Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease.
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.
Mention
Jean-Jacques
JJ
INSERM EMI 0212, Faculté Necker, Paris.
Ben Ahmed
Mélika
M
Bègue
Bernadette
B
Barbe
Ullah
U
Verkarre
Virginie
V
Asnafi
Vahid
V
Colombel
Jean-Frédéric
JF
Cugnenc
Paul-Henri
PH
Ruemmele
Frank M
FM
McIntyre
Elisabeth
E
Brousse
Nicole
N
Cellier
Chistophe
C
Cerf-Bensussan
Nadine
N
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
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