Immunity

Review
Celiac Disease: An Immunological Jigsaw
Bertrand Meresse,
1,2,
* Georgia Malamut,
1,2,3
and Nadine Cerf-Bensussan
1,2,
*
1
INSERM, U989, 75015 Paris, France
2
Universite Paris Descartes, Paris Sorbonne Centre, Institut IMAGINE, 75015 Paris, France
3
AP-HP, Department of Gastroenterology, Ho pital Europe en Georges Pompidou, 75015 Paris, France
*Correspondence: bertrand.meresse@inserm.fr (B.M.), nadine.cerf-bensussan@inserm.fr (N.C.-B.)
DOI 10.1016/j.immuni.2012.06.006
Celiac disease (CD) is a chronic enteropathy induced by dietary gluten in genetically predisposed people. The
keystone of CD pathogenesis is an adaptive immune response orchestrated by the interplay between gluten
and MHCclass II HLA-DQ2 and DQ8 molecules. Yet, other factors that impair immunoregulatory mechanisms
and/or activate the large population of intestinal intraepithelial lymphocytes (IEL) are indispensable for
driving tissue damage. Herein, we summarize our current understanding of the mechanisms and conse-
quences of the undesirable immune response initiated by gluten peptides. We show that CD is a model
disease to decipher the role of MHC class II molecules in human immunopathology, to analyze the mecha-
nisms that link tolerance to food proteins and autoimmunity, and to investigate how chronic activation of
IEL can lead to T cell lymphomagenesis.
Introduction
Celiac disease (CD) is dened as a chronic small intestinal
immune-mediated enteropathy induced by dietary gluten in
genetically predisposed individuals (Ludvigsson et al., 2012).
The termceliac (hollow in Greek) referred to its digestive origin
and was coined by the Greek physician Aretaeus, who describes
the disease circa 100 AD in Roma. The link with the diet was
denitively established in the 1950s, when W. Dicke, a Dutch
pediatrician, demonstrated the causal role of grain storage
proteins from wheat, barley, and rye (collectively called gluten),
and proposed to treat patients by a long-life gluten-free diet
(GFD) (Van de Kamer et al., 1953). Our present view of CD path-
ogenesis derives from several landmark ndings. Major steps
have been the recognition of HLA-DQ2 and DQ8 molecules as
the main genetic predisposing factor and the demonstration of
their role in orchestrating an adaptive immune response against
gluten peptides (reviewed in Sollid, 2002). It is however now
clear that this response, although necessary, is not sufcient
and that other factors that impair immunoregulatory mecha-
nisms and/or activate the large population of intestinal intraepi-
thelial lymphocytes (IELs) are indispensable for driving tissue
damage. Herein, we consider whether and how genetic and
immunological studies can be integrated into a comprehensive
plot and discuss possible clues for lling remaining gaps in our
understanding of this complex disorder.
Lessons from the Bedside
The high prevalence and broad clinical spectrumof CDhas been
progressively uncovered since the 1970s after the demonstra-
tion that CDis specically associated with serumautoantibodies
against a tissue antigen (Seah et al., 1971), later identied with
the ubiquitous enzyme tissue transglutaminase 2 (TG2) (Dieter-
ich et al., 1997). TG2 antibodies are detected in 0.3% 2% of
individuals in Europe and in the US, and comparable prevalence
rates are observed in a growing number of countries in which
gluten is an important component of the diet (Aggarwal et al.,
2012; Lionetti and Catassi, 2011). Positive serology is more
particularly frequent in rst-degree relatives, a nding consistent
with the importance of genetic predisposing factors (see below)
and in patients with autoimmune diseases notably with type 1
diabetes (T1D) and thyroiditis (Aggarwal et al., 2012). Indeed,
there is a strong link between CD and autoimmunity given that
5%10% of patients with T1D develop CD, whereas, 15%
20% of CD patients have or will develop autoimmune diseases
(Cosnes et al., 2008).
In individuals with positive serology, the diagnosis of CD is
conrmed by duodenal biopsies that demonstrate the typical
small intestinal lesions combining villous attening, crypt hyper-
plasia, and increased numbers of IELs. Histological lesions and
symptoms are however very variable and three situations are
now dened (Ludvigsson et al., 2012). The rst is symptomatic
CD that can develop at all ages of life, with two peaks, in early
childhood and in young women. Most symptoms can be
ascribed to impaired absorption of nutrients. Several extraintes-
tinal manifestations are less well understood and may be the
consequence of the abnormal immune response initiated by
gluten peptides (see below). A second condition, dened as
silent CD, refers to the many individuals with positive serology
and typical intestinal histology but no symptoms. The risk is
the development of complications, notably autoimmune (Cosnes
et al., 2008) or more rarely malignant (Elfstro m et al., 2011).
Finally, a smaller group of asymptomatic individuals have serum
TG2 antibodies but normal intestinal histology. Because some
but not all can later develop epithelial lesions, this third situation
is dened as latent or potential CD. In potential CD, there are
often greater numbers of IELs and more particularly of TCRgd
+
IELs, and TG2 antibodies can be detected in situ (Koskinen
et al., 2008; Ludvigsson et al., 2012). Latent CD illustrates that
the intestinal immune response revealed by the production of
antibodies does not necessarily lead to intestinal tissue damage
and may be restrained by regulatory mechanisms.
Most CD patients are relieved by a life-long GFD, which
interrupts the intestinal immune response triggered by gluten
and allows recovery of a normal villous architecture. However,
a few patients develop resistance to GFD. In so-called type I
refractory celiac disease (RCD), immunological ndings in the
Immunity 36, June 29, 2012 2012 Elsevier Inc. 907
intestine, and notably the phenotype of IELs, resemble those
observed in uncomplicated active CD. One plausible hypothesis
is that the immunological reaction initiated by gluten has evolved
toward autoimmunity. Accordingly, symptoms improve under
immunosuppressive treatments. In contrast, in type II RCD, the
normal population of CD3
+
IELs is progressively replaced by
clonal IELs with an abnormal phenotype and RCDII is now
considered as an intraepithelial lymphoma. RCDII is the frequent
rst step toward the development of overt T lymphomas, the rare
but most severe complication of CD (Malamut et al., 2009).
Overall, clinical observations in CD reveal a striking overlap
between CD and bona de autoimmune diseases. Severity and
age at onset of symptomatic CD are highly variable and might
be inuenced by life events that alter local immune regulation.
IEL hyperplasia, a hallmark of CD and the origin of T lymphomas,
points to severe impairment of IEL homeostasis in CD.
The Keystone of CD: The Interplay between Gluten and
MHC Class II HLA-DQ2 or -DQ8 Molecules
Following studies highlighting a strong association between
CD and the HLA complex, it was established in the late 1980s
Figure 1. Human Leukocyte Antigen Class II
Associations with Celiac Disease and Type
1 Diabetes
The majority of CD patients express the HLA-
DQ2.5 heterodimer encoded by the HLA-DQA1*05
(a-chain) and HLA-DQB1*02 (b-chain) alleles.
These two alleles are carried either in cis on the
DR3-DQ2.5 haplotype or in trans in individuals
who are DR5DQ7 and DR7DQ2 heterozygous.
HLA-DQ8 that is encoded by the DR4DQ8 haplo-
type confers a lesser risk of CD. In individuals
who are DR3DQ2.5 and DR4DQ8 heterozygous,
transdimers DQ8.5 can form and confer high
susceptibility to TID.
that genetic susceptibility to CD is
determined mainly by the HLA-DQ locus
(Sollid et al., 1989). The strongest associ-
ation is observed with HLA-DQ2.5 (Fal-
lang et al., 2009). Thus, more than 90%
of CDpatients possess one or two copies
of HLA-DQ2.5 encoded by HLA-DQA1*05
(for the a chain) and HLA-DQB1*02 (for
the b chain). In individuals who carry the
DR3DQ2 haplotype, this molecule is en-
coded by DQA1 and DQB1 alleles located
on the same chromosome (cis congura-
tion) whereas in individuals who are
DR5DQ7 or DR7DQ2 heterozygous, it is
encoded by alleles located on opposite
chromosomes (trans conguration) (re-
viewed in Sollid et al., 2012; Figure 1).
The resulting HLA-DQ2.5 heterodimers
differ only by two amino acids, which
do not inuence their functional proper-
ties. In contrast, the highly homologous
HLA-DQ2.2 molecule confers a much
lesser risk due to the replacement of
a tyrosine by a phenylalanine residue
in DQa at position 22 that is important for peptide binding
(Bodd et al., 2012; Fallang et al., 2009). Most of the remaining
patients carry DR4DQ8 haplotypes and express a DQ8 molecule
encoded by DQA1*03DQB1*03:02 (Sollid et al., 2012). Strikingly,
individuals who are heterozygous for DQ2.5 (DQA1*05:01 and
DQB1*02:01) or DQ8 (DQA1*03:01 and DQB1*03:02) are also
predisposed to T1D with an almost ve-fold higher risk than
those whoare homozygous for either of the DQvariants (Concan-
non et al., 2009). This high risk was recently associated with the
formation of HLA-DQ8 transdimers between the a-chain of HLA-
DQ2 (DQA1*05:01) and the b-chain of HLA-DQ8 (DQB1*03:02)
or of HLA-DQ2 transdimers between the a-chain of HLA-DQ8
(DQA1*03:01) and the b-chain of HLA-DQ2 (DQB1*02:01) (Tollef-
sen et al., 2012; van Lummel et al., 2012) (Figure 1).
In CD, the link between the main environmental factor, gluten,
and the main genetic predisposing factor, the HLA-DQ2.5 mole-
cule, was rst disclosed by a seminal work demonstrating the
presence of HLA-DQ2-restricted gluten-specic CD4
+
T cells
in the intestinal mucosal of CD patients (Lundin et al., 1993).
The molecular bases of the interactions between gluten-derived
peptides and HLA-DQ2.5/8 molecules are now well established
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Review
and depend on the physicochemical properties of the two
partners. HLA-DQ2.5 and HLA-DQ8 have positively charged
pockets, which preferentially bind peptides with negatively
charged residues at anchor positions P4, P6, and P7 for HLA-
DQ2 and P1, P4, and P9 for HLA-DQ8 (reviewed in Abadie
et al., 2011). One common feature of gluten proteins immuno-
genic for CD patients is their high content in glutamine (Q) and
proline (P) residues assembled in related repetitive sequences.
Proline-rich peptides are particularly resistant to proteolysis by
digestive enzymes, so that large immunogenic peptides remain
undigested in the intestinal lumen and may come into contact
with intestinal immune cells (Shan et al., 2002). Peptides contain-
ing glutamine (Q)-proline (P) rich motifs (notably the Q-X-P
sequence) are excellent substrates for TG2. This multifunctional
Figure 2. Activation of Gluten-Specic
CD4
+
T Cell Responses by HLA-DQ2.5
Molecule
Transglutaminase 2 (TG2) binds to and deami-
dates glutamine residues in Q-X-P sequences of
gluten peptides into glutamic acid, introducing
a negative charge that can interact with a
positively charged lysine residue in position 6
of the peptide pocket of HLA-DQ2.5, resulting
in enhanced peptide avidity for HLA-DQ2.5.
HLA-DQ2.5-gluten peptide complexes expressed
on antigen-presenting cells (APCs) can prime
gluten-specic CD4 T cells. As for other dietary
antigens, priming may occur in Peyers patches
or in mesenteric lymph nodes after migration
of CD103
+
dendritic cells loaded with gluten
peptides in lamina propria (Worbs et al., 2006).
Unusual priming outside the gut has however
been reported in HLA-DQ2 mice (Du Pre et al.,
2011). Priming is followed by selection and clonal
expansion of T cells diplaying high-avidity TCR
(Qiao et al., 2011).
enzyme is abundantly expressed in many
tissues and with both intra- and extracel-
lular localization and can convert neutral
glutamine residues within Q-X-P se-
quences into negatively charged gluta-
mate residues, thereby strongly in-
creasing peptide avidity for HLA-DQ2.5
(reviewed in Abadie et al., 2011; Figure 2)
or for HLA-DQ8 (Henderson et al., 2007).
Finally, proline residues introduce struc-
tural constraints that are compatible with
peptide binding to HLA-DQ2/8 molecules
but not to other MHC class II molecules
(Bergsenget al., 2005). Asaconsequence,
HLA-DQ2/8
+
dendritic cells can electively
activate gluten-specic CD4
+
T cells
(Figure 2). Several gluten epitopes pre-
ferentially recognized in the context
of either HLA-DQ2.5 or HLA-DQ8 have
been dened (Sollid et al., 2012). Such
epitopes may in turn drive the selection
of T cells harboring a T cell receptor
(TCR) of high avidity. Thus, a recent study
showed clonal expansion, convergent
recombination, and semipublic response of T cells recognizing
the dominant gluten epitope DQ2.5-glia-a2. Reactive T cells
preferentially used a TCR Vb6.7 chain with a conserved non-
germline-encoded arginine residue in the CDR3b loop. This
positively charged residue probably interacts with the negatively
charged deamidated residue of DQ2.5-glia-a2 that binds to the
HLA-DQ2.5 pocket in position P4 (Qiao et al., 2011).
Further supporting the importance of HLA-DQ-restricted
anti-gluten CD4
+
T cell response in CD onset, correlations
have been established between the richness in motifs predicted
to be substrates for TG2 and to bind HLA-DQ molecules and
the toxicity of individual cereal proteins (Vader et al., 2002).
Conversely, that HLA-DQ8 and HLA-DQ2.2 bind a lesser number
of gluten peptides than HLA-DQ2.5 and/or with a lesser avidity is
Immunity 36, June 29, 2012 2012 Elsevier Inc. 909
Immunity
Review
thought to explain the lesser risk of CD associated with these
molecules (Bodd et al., 2012; Fallang et al., 2009). Finally,
disease susceptibility has been associated with a dosage effect
and DR3DQ2 homozygous individuals who express more at-risk
molecules on antigen-presenting cells (APCs) have the highest
risk for CD (Vader et al., 2003). Interestingly, recent observations
might explain the high risk of HLA-DQ2-DQ8 heterozygous indi-
viduals for TID. Indeed the HLA-DQ8 transdimer can not only
present a signicant repertoire of gluten peptides but it can
also bind with high avidity a much larger repertoire of peptides
derived from the diabetogenic proteins GAD65, IA-2 and pre-
proinsulin than the cis HLA-DQ8 dimer (Kooy-Winkelaar et al.,
2011; van Lummel et al., 2012).
Overall these data show how the main genetic risk factor for
CD, the HLA-class II molecules DQ2 and DQ8, can orchestrate
the activation of lamina propria CD4
+
T cells against dietary
gluten. They also provide evidence of the strong similarities
between the mechanisms governing the recognition of exoge-
nous gluten in CD and of pancreatic autoantigens in T1D.
Loss of Tolerance and Tissue Damage in CD: A Need for
Additional Environmental and Genetic Factors
Only a small fraction of individuals with at-risk HLA and who are
exposed to gluten develop CD, indicating that both factors,
although necessary, are not sufcient for developing CD. This
common observation was recently extended into a worldwide
comparison of the prevalence of CD between countries depend-
ing on the frequencies of DR3DQ2 and DR4DQ8 haplotypes and
on the amount of wheat consumption. Many but not all countries
could be tted into a correlation curve, and CD prevalence was
notably much higher in Finland and Mexico or, on the contrary,
much lower in Russia and Tunisia than expected (Abadie et al.,
2011). Humanized mouse models further support the notion
that an adaptive CD4
+
T cell response to gluten is not sufcient
to recapitulate CD and induce intestinal tissue damage. No
enteropathy has been observed in mice expressing HLA-DQ8
and human CD4 (Black et al., 2002), nor in mice transgenic for
HLA-DQ2.5 and a gluten-specic T cell receptor upon gluten
feeding (de Kauwe et al., 2009; Du Pre et al., 2011). In these
models, gluten-responsive T cells produced tumor-growth
factor b (TGF-b) or Interleukin-10 (IL-10), reecting the induction
of immunoregulatory mechanisms (Black et al., 2002; Du Pre
et al., 2011). Crossing HLA-DQ8 mice on a NOD background
to promote autoimmunity resulted in the appearance of TG2
autoantibodies and of a skin disease reminiscent of dermatitis
herpetiformis, but the mice did not develop intestinal lesions
(Marietta et al., 2004). Therefore, complementary genetic and
or environmental factors must inuence CD penetrance and
are likely necessary to break intestinal tolerance to gluten
and induce intestinal tissue damage.
Genetic Clues to Celiac Disease from Outside the HLA
Locus
In CD, the sibling recurrence risk of 10% and the concordance
of 75%80% between monozygotic twins stress the importance
of genetic predisposition. Comparison between siblings also
suggests that HLA contributes for no more than 35% of the
genetic risk (Bevan et al., 1999; Nistico` et al., 2006). Twenty-
six non-HLA genomic loci signicantly associated with CD,
most of which containing immune genes were rst identied
by genome wide associations studies (GWAS) (Dubois et al.,
2010; Hunt et al., 2008). Dense genotyping using a custom
Immunochip designed for 183 non-HLA risk loci associated
with immune-mediated diseases then demonstrated 57 inde-
pendent CD association signals in 39 separate non-HLA loci
(Trynka et al., 2011). Twenty-nine of the total 54 independent
non-HLA signals could be assigned to a single gene. Overall,
these signals might explain 13.7% of the genetic variance of
CD in individuals of European ancestry (Trynka et al., 2011).
Yet, most identied variants are common allelic variants (de-
tected in >5% of individuals in the general population) and
each confers only small positive or negative risk with odd ratios
(OR) between 0.7 and 1.5. Lower frequency variants were iden-
tied at four separate loci (RGS1, CD28-CTLA4-ICOS, SOCS1-
PRM1-PRM2, and PTPN2) by dense genotyping but OR did
not exceed 1.7. One exome sequencing study in a CD family
with six affected members also failed in identifying a rare causal
variant (Szperl et al., 2011).
Despite the now large number of loci associated with CD,
causative mutations thus remain tobe identied. Ameta-analysis
of genome-wide data sets for eQTLs (expression quantitative
trait loci) mapping has suggested that 50% of CD-associated
SNPs might affect the expression of nearby genes (Dubois
et al., 2010). Using dense genotyping, the same authors further
suggested that several signals are localized either around the
transcription start site of specic genes (such as RUNX3,
RGS1, ETS1, TAGAP, and ZFP36L1) or in the 3
0
untranslated
region (IRF4, PTPRK, and ICOSLG). They notably observed that
one variant present in the 3
0
UTR of the PTPRK locus is located
in a predicted binding site for a microRNA (hsa-miR-1910)
(Trynka et al., 2011). Strikingly, only very fewCD-associated vari-
ants were found within coding sequences. One such interesting
variant is a nonsynonymous SNPs in SH2B3 that is associated
with other autoimmune (T1D, rhumatoid arthritis) and metabolic
disorders. This gene encodes the adaptor protein LNK that inu-
ences a variety of signaling pathways, notably those mediated by
Janus kinases and receptor tyrosine kinases (Devallie` re and
Charreau, 2011).
Overall, these data raise the question of the biological signi-
cance of the observed associations and of their exact contribu-
tion to CD pathogenesis. One interesting hypothesis is that
CD-associated immune genes have been positively selected
as conferring a benet to the carriers, notably to resist against
infectious diseases. Two studies have used the test of integrated
haplotype similarity to detect signature of positive selection
for SNPs tagging CD-associated genomic regions. Only three
CD-associated regions showed evidence of positive selection:
IL-18RAP, IL12A, and SH2B3 (Abadie et al., 2011; Zhernakova
et al., 2010). Given that the selective sweep on SH2B3 might
have occurred between 1,200 and 1,700 years ago, a possible
link was suggested with the Justinian plague in 481482 AD
(Zhernakova et al., 2010).
Given the lack of identied causal mutation and the low
change in risk conferred by each variant, their individual role in
CD pathogenesis remains uneasy to anticipate. A recent com-
prehensive review has compared variants identied in CD and
in other immune-mediated disorders and used functional anno-
tation databases to cluster variants into functional pathways
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(Abadie et al., 2011). Strikingly, many loci are shared between
CD and autoimmune diseases, and notably 12 overlapping
loci were noted with T1D. CD-associated loci appeared more
particularly enriched in genes predicted to control chemokine
receptor activity, cytokine binding and production, and T and
NK cell activation. In Figure 3, we have analyzed how genes
associated with CD variants can be integrated into putative
immune pathways, on the basis of the role(s) assigned to the
corresponding genes in the literature. The obtained scheme illus-
trates the prominent association of CD with genes controlling
T cell activation and recruitment. The association with the IL2-
IL21 locus, shared with T1D, is particularly interesting. Indeed,
IL-21 is strongly increased in intestinal biopsies from active CD
(Fina et al., 2008) and is produced in response to gluten peptides
by specic CD4
+
T cells from CD patients (Bodd et al., 2010).
Moreover, CD-associated variants are also found in the IRF4
gene, a transcription factor that is activated in response to
TCR stimulation and controls IL-21 production by CD4
+
T cells
(Biswas et al., 2010). The potential importance of IL-21 in CD
and associated autoimmunity is further suggested by a recent
study showing how IL-21-producing CD4
+
T cells that express
the gut CCR9 homing receptor can target the pancreas of NOD
mice and promote CD8-dependent tissue damage (McGuire
et al., 2011). CD association with the TLR7-TLR8 region needs
to be conrmed but is of potential interest given that the celiac
risk variant correlated with changes in TLR8 expression in whole
peripheral blood (Dubois et al., 2010). TLR7 and TLR8 are innate
receptors for single-stranded viral RNA. They have been associ-
ated with susceptibility to hepatitis C (Wang et al., 2011a), which
may play a favoring role in CD (see below). The genetic link with
innate antiviral responses seems however less strong in CD than
in T1D, in which a combination of GWAS and eQTL data has
revealed an association with a whole network of antiviral innate
immune genes (Foxman and Iwasaki, 2011).
In conclusion, the search of genetic factors outside the HLA
locus has not yet identied a rare causative variant. Rather,
Figure 3. Hypothetical Role of Non-HLA CD-Associated Genes in Immune Responses
Non-HLA loci associated with CDare enriched in genes predicted to control T cell activation (TCR signaling, antigen presentation, and recruitment differentiation
into effector cells) and B cell help. Loci specic for CDare in red. Those shared with other autoimmune diseases (including T1D) are in black. Hypothetical groups
of genes that may participate in T cell activation, T cell cytotoxicity, IL-21 production, and IgA response, are shown. The possible interplay between IL-21 and
IL-15 in tissue damage is suggested (see also Figure 4 and text).
Immunity 36, June 29, 2012 2012 Elsevier Inc. 911
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Review
a variable combination of common variants also often associ-
ated with autoimmune diseases may tune the immune system
toward too energetic T cell immune responses.
Clues for Infectious Cofactors in CD
The role of infectious cofactors is a long-lasting hypothesis in CD
that is supported by some epidemiological data. In a Swedish
population-based register study comparing perinatal data in
controls and in z3,400 infants who were born between the years
19871997 and developed CD, one main risk factor for contract-
ing CD was exposure to neonatal infections (odds ratio [OR] =
1.52) (Sandberg-Bennich et al., 2002). Of note the period of
study largely coincides with the so-called Swedish CD epidemic
(19851996) during which CD incidence underwent a 4-fold
increase. This epidemic is however usually ascribed to changes
in infant feeding habits and notably to the delayed introduction of
large amounts of gluten without the protection by breast feeding
(Ivarsson, 2005). Two other observations are consistent with the
triggering role of a virus. In children, early CD onset has been
correlated with serological evidence of repeated rotavirus infec-
tion (Stene et al., 2006). In adults, recurrent observations report
the development of CDin patients treated with IFN-a for hepatitis
C (Bourlie` re et al., 2001). Despite strong suspicion that gastroin-
testinal or hepatic viruses may participate in CD onset, there has
been however no formal demonstration of this (reviewed in Plot
and Amital, 2009). In a recent study, viral RNAfromenteroviruses
was often detected in the intestinal mucosa of T1D but no
signicant difference was observed between controls and CD
patients (Oikarinen et al., 2012), arguing against the hypothesis
of a persistent enterovirus as incriminated in T1D or in Crohns
disease (Foxman and Iwasaki, 2011). The role of transient or
repeated intestinal infections such as by rotavirus(es) is however
attractive. In mice, rotavirus induced Toll-like receptor 3 (TLR3)-
dependent production of CCL5 chemokine and of type I IFN-l
and recruitment of cytotoxic IELs (Pott et al., 2012). Activation
of TLR3 by poly-IC has also been associated in mice with the
activation of TG2 and with the production of IL-15 (Dak et al.,
2012) and may thus simultaneously promote the activation of
CD4
+
LPL and of CD8
+
IELs (see below).
Recent studies have also considered a possible role for the
microbiota. Not surprisingly, some changes in the composition
of the fecal and duodenal microbiota have been reported (Nistal
et al., 2012). The most original nding is the detection of rod-
shaped bacteria closely associated with the duodenal mucosa
in biopsies of children born during the Swedish CD epidemic
but not in more recent cases of CD. The pathogenic role of these
bacteria, which belong to three distinc genders, remains unclear
(Ou et al., 2009). Bacterial adhesion may be favored by gluten-
induced inammation and induce the activation of some Th17
+
cells. Indeed a moderate induction of IL-17 is observed in
duodenal biopsies in active CD but IL-17, in contrast with IL-21
and IFN-g, is not produced by gluten-specic CD4
+
T cells
(Bodd et al., 2010).
Overall, the search for additional genetic and environment
risk factors has provided interesting hypotheses but no decisive
insight into the mechanisms, which convert immune tolerance to
gluten into inammation and tissue damage. We discuss below
how to integrate other immunological features of CD into a
comprehensive plot.
Roles of IgA Antibodies to Gluten Peptides and Tissue
Transglutaminases in and Outside the Gut
Serum IgA specic for gluten peptides and for the autoantigen
TG2 are hallmarks of active CD. They are enriched in polymeric
IgA and produced by intestinal plasma cells, the density of which
is markedly increased in CD LP (Colombel et al., 1990; Di Niro
et al., 2012). A recent study showed that 10%of IgA plasma cells
isolated from the intestinal LP of untreated CD produced TG2
antibodies. Despite their extensive characterization through the
derivation of a large panel of monoclonal antibodies from single
anti-TG2 lamina propria plasma cells (Di Niro et al., 2012), the
mechanism that explains their specic production in active CD
and their disappearance after a strict GFD remains unclear.
Hapten-like recognition of TG2 crosslinked to gluten has been
suggested. Indeed, in the presence of acyl acceptors bearing
a lysine side chain, modication of glutamine residues by TG2
results in the formation of isopeptide bounds and protein cross-
linking and TG2 is known to interact electively with gluten-
derived peptides. This hypothesis is also compatible with the
observation that TG2 antibodies do not inhibit the crosslinking
activity of TG2. It remains however to be substantiated (Di Niro
et al., 2012).
Other pending questions are the exact roles of TG2 and
TG2 antibodies in CD pathogenesis. TG2 is a multifunctional
enzyme that has been involved in a variety of physiological
functions, including matrix assembly and tissue repair, receptor
signaling, proliferation, cell motility, and endocytosis. A role of
TG2 in CD beyond its established function in deamidation
and presentation of gluten peptides to the adaptive immune
system is thus suspected although not clearly delineated.
In vitro studies have also suggested that TG2 IgA autoanti-
bodies might modulate enterocyte proliferation and differentia-
tion as well as epithelial barrier function (reviewed in Klo ck
et al., 2012). Yet, the presence of TG2 IgA in the mucosa of
latent CD indicates that they are not sufcient to induce intes-
tinal tissue damage (Koskinen et al., 2008). Transglutaminase
antibodies may however play a central role in some extrain-
testinal manifestations of autoimmunity, notably in dermatitis
herpetiformis (DH), a gluten-dependent blistering skin disease.
Patients with DH have serum antibodies reactive against
TG2 but also against TG3, the epidermal version of TG2, due
either to cross-reactivity or epitope spreading (Sa rdy et al.,
2002). DH skin lesions do not contain T cells but dermal
deposits of IgA and TG3 that are associated with neutrophil
inltrates in blistering areas. Formation of dermal IgA and
TG3 deposits are recapitulated in human skin grafted into
SCID mice injected with goat-anti-human TG3, or serum from
CD or DH patients (Zone et al., 2011). Moreover, a gluten-
dependent blistering disease was observed in gluten-fed
HLA-DQ8xNOD mice, which developed circulating TG2 anti-
bodies, dermal IgA deposits, and neutrophil inltrates (Marietta
et al., 2004; Figure 4).
Finally, a possible pathogenic role of antigliadin secretory
IgA (SIgA) has recently been suggested because of its binding
to CD71. CD71 is best known as a high avidity receptor for
transferrin. In humans, it is also a receptor of weak afnity for
polymeric IgA (Moura et al., 2001). In active CD, this receptor
is strongly upregulated in small intestinal enterocytes and
becomes expressed at the apical surface, allowing the binding
912 Immunity 36, June 29, 2012 2012 Elsevier Inc.
Immunity
Review
of intraluminal SIgA complexed to gliadin peptides and their
subsequent retrotransport into lamina propria via the recycling
endocytic pathway (Matysiak-Budnik et al., 2008; Lebreton
et al., 2012). In active CD, SIgA thus fail to play a normal protec-
tive role in excluding dietary antigens, but rather behaves as a
Trojan horse facilitating the entrance of intact peptides into the
mucosa (Figure 4, left). Our recent data indicate that TG2 partic-
ipates in this process as necessary for the endocytosis of CD71
(Lebreton et al., 2012). How this mechanism contributes to CD
pathogenesis remains to be evaluated. IgA-decient patients
are prone to develop CD, indicating that SIgA are dispensable
for CD. However, inadvertent transepithelial passage of gluten
peptides may be facilitated in the latter patients by the lack of
an efcient SIgA barrier (Wang et al., 2011b). In immunopro-
cient patients with active CD, CD71-mediated retrotranscytosis
of SIgA-gliadin complexes may thus also sustain the immune
response by enhancing epithelial permeability to immunogenic
peptides. Of note, the binding of polymeric IgA to CD71 can
activate signal transduction into erythropoietic precursors (Cou-
lon et al., 2011). It will be interesting to determine whether
binding of SIgA to CD71 might also induce a signaling cascade
in enterocytes.
Figure 4. Hypothetic Scheme of Immune Responses in CD
As shown on the left, the B cell response. IgA-producing B cells primed in gut-associated lymphoid tissue (GALT, center) migrate into LP and differentiate into
plasma cells, which produce dimeric IgA released into the intestinal lumen as secretory IgA. In active CD, SIgA-gluten complexes formed in the intestinal lumen
can bind the CD71 receptor up-regulated at the apical surface of enterocytes, resulting in their rapid retro-transport into LP. Binding of SIgA to CD71 may also
activate signal transduction into epithelial cells. These mechanisms may exacerbate immune responses. Intestinal dimeric IgA can be released into blood and
participate in extra-intestinal autoimmunity, notably in dermatitis herpertiformis (see text). As shown on the right, the T cell response. In active CD, IL-15,
produced by enterocytes and LPdendritic cells and macrophages, favors the activation of IFN-g-producing and cytotoxic CD8
+
IELs harboring NKcell receptors.
Gluten-specic CD4
+
T cells may participate in IEL activation via cross-priming or via the production of IL-21 that synergizes with IL-15 to activate cytotoxic CD8
+
T cells. In the presence of IL-15, CD8-T IELs can induce epithelial lesions via the interactions of their NK receptors NKG2D and NKG2C with their respective
ligands MICA and HLA-E upregulated on enterocytes. IL-15 and IL-21 may also cooperate and enable autoreactive CD8
+
T cells to respond to weakly agonistic
TCR self-ligands (bottom right). IL-15 then favors accumulation of activated CD8
+
T cells by stimulating their survival and inhibiting their responses to immu-
noregulatory mechanisms, further increasing the risk of developing T-dependent autoimmune diseases (T1D), thyroiditis, and perhaps type I refractory celiac
disease (RCDI). Finally, IL-15 can promote the emergence of unusual IEL-derived T lymphomas sharing characteristics of both NK and T cells and able to drive
epithelial lesions. Onset of lymphoma is revealed by refractoriness to the gluten-free-diet. In a majority of patients, the lymphoma is rst intraepithelial (type II
refractory celiac disease [RCDII]) and can secondarily transform into overt enteropathy-associated type T lymphoma (EATL).
Immunity 36, June 29, 2012 2012 Elsevier Inc. 913
Immunity
Review
Intraepithelial Lymphocytes: Role in Intestinal Damage
and T cell Lymphomagenesis
IELs form a large population of lymphocytes that are thought to
act as sentinels protecting the epithelial barrier. In CD, however,
their chronic activation leads to epithelial damage and, in a
small subset of patients, to T cell lymphomagenesis. The mech-
anisms that switch on their abnormal activation and drive their
transformation are only partially elucidated. Upregulation of IL-
15 observed in the intestine of patients with active CD and RCDII
probably plays an important role although the mechanism that
drives IL-15 expression remains poorly understood (Di Sabatino
et al., 2006; Hu e et al., 2004; Mention et al., 2004; Meresse et al.,
2004).
A rst puzzling observation in CD is the increase in TCRgd
+
IELs. The role of the latter cells remains largely enigmatic.
The current consensus assumes that TCRgd
+
IELs recognize
tissue-specic stress signals and might help maintain epithelium
integrity by exerting cytotoxicity or releasing soluble factors. This
protective function may be preserved in CD. Indeed an increase
in TCRgd
+
IELs is observed at all stages of CD, except in severe
cases of RCD II where they tend to disappear (reviewed in
Meresse and Cerf-Bensussan, 2009). Their early and persistent
increase in CD may reect chronic epithelial stress favored by
exposure to gluten. An alternative but nonexclusive hypothesis
may be IL-15-driven accumulation. Thus, mouse TCRgd
+
IELs
strictly depend on survival signals delivered by enterocyte-
derived IL-15 (Schluns et al., 2004). Whether TCRgd
+
IELs can
turn into epithelial aggressors in active CD is not excluded but
not yet documented.
In contrast, the second and main subset of human IELs, con-
sisting in CD8
+
TCRab
+
cells (CD8-T IELs), is now held respon-
sible for intestinal tissue damage (Figure 4, right). In active CD,
CD8-T IELs undergo a marked expansion that is associated with
enhanced intraepithelial expression of IFN-g (Olaussen et al.,
2002), perforin, and granzymes and with epithelial apoptosis
(Di Sabatino et al., 2006; Oberhuber et al., 1996). Because all
changes subside after GFD, one rst possible hypothesis is
that CD8-T IELs are activated through cross-presentation of
gluten peptides. This mechanism is suggested by data from
Gianfrani and coworkers who have identied a peptide mapping
to the 123132 position of A-gliadin (QLIPCMDVVL), which can
be recognized in the context of HLA-A*0201 by CD8
+
T lympho-
cytes isolated from CD mucosa. This peptide stimulates their
in vitro production of IFN-g and their cytotoxicity against the
intestinal epithelial cell line Caco-2 (Mazzarella et al., 2008).
A second nonexclusive hypothesis involves the coordinated
activation of CD8-T IELs by IL-15 and by NK receptors interact-
ing with their epithelial ligands. CD8-T IELs express several
NK receptors, notably CD94 and the activating NK receptor
NKG2D. Both receptors are upregulated in CD, probably in
response to IL-15 (Jabri et al., 2000; Meresse et al., 2004). More-
over, whereas CD94 associates with NKG2A in control IELs,
forming heterodimers that induce inhibitory signals, NKG2A
is downregulated in active CD, and CD94 associates on a
substantial fraction of IELs with a second partner, NKG2C, that
recruits the DAP12 adaptor and transduces activating signals
(Meresse et al., 2006). Accordingly, CD8-T IELs from active CD
can in vitro kill targets expressing MICA and HLA-E, the two
nonclassical MHC class I molecules that are the respective
ligands of NKG2D and CD94-NKG2C. Because MICA and
HLA-E are upregulated on enterocytes in active CD, the latter
cells may become in vivo the target of a cytolytic attack by
IELs (Meresse et al., 2004; Meresse et al., 2006; Figure 4, right).
If activation of CD94-NKG2C heterodimers seems sufcient to
stimulate IFN-g production and cytotoxicity by CD8-T IELs, the
exact role of NKG2D as a direct trigger or as a cosignal for
the TCR remains controversial. In vitro evidence indicates that
signals delivered by IL-15 may bypass a requirement for the
TCR (Meresse et al., 2004). Signals delivered by NKG2D and
IL-15 might also lower the activating threshold of the TCR (Hu e
et al., 2004; Roberts et al., 2001) and thus foster the activation
of gliadin-specic CD8
+
T cells or of CD8
+
T cells bearing TCR
with a low afnity for self-antigens. That NKG2D signaling can
trigger or exacerbate autoimmunity is supported by observations
in the NOD model of TID. RAE-1, the mouse homolog of MICA
was found upregulated in prediabetic pancreas islets, whereas
NKG2D was expressed on autoreactive intrapancreatic CD8
+
T cells, and progression to diabetes was prevented by a nonde-
pleting anti-NKG2D antibody (Ogasawara et al., 2004). More
recently, it was also shown that transgenic expression of
RAE1 in pancreas b-islet cells, although not sufcient to induce
diabetes, could stimulate the recruitment of CD8
+
T cells regard-
less of their antigen specicity and induce insulitis (Markiewicz
et al., 2012). In CD, chronic upregulation of activating NKR on
CD8-T IELs and of their ligands in intestinal and extraintestinal
tissues may thus favor the emergence of autoreactivity in and
outside the gut (Figure 4, right).
Finally, gluten-driven chronic activation is also associated in
a small subset of patients with the emergence of IEL-derived
lymphomas (Cellier et al., 2000; Malamut et al., 2009; Spencer
et al., 1988). Characterization of malignant IELs in RCDII patients
indicates that, alike CD8-T IELs in active CD, they share charac-
teristics of both T and NK cells: they contain clonal TCR
rearrangements and all chains of CD3 but also express several
NK markers, notably CD94, NKG2D, and NKP46. One major
difference is the lack of membrane expression of TCR-CD3
complexes and generally of CD8 (Cellier et al., 1998; Tjon
et al., 2008). In vitro, they exert a strong cytotoxicity against
enterocyte lines that can be blocked by NKG2D antibody (Hu e
et al., 2004). This functional property probably accounts for
the severe epithelial lesions observed in RCDII. Consistent with
data in mice showing that chronic upregulation of IL-15 drives
the emergence of T leukemias or lymphomas with NK markers
(Fehniger et al., 2001), we have observed that IL-15 plays
a central role in RCDII (Figure 4, right). In RCDII, IL-15 is upregu-
lated in enterocytes and drives the NK-like cytotoxicity of RCDII
IELs (Hu e et al., 2004; Mention et al., 2003). Via Janus kinase 3
(JAK3) and signal transducer and activator of transcription 5
(STAT5), IL-15 stimulates expression of the antiapoptotic B cell
lymphoma-extra large (Bcl-xL) protein, which rescues trans-
formed RCDII IELs from apoptosis and allowed their massive
accumulation and malignant progression (Malamut et al.,
2010). Our most recent data further suggest that IL-15 drives
the emergence of RCDII IELs from a T cell precursor reprog-
rammed into induced T to NK cells (N. Montcuquet et al., unpub-
lished data).
Overall these data illustrate how the interplay between IEL
and enterocyte-derived IL-15 can orchestrate intestinal tissue
914 Immunity 36, June 29, 2012 2012 Elsevier Inc.
Immunity
Review
damage and promote the onset of T cell lymphoma, a rare but
most severe complication of CD.
Which Clues for the Missing Pieces of the CD Jigsaw?
No activation of IELs is observed in humanized gluten-fed
HLA-DQ2 or -DQ8 mice, suggesting that IELs are not activated
or that immunoregulatory mechanisms curb their activation
(Black et al., 2002; de Kauwe et al., 2009). In contrast, mice
overexpressing IL-15 in their gut epithelium develop a massive
expansion of activated intestinal NK1.1
+
CD8
+
T cells and a
small intestinal enteropathy that progresses with age (Ohta
et al., 2002). Therefore, why is gluten-specic activation of
CD4
+
T cells necessary in CD to drive CD8-T IEL activation
that appears largely IL-15 dependent? Using OTII mice with
CD4
+
T cells specic for OVA crossed with mice overexpressing
IL-15 in the gut epithelium, we have observed that CD4
+
T cell
activation by OVA feeding strongly accelerates the onset of
the enteropathy (E. Ramiro et al. unpublished data). Help from
CD4
+
T cells may be necessary to license dendritic cells for
CD8
+
T cell cross-priming (Kurts et al., 2010). IL-15 might
then stimulate the survival of activated CD8
+
T cells (see above)
and also interfere with two important immunoregulatory mecha-
nisms. Indeed, by activating JNK, IL-15 can inhibit the Smad3
cascade of TGF-b in human T cells, notably CD8
+
(Benahmed
et al., 2007). Of note, mice lacking Smad3 develop intestinal
inammation and expansion of activated CD8
+
T cells (Yang
et al., 1999) and mice with T cells lacking a functional TGF-b
receptor develop autoimmunity and expanded numbers of
CD8
+
T cells harboring activating NK receptors (Marie et al.,
2006). In addition, by activating phosphoinositide 3 kinase,
IL-15 can also block the response of effector T cells, notably
CD8
+
to the immunoregulatory effect of FOXP3
+
regulatory T
(Treg) cells (Ben Ahmed et al., 2009). Accordingly, lymphocytes
from patients with active CD, and notably IELs, do not respond
to the immunosuppressive effects of autologous or heterologous
Treg cells (Hmida et al., 2012; Zanzi et al., 2011). Finally, IL-15
combined with retinoic acid may inhibit the generation of
induced Treg cells, but it is unclear whether the later mechanism
operates in CD (DePaolo et al., 2011).
If evidence converges toward a role for IL-15 in IEL activation
in CD, unsolved questions remain regarding the mechanisms
involved in stimulating the expression of this cytokine in CD.
IL-15 can be synthesized by many cell types and is generally
expressed linked to the a-chain of its receptor (IL-15Ra), which
trans-presents IL-15 to adjacent lymphocytes bearing the
signaling module IL15Rb/g
c
. In humans, IL-15 regulation is
thought to be mainly posttranscriptional, although the underlying
mechanism(s) remain largely unknown (reviewed in Fehniger and
Caligiuri, 2001). Consistent with this notion, increased expres-
sion of IL-15 protein but not of IL-15 mRNA has been observed
in situ in active CD and in RCDII. IL-15 was detected in lamina
propria cells and in enterocytes, notably at the cell surface of
the latter cells (Di Sabatino et al., 2006; Mention et al., 2003).
Using intestinal organ cultures, we and others have observed
that gluten peptides and notably peptide 31-49 common to the
N terminus of A-gliadin might upregulate intestinal synthesis of
IL15 (Hu e et al., 2004; Maiuri et al., 2003). Whether and how
this peptide, which is not presented by HLA-DQ2, might exert
this inducing effect remains hotly debated, however. Other
mechanisms may participate in IL-15 upregulation. IL-15 may
be retained at the surface of intestinal cells as a consequence
of the increased expression of IL-15Ra observed at the mRNA
and protein levels in CD mucosa (Bernardo et al., 2008).
Synthesis of both IL-15Ra and IL-15 might also be stimulated
by IFN-a. This cytokine is upregulated in CD intestine (Di Saba-
tino et al., 2007) and a recent study in transgenic mouse express-
ing emerald-green uorescence protein under IL-15 promoter
showed its inducing effect on IL-15 production (Colpitts et al.,
2012). Of note, it has been suggested that IL-15 is not increased
in all CD patients (Abadie et al., 2011). Because of IL-15 binding
to IL-15Ra and to a generally low level of expression, precise
quantitation of IL-15 is difcult and its upregulation might be
difcult to demonstrate. However, it is also possible that other
signals present in the CD mucosa might synergize with IL-15
and stimulate IEL activation even at low concentrations of
IL-15. Such signals may notably be delivered by IL-21 that is
produced by gluten-specic CD4
+
T cells in active CD (Bodd
et al., 2010; Fina et al., 2008). This cytokine exerts overlapping
effects with IL-15 on IFN-g production, cytotoxicity, proliferation,
and survival of NK and CD8
+
T cells. Strikingly, IL-21 alone has
only very moderate effects and this cytokine seems to act mainly
on CD8
+
T cells via its strong synergistic effects with IL-15 (Zeng
et al., 2005), a conclusion supported by our unpublished data
in human IELs. IL-21 released by CD4
+
T cells and enterocyte-
derived IL-15 might thus work in concert to stimulate activation
and expansion of CD8
+
T cells in CD (Figure 4, right). Consistent
with this hypothesis, prior stimulation with both cytokines but not
with either cytokine alone enabled autoreactive CD8
+
T cells to
respond to weakly agonistic TCR self-ligands and to induce
tissue damage when adoptively transferred into a murine model
of autoimmune diabetes. Moreover, no induction of diabetes
was observed in the absence of endogenous production of
IL-15, indicating that IL-21 effect depended in vivo on IL-15
(Ramanathan et al., 2011). The low amount of IL-15 produced
by enterocytes at steady state may be sufcient to initiate the
cooperation that may be amplied upon upregulation of IL-15.
Interestingly, IL-21 is not upregulated in latent CD, suggesting
that switching on IL-21 production is an important step toward
overt CDand tissue damage (Sperandeo et al., 2011). The mech-
anism initiating the production of IL-21 in CD is however
unknown. The critical role of IL-21 in the generation of efcient
and sustained antiviral CD8
+
T cell responses (Yi et al., 2010)
points again to the possible cofactor role of viral infections in
CD. It will also be interesting to dene whether CD-associated
gene polymorphisms in IL2-IL21 and IRF4 loci might inuence
IL-21 synthesis.
In conclusion, more work is needed to delineate precisely how
the HLA-DQ-driven gluten-specic CD4
+
T cell response that is
mandatory for CDonset can, in concert with IL-15, favor IEL acti-
vation, which is essential for tissue damage. The mechanisms
underlying the excessive production of IL-15 remain also elusive.
Because of its synergistic effects with IL-15, IL-21 may be one
important actor of the dialog between CD4
+
and CD8
+
T cells.
Concluding Remarks and Perspectives
Two thousand years after the rst description of CD, functional
and genetic approaches progressively converge into a scheme
in which immune responses triggered by dietary gluten share
Immunity 36, June 29, 2012 2012 Elsevier Inc. 915
Immunity
Review
broad similarities with responses conferring protection against
viruses but also causing tissue damage in autoimmune diseases.
As suspected in chronic viral infections, chronic exposure to
gluten may lead to the onset of autoimmunity, either due to
cross-reactivity of antibodies or of T cells generated in the gut
in response to gluten or to impaired regulatory control of CD8
+
T cells and emergence of autoreactive T cells. The role of MHC
class II is now well understood, but much more work is needed
to elucidate how a combination of predisposing traits and
environmental cofactors may control the onset and the highly
variable presentation and severity of CD.
How can we translate present knowledge into help for CD
patients? Sixty years after W. Dickes discovery that treating
CD patients with a gluten-free diet is efcacious and without
danger, this remains the gold-standard treatment for uncompli-
cated CD. Yet, GFD is a social burden for many patients and
several approaches are being considered to alleviate the diet,
including tolerogenic vaccines, which may perhaps reverse
overt CD to latent CD, inhibitors of TG2 able to impair gluten
presentation, or proteases able to digest gluten within the intes-
tinal lumen (Sollid and Khosla, 2011). The most urgent unmet
need is however an efcient treatment for patients who develop
refractory celiac disease, notably those developing RCDII. The
important role of IL-15 in the pathogenesis of RCDII suggests
that blocking IL-15 or its signaling pathway might help to
control the disease and prevent the evolution toward aggressive
T lymphomas (Malamut et al., 2010).
ACKNOWLEDGMENTS
The authors acknowledge funding fromINSERM, Ligue Contre le Cancer, Fon-
dation Pour la Recherche Me dicale, Agence Nationale pour la Recherche,
Association pour la Recherche contre le Cancer, Association franc aise des
Patients Intole rants au Gluten, and Fondation Princesse Grace. They thank
all members of INSERM U989 for sharing work and helpful discussions and
J.C. Weill for critical review of the manuscript.
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