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Here are two somewhat technical but important CD studies. In previous
studies (Science Magazine, Vol 297, Sept 27, 2002), a gliadin peptide was
identified as an initiator of the CD T cell response. It was found to be
highly resistant to breakdown by normal digestive enzymes. The following
study shows that this peptide can, in fact, be fully digested by the
enterocytes in the intestines of normal controls and treated-celiac
patients, but not in patients with ACTIVE celiac disease. Enterocytes are
epithelial cells which comprise the villi and crypts of the intestine
lining. See:
http://biology.about.com/library/organs/bldigestsmallint2.htm
Another study identifies over expressed IL-15 (interleukin-15) as an immune
system chemical that contributes to villous atrophy, suggesting that
blocking IL-15 may be a way of treating complications of CD.
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Gastroenterology, Sept 2003, Vol 125, No 3, p 696-707
Alterations of the intestinal transport and processing of gliadin peptides
in celiac disease
Tamara Matysiak-Budnik, Celine Candalh, Christophe Dugave, Abdelkader
Namane, Christophe Cellier, Nadine Cerf-Bensussan, Martine Heyman
INSERM EMI 0212, Faculté Necker-Enfants Malades, Paris, France
Laboratoire DIEP, CEA/Saclay, Gif sur Yvette, France
Proteomic Platform, Institut Pasteur, Paris, France
Hôpital Européen G. Pompidou, Paris, France
Supported by the Nutricia Research Foundation, the Princess Grace de Monaco
Foundation, INSERM, PROGRES, and IRMAD.
Address requests for reprints to: Martine Heyman, Ph.D., INSERM EMI 0212,
Faculté Necker-Enfants Malades, 156 rue de Vaugirard, 75730, Paris, France
fax: (33) 1 40 61 56 38; Email: [log in to unmask]
Abstract
Background & aims: The hypothesis of a defect in the intestinal transport
and processing of toxic (31-49) or immunostimulant (57-68 and the 33-mer 56-
89) gliadin peptides was tested in patients with active celiac disease
(ACD), patients with treated celiac disease (TCD), and controls.
Methods: Using duodenal biopsy specimens mounted in Ussing chambers, we
measured electrical resistance, mucosal-to-serosal radiolabeled-peptide
fluxes, and peptide processing during transport using radio-reverse-phase
high-performance liquid chromatography.
Results: Peptide 31-49 fluxes (24.7 µg · 3 h(-1) · cm(-2)) were increased
in patients with ACD compared with controls and patients with TCD (12.7 and
12.3 µg · 3 h(-1) · cm(-2); P < 0.01). In contrast, no increase was
observed for peptide 57-68 or 56-89 (33-mer). Electrical resistance was
decreased in patients with ACD versus controls (15.3 vs. 23.9 ohms · cm(2);
P < 0.001). Peptide 57-68 was partially degraded by brush-border peptidases
in controls but not in patients with celiac disease. However, it was
totally degraded after intestinal transport both in controls and patients
with celiac disease. Peptides 31-49 and 56-89 were resistant to brush-
border peptidases in all groups of patients but were totally degraded
during intestinal transport in controls and patients with TCD. In patients
with ACD, however, 50% of peptide 31-49 was delivered intact into the
serosal compartment and only partial degradation of the 33-mer was
observed. These abnormalities were not related to a nonspecific
paracellular leakage.
Conclusions: Our data indicate that gliadin peptides, although poorly or
not digested by intraluminal enzymes, can be fully digested by enterocytes
in controls and patients with TCD. In patients with ACD, incomplete
degradation of the 33-mer and protected transport of the peptide 31-49
might favor their respective immunostimulatory and toxic effects.
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Gastroenterology, Sept 2003, Vol 125, No 3, p 730-745
Interleukin 15: A key to disrupted intraepithelial lymphocyte homeostasis
and lymphomagenesis in celiac disease
Jean-Jacques Mention, Mélika Ben Ahmed, Bernadette Bègue, Ullah Barbe,
Virginie Verkarre, Vahid Asnafi, Jean-frédéric Colombel, Paul-henri
Cugnenc, Frank M. Ruemmele, Elisabeth Mcintyre, Nicole Brousse, Chistophe
Cellier, Nadine Cerf-Bensussan
INSERM EMI-0212, Faculté Necker, Paris, France
Department of Pathology, Hôpital Necker-Enfants Malades, Paris, France
Department of Hematology, Hôpital Necker-Enfants Malades, Paris, France
Department of Gastroenterology, Hôpital Huriez, Lille, France
Department of Surgery, Hôpital Georges Pompidou, Paris, France
Department of Gastroenterology, Hôpital Georges Pompidou, Paris, France
Supported by INSERM (Réseau Progrès), Assistance Publique des Hôpitaux de
Paris (PHRC96096), La Fondation pour la Recherche sur le Cancer (ARC9216),
and La Fondation Princesse Grace de Monaco. J.-J.M. has a fellowship from
the Institut Danone, and M.B.A. has a fellowship from INSERM.
Address requests for reprints to: Nadine Cerf-Bensussan, M.D., Ph.D.,
INSERM EMI-0212, Faculté Necker 156, rue de Vaugirard, 75730 Paris Cedex
15, France fax: (33) 1-40-61-56-38; Email: [log in to unmask]
Abstract
Background & Aims: 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.
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