Evidence for the role of interferon-alfa production by dendritic cells in the Th1 response in celiac disease.
OBJECTIVE
Dendritic cells (DCs) play a crucial role in immune responses by controlling the extent and type of T-cell response to antigen. Celiac disease is a condition in which T-cell immunity to gluten plays an important pathogenic role, yet information on DCs is scant. We examined mucosal DCs in celiac disease in terms of phenotype, activation/maturation state, cytokine production, and function.


METHODS
Mucosal DCs from 48 celiacs and 30 controls were investigated by flow cytometry. In situ distribution of DCs was analyzed by confocal microscopy. Interferon (IFN)-alfa, interleukin (IL)-4, IL-5, IL-12p35, IL-12p40, IL-18, IL-23p19, IL-27, and transforming growth factor-beta transcripts were measured by real-time reverse-transcription polymerase chain reaction in sorted DCs. DC expression of IL-6, IL-12p40, and IL-10 was assessed by intracellular cytokine staining. The effect of IFN-alfa and IL-18 blockade on the gluten-induced IFN-gamma response in celiac biopsy specimens grown ex vivo also was investigated.


RESULTS
Mucosal DCs were increased in untreated, but not treated, celiacs. The majority of them were plasmacytoid with higher levels of maturation (CD83) and activation (CD80/CD86) markers. Higher transcripts of Th1 relevant cytokines, such as IFN-alfa, IL-18, and IL-23p19, were produced by celiac DCs, but because IL-12p40 was undetectable, a role for IL-23 is unlikely. Intracellular cytokine staining of celiac DCs showed higher IL-6, but lower IL-10 expression, and confirmed the lack of IL-12p40. Blocking IFN-alfa inhibited IFN-gamma transcripts in ex vivo organ culture of celiac biopsy specimens challenged with gluten.


CONCLUSIONS
These data suggest that IFN-alfa-producing DCs contribute to the Th1 response in celiac disease.
Di Sabatino
Antonio
A
Centre for Infectious Disease, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, London, United Kingdom.
Pickard
Karen M
KM
Gordon
John N
JN
Salvati
Virginia
V
Mazzarella
Giuseppe
G
Beattie
Robert M
RM
Vossenkaemper
Anna
A
Rovedatti
Laura
L
Leakey
Nicholas A B
NA
Croft
Nicholas M
NM
Troncone
Riccardo
R
Corazza
Gino R
GR
Stagg
Andrew J
AJ
Monteleone
Giovanni
G
MacDonald
Thomas T
TT
D000906:Antibodies; D015703:Antigens, CD / Q000032:analysis; D016022:Case-Control Studies; D002446:Celiac Disease / Q000178:diet therapy / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D002469:Cell Separation; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000032:analysis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism*; D018753:Diet, Protein-Restricted; D005434:Flow Cytometry; D005903:Gliadin / Q000276:immunology; D005983:Glutens / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D018928:Immunity, Mucosal; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D018613:Microscopy, Confocal; D010446:Peptide Fragments / Q000276:immunology; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D046509:Tissue Culture Techniques; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D000906:Antibodies; D015703:Antigens, CD; D016898:Interferon-alpha; D007378:Interleukins; D010446:Peptide Fragments; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D005983:Glutens; D007371:Interferon-gamma; D005903:Gliadin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human