title: Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease.
abstract: OBJECTIVE
  The mechanism of intraepithelial lymphocyte hyperplasia, a hallmark of celiac disease, is unknown. We have investigated the role of epithelium-derived interleukin (IL)-15 in the alterations of epithelial homeostasis in refractory celiac sprue, a privileged situation to study the first step of lymphoid transformation and the contribution of intraepithelial lymphocytes to villous atrophy in celiac disease.
  
  
  METHODS
  IL-15 expression was assessed in biopsy specimens and isolated enterocytes by combining immunohistochemistry, flow cytometry, and real-time quantitative polymerase chain reaction. The ability of IL-15 to induce growth and survival of clonal intraepithelial lymphocytes lacking surface CD3 and to induce their cytotoxicity and secretion of interferon gamma was tested using soluble IL-15 and coculture in the presence of epithelial cell lines expressing membrane IL-15.
  
  
  RESULTS
  IL-15 was massively overexpressed not only in lamina propria but also in the intestinal epithelium of patients with active celiac disease and refractory celiac sprue. IL-15 was not secreted but delivered at the surface of enterocytes. IL-15 specifically induced the expansion and survival of the clonal abnormal intraepithelial lymphocytes that characterize refractory celiac sprue and triggered their secretion of interferon gamma and their cytotoxicity against intestinal epithelial cells. Comparable activating signals could be delivered by IL-15 expressed at the membrane of the T84 enterocyte cell line.
  
  
  CONCLUSIONS
  These data provide strong evidence that uncontrolled overexpression of IL-15 in refractory celiac sprue perpetuates epithelial damage and promotes the emergence of T-cell clonal proliferations. Blocking IL-15 might prove useful to treat this severe complication of celiac disease.
authors.affiliation: INSERM EMI 0212, Faculté Necker, Paris.
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Mention
authors.forename: Mélika
authors.initials: M
authors.lastname: Ben Ahmed
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bègue
authors.forename: Ullah
authors.initials: U
authors.lastname: Barbe
authors.forename: Virginie
authors.initials: V
authors.lastname: Verkarre
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
authors.forename: Jean-Frédéric
authors.initials: JF
authors.lastname: Colombel
authors.forename: Paul-Henri
authors.initials: PH
authors.lastname: Cugnenc
authors.forename: Frank M
authors.initials: FM
authors.lastname: Ruemmele
authors.forename: Elisabeth
authors.initials: E
authors.lastname: McIntyre
authors.forename: Nicole
authors.initials: N
authors.lastname: Brousse
authors.forename: Chistophe
authors.initials: C
authors.lastname: Cellier
authors.forename: Nadine
authors.initials: N
authors.lastname: Cerf-Bensussan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000032:analysis; D002446:Celiac Disease / Q000276:immunology*; D053804:Granzymes; D006706:Homeostasis; D006801:Humans; D039001:Integrin alpha Chains / Q000032:analysis; D007371:Interferon-gamma / Q000235:genetics; D019409:Interleukin-15 / Q000502:physiology*; D007413:Intestinal Mucosa / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology*; D008223:Lymphoma / Q000209:etiology*; D008875:Middle Aged; D012697:Serine Endopeptidases / Q000235:genetics
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; D019409:Interleukin-15; C091367:alpha E integrins; D007371:Interferon-gamma; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases