.initials: JA
authors.lastname: Garrote
authors.affiliation: Mucosal Immunology Lab, IBGM, University of Valladolid-CSIC, Sanz y Forés 3, 47003 Valladolid, Spain. earranz@med.uva.es.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Arranz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002446:Celiac Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D055050:Diet, Gluten-Free; D004386:Duodenum / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005983:Glutens / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007694:Killer Cells, Natural / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D055815:Young Adult
chemical_list: D011948:Receptors, Antigen, T-Cell; C528689:Valpha24 protein, human; D005983:Glutens; D007371:Interferon-gamma
keywords: Celiac  Disease-like molecular profile; Celiac Disease; IFNγ; Intraepithelial Lymphocytes; Vα24-Jα18; iNKT