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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 frequentfirst step towardthe 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 fide autoimmune diseases. Severity and

age at onset of symptomatic CD are highly variable and might

be influenced 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

Figure1. Human Leukocyte Antigen Class IIAssociations with Celiac Disease and Type1 DiabetesThe majority of CD patients express the HLA-

DQ2.5 heterodimer encoded by theHLA-DQA1*05

(a-chain) and HLA-DQB1*02 (b-chain) alleles.These two alleles are carried either in cison 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 CD patients possess oneor 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 andDQB1 alleles located

on the same chromosome (cisconfigura-

tion) whereas in individuals who are

DR5DQ7 or DR7DQ2 heterozygous, it is

encoded by alleles located on opposite

chromosomes (trans configuration) (re-

viewed in Sollid et al., 2012; Figure 1).

The resulting HLA-DQ2.5 heterodimers

differ only by two amino acids, which

do not influence 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 five-fold higher risk than

those whoare homozygous foreither of theDQ variants (Concan-non et al., 2009). This high risk was recently associated with the

formation of HLA-DQ8 transdimers between thea-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 theb-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 first disclosed by a seminal work demonstrating the

presence of HLA-DQ2-restricted gluten-specific 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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and depend on the physicochemical properties of the twopartners. 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 immunecells (Shan etal.,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-SpecificCD4+ T Cell Responses by HLA-DQ2.5MoleculeTransglutaminase 2 (TG2) binds to and deami-

dates glutamine residues in Q-X-P sequences of

gluten peptides into glutamic acid, introducinga 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-specific 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 inAbadie 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

(Bergsengetal.,2005). As a consequence,

HLA-DQ2/8+ dendritic cells can electively

activate gluten-specific CD4+ T cells

(Figure 2). Several gluten epitopes pre-

ferentially recognized in the context

of either HLA-DQ2.5 or HLA-DQ8 have

been defined (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 recognizingthe 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 andHLA-DQ2.2 bind a lesser number

of gluten peptides than HLA-DQ2.5 and/or with a lesser avidity is

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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 highestrisk 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 significant 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 sufficient 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 fitted 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 sufficient

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-specific 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), reflecting 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 influence 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 significantly associated with CD,

most of which containing immune genes were first identified

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 identified 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-

tified 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,

causativemutationsthus remain to be identified. A meta-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 specific genes (such as RUNX3,

RGS1, ETS1, TAGAP, and ZFP36L1) or in the 30 untranslated

region (IRF4, PTPRK, and ICOSLG). They notably observed that

one variant present in the 30 UTR of the PTPRK locus is located

in a predicted binding site for a microRNA (hsa-miR-1910)

(Trynkaet al., 2011). Strikingly, only very few CD-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 influ-

ences a variety of signalingpathways, notably those mediated by

Janus kinases and receptor tyrosine kinases (Devallie` re and

Charreau, 2011).

Overall, these data raise the question of the biological signifi-

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 benefit to the carriers, notably to resist against

infectious diseases. Twostudies have used the test of integrated

haplotype similarity to detect signature of positive selectionfor 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 identified 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 identified 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 andNK 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 specific 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 (McGuireet al., 2011). CD association with the TLR7-TLR8 region needs

to be confirmed 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 identified a rare causative variant. Rather,

Figure 3. Hypothetical Role of Non-HLA CD-Associated Genes in Immune ResponsesNon-HLA lociassociated withCD are enriched in genes predicted to control T cellactivation (TCR signaling, antigenpresentation, and recruitment differentiation

into effectorcells) andB cellhelp.Loci specific forCD arein red. Those sharedwithotherautoimmunediseases (including T1D) arein 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 4and text).


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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 CDThe 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 andinz3,400 infants who were born between theyears

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 andnotably to thedelayed 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 beencorrelated with serological evidence of repeated rotavirus infec-

tion (Stene et al., 2006). In adults, recurrent observations report

thedevelopmentof CD in 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 inPlot

and Amital, 2009). In a recent study, viral RNA from enteroviruses

was often detected in the intestinal mucosa of T1D but no

significant 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 (Dafik 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 finding 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 thesebacteria, which belong to three distinc genders, remains unclear

(Ou et al., 2009). Bacterial adhesion may be favored by gluten-

induced inflammation 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-specific 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 inflammation 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 specific for gluten peptides and for the autoantigen

TG2 are hallmarks of active CD. They are enriched in polymeric

IgA andproduced by intestinal plasma cells, the density of whichis 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 specific 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, modification 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 theobservation 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 Klock

et al., 2012). Yet, the presence of TG2 IgA in the mucosa of

latent CD indicates that they are not sufficient 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 (Sardy et al.,

2002). DH skin lesions do not contain T cells but dermal

deposits of IgA and TG3 that are associated with neutrophil

infiltrates in blistering areas. Formation of dermal IgA and

TG3 deposits are recapitulated in human skin grafted intoSCID 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 infiltrates (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 affinity 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


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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-deficient 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 efficient SIgA barrier (Wang et al., 2011b). In immunoprofi-

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 CDAs 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,

producedby enterocytesand LP dendriticcellsand macrophages, favors theactivationof IFN-g-producing and cytotoxic CD8+ IELsharboring NK cell receptors.

Gluten-specific CD4+ T cells mayparticipatein IELactivation viacross-priming or viathe production of IL-21that synergizes withIL-15 to activatecytotoxic 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 first intraepithelial (type II

refractory celiac disease [RCDII]) and can secondarily transform into overt enteropathy-associated type T lymphoma (EATL).


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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 asmall 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; Hue et al., 2004; Mention et al., 2004; Meresse et al.,

2004).

A first 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-specific 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 increasein 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 reflect 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 first 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 identified 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 coordinatedactivation 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 sufficient tostimulate IFN-gproduction 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 (Hue

et al., 2004; Roberts et al., 2001) and thus foster the activation

of gliadin-specific CD8+ T cells or of CD8+ T cells bearing TCR

with a low affinity 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

RAE1in pancreasb-islet cells, although not sufficient to induce

diabetes, could stimulate the recruitment of CD8+ T cells regard-

less of their antigen specificity 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 (Hue

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 (Hue 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


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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-fedHLA-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-specific 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 specific 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 forCD8+ 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

inflammation 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/gc. In humans, IL-15 regulation isthought 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 (Hue 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 stimulatedby 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 fluorescence 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 difficult and its upregulation might be

difficult 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-specific CD4+ T cells in active CD (Bodd

et al., 2010; Fina et al., 2008). This cytokine exerts overlappingeffects 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 cytokinesbut 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 sufficient to initiate the

cooperation that may be amplified 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 CD andtissue damage(Sperandeoet 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 efficient

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 define whether CD-associated

gene polymorphisms in IL2-IL21

and IRF4

loci might influenceIL-21 synthesis.

In conclusion, more work is needed to delineate precisely how

the HLA-DQ-driven gluten-specific CD4+ T cell response that is

mandatory forCD onset 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 first description of CD, functional

and genetic approaches progressively converge into a scheme

in which immune responses triggered by dietary gluten share


Immunity

Review


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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 gutin 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 efficacious 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 glutenpresentation, or proteases able to digest gluten within the intes-

tinal lumen (Sollid and Khosla, 2011). The most urgent unmet

need is however an efficient 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 Medicale, Agence Nationale pour la Recherche,

Association pour la Recherche contre le Cancer, Association francaise desPatients Intolerants 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.

REFERENCES

Abadie, V., Sollid, L.M., Barreiro, L.B., and Jabri, B. (2011). Integration ofgenetic and immunological insights into a model of celiac disease pathogen-esis. Annu. Rev. Immunol. 29, 493525.

Aggarwal, S., Lebwohl, B., and Green, P.H. (2012). Screening for celiacdisease in average-risk and high-risk populations. Therap Adv Gastroenterol5, 3747.

Ben Ahmed, M.B., Belhadj Hmida, N., Moes, N., Buyse, S., Abdeladhim, M.,Louzir, H., and Cerf-Bensussan, N. (2009). IL-15rendersconventional lympho-cytes resistant to suppressive functionsof regulatory T cells through activation

of the phosphatidylinositol 3-kinase pathway. J. Immunol.182, 67636770.

Benahmed, M., Meresse, B., Arnulf, B., Barbe, U., Mention, J.J., Verkarre, V.,Allez, M., Cellier, C., Hermine, O., and Cerf-Bensussan, N. (2007). Inhibition ofTGF-betasignaling by IL-15:a newrolefor IL-15 in thelossof immunehomeo-stasis in celiac disease. Gastroenterology132, 9941008.

Bergseng, E., Xia, J., Kim, C.Y., Khosla, C., and Sollid, L.M. (2005). Main chainhydrogen bond interactionsin the binding of proline-rich gluten peptidesto theceliac disease-associated HLA-DQ2 molecule. J. Biol. Chem. 280, 2179121796.

Bernardo,D., Garrote,J.A., Allegretti, Y., Leon,A.,Gomez, E., Bermejo-Martin,J.F., Calvo, C., Riestra, S., Fernandez-Salazar, L., Blanco-Quiros, A., et al.(2008). Higher constitutive IL15R alpha expression and lower IL-15 responsethreshold in coeliac disease patients. Clin. Exp. Immunol.154, 6473.

Bevan, S., Popat, S., Braegger, C.P., Busch, A., ODonoghue, D., Falth-Mag-nusson, K., Ferguson, A., Godkin, A., Hogberg, L., Holmes, G., et al. (1999).

Contribution of the MHC region to the familial risk of coeliac disease. J.Med. Genet.36, 687690.

Biswas, P.S., Bhagat, G., and Pernis, A.B. (2010). IRF4 and its regulators:evolving insights into the pathogenesis of inflammatory arthritis? Immunol.Rev. 233, 7996.

Black, K.E., Murray, J.A., and David, C.S. (2002). HLA-DQ determines theresponse to exogenous wheat proteins: a model of gluten sensitivity in trans-genic knockout mice. J. Immunol. 169, 55955600.

Bodd, M., Raki, M., Tollefsen, S., Fallang, L.E., Bergseng, E., Lundin, K.E., andSollid, L.M. (2010). HLA-DQ2-restricted gluten-reactive T cells produce IL-21but not IL-17 or IL-22. Mucosal Immunol. 3, 594601.

Bodd, M., Kim, C.Y., Lundin, K.E., and Sollid, L.M. (2012). T-cell response togluten in patients with HLA-DQ2.2 reveals requirement of peptide-MHCstability in celiac disease. Gastroenterology142, 552561.

Bourlie` re, M., Oules, V., Perrier, H., and Mengotti, C. (2001). Onset of coeliacdisease and interferon treatment. Lancet 357, 803804.

Cellier,C., Patey, N., Mauvieux, L., Jabri, B., Delabesse, E., Cervoni, J.P., Bur-tin, M.L., Guy-Grand, D., Bouhnik, Y., Modigliani, R., et al. (1998). Abnormalintestinal intraepithelial lymphocytes in refractory sprue. Gastroenterology

114, 471481.

Cellier, C., Delabesse, E., Helmer, C., Patey, N., Matuchansky, C., Jabri, B.,Macintyre, E., Cerf-Bensussan, N., and Brousse, N.; French Coeliac DiseaseStudy Group. (2000). Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet 356, 203208.

Colombel, J.F., Mascart-Lemone, F., Nemeth, J., Vaerman, J.P., Dive, C., andRambaud,J.C. (1990). Jejunalimmunoglobulin and antigliadin antibody secre-tion in adult coeliac disease. Gut31,13451349.

Colpitts, S.L., Stoklasek, T.A., Plumlee, C.R., Obar, J.J., Guo, C., and Lefran-cois, L. (2012). Cutting edge: theroleof IFN-a receptor and MyD88 signalingininduction of IL-15 expression in vivo. J. Immunol. 188, 24832487.

Concannon, P., Rich, S.S., and Nepom, G.T. (2009). Genetics of type 1Adiabetes. N. Engl. J. Med.360, 16461654.

Cosnes, J., Cellier, C., Viola, S., Colombel, J.F.,Michaud, L., Sarles, J., Hugot,J.P., Ginies, J.L., Dabadie, A., Mouterde, O., et al; Groupe DEtude et de Re-cherche Sur la Maladie Coeliaque. (2008). Incidence of autoimmune diseasesin celiac disease: protective effect of the gluten-free diet. Clin. Gastroenterol.Hepatol.6, 753758.

Coulon, S., Dussiot, M., Grapton, D., Maciel, T.T., Wang, P.H., Callens, C.,Tiwari, M.K., Agarwal, S., Fricot, A., Vandekerckhove, J., et al. (2011). Poly-meric IgA1 controls erythroblast proliferation and accelerates erythropoiesisrecovery in anemia. Nat. Med. 17, 14561465.

Dafik, L., Albertelli, M., Stamnaes, J., Sollid, L.M., and Khosla, C. (2012).Activation and inhibition of transglutaminase 2 in mice. PLoS ONE 7, e30642.

de Kauwe, A.L.,Chen, Z., Anderson,R.P., Keech, C.L., Price, J.D., Wijburg,O.,Jackson, D.C., Ladhams, J., Allison, J., and McCluskey, J. (2009). Resistanceto celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressingspecific anti-gliadin CD4+ T cells. J. Immunol. 182, 74407450.

DePaolo, R.W., Abadie, V., Tang, F., Fehlner-Peach, H., Hall, J.A., Wang, W.,Marietta, E.V., Kasarda, D.D., Waldmann, T.A., Murray, J.A., et al. (2011). Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity todietary antigens. Nature 471, 220224.

Devallie` re, J., and Charreau, B. (2011). The adaptorLnk (SH2B3): an emergingregulator in vascular cells and a link between immune and inflammatorysignaling. Biochem. Pharmacol. 82, 13911402.

Di Niro, R., Mesin, L., Zheng, N.Y., Stamnaes, J., Morrissey, M., Lee, J.H.,Huang, M., Iversen, R., du Pre, M.F., Qiao, S.W., et al. (2012). High abundanceof plasma cells secreting transglutaminase 2-specific IgA autoantibodies withlimited somatic hypermutation in celiac disease intestinal lesions. Nat. Med.18, 441445.

Di Sabatino, A., Ciccocioppo, R., Cupelli, F., Cinque, B., Millimaggi, D., Clark-son, M.M., Paulli, M., Cifone, M.G., and Corazza, G.R. (2006). Epitheliumderived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokineproduction, cytotoxicity, and survival in coeliac disease. Gut 55, 469477.


Immunity

Review


11/13

Di Sabatino, A., Pickard, K.M., Gordon, J.N., Salvati, V., Mazzarella, G., Beat-tie, R.M., Vossenkaemper, A., Rovedatti, L., Leakey, N.A., Croft, N.M., et al.(2007). Evidence for the role of interferon-alfa production by dendritic cells inthe Th1 response in celiac disease. Gastroenterology 133, 11751187.

Dieterich, W., Ehnis, T., Bauer, M., Donner, P., Volta, U., Riecken, E.O., and

Schuppan, D. (1997). Identification of tissue transglutaminase as the autoanti-gen of celiac disease. Nat. Med. 3, 797801.

Du Pre, M.F., Kozijn, A.E., van Berkel, L.A., ter Borg, M.N., Lindenbergh-Kor-tleve, D., Jensen, L.T., Kooy-Winkelaar, Y., Koning, F., Boon, L., Nieuwenhuis,E.E., et al. (2011). Tolerance to ingested deamidated gliadin in mice is main-tained by splenic, type 1 regulatory T cells. Gastroenterology141, 610620,620, e1e2.

Dubois, P.C., Trynka, G., Franke, L., Hunt, K.A., Romanos, J., Curtotti, A.,Zhernakova, A., Heap, G.A., Adany, R., Aromaa, A., et al. (2010). Multiplecommon variants for celiac disease influencing immune gene expression.Nat. Genet. 42, 295302.

Elfstrom, P., Granath, F., Ekstrom Smedby, K., Montgomery, S.M., Askling, J.,Ekbom, A., and Ludvigsson, J.F. (2011). Risk of lymphoproliferative malig-nancy in relation to small intestinal histopathology among patients with celiacdisease. J. Natl. Cancer Inst.103, 436444.

Fallang, L.E., Bergseng, E., Hotta, K., Berg-Larsen, A., Kim, C.Y., and Sollid,L.M. (2009). Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation.Nat. Immunol. 10, 10961101.

Fehniger, T.A.,and Caligiuri, M.A. (2001). Interleukin 15: biology and relevanceto human disease. Blood 97, 1432.

Fehniger, T.A., Suzuki, K., Ponnappan, A., VanDeusen, J.B., Cooper, M.A.,Florea, S.M., Freud, A.G., Robinson, M.L., Durbin, J., and Caligiuri, M.A.(2001). Fatal leukemia in interleukin 15 transgenic mice follows early expan-sions in natural killer and memory phenotype CD8+ T cells. J. Exp. Med.193, 219231.

Fina, D., Sarra, M., Caruso, R., Del Vecchio Blanco, G., Pallone, F., MacDon-ald, T.T., and Monteleone, G. (2008). Interleukin 21 contributes to the mucosalT helper cell type 1 response in coeliac disease. Gut57, 887892.

Foxman, E.F., and Iwasaki, A. (2011). Genome-virome interactions: examiningthe role of common viral infections in complex disease. Nat. Rev. Microbiol.9,

254264.

Henderson, K.N., Reid, H.H., Borg, N.A., Broughton, S.E., Huyton, T., Ander-son,R.P., McCluskey, J., and Rossjohn, J. (2007). The productionand crystal-lization of the human leukocyte antigen class II molecules HLA-DQ2 andHLA-DQ8 complexed with deamidated gliadin peptides implicated in coeliacdisease.Acta Crystallogr.Sect. F Struct.Biol. Cryst. Commun.63, 10211025.

Hmida, N.B., Ben Ahmed, M., Moussa, A., Rejeb, M.B., Said, Y., Kourda, N.,Meresse, B., Abdeladhim, M., Louzir, H., and Cerf-Bensussan, N. (2012).Impaired control of effector T cells by regulatory T cells: a clue to loss of oraltolerance and autoimmunity in celiac disease? Am. J. Gastroenterol. 107,604611.

Hue, S., Mention, J.J., Monteiro, R.C., Zhang, S., Cellier, C., Schmitz, J., Ver-karre, V., Fodil, N., Bahram, S., Cerf-Bensussan, N., and Caillat-Zucman, S.(2004). A direct role for NKG2D/MICA interaction in villous atrophy duringceliac disease. Immunity 21, 367377.

Hunt, K.A., Zhernakova, A., Turner, G., Heap, G.A., Franke, L., Bruinenberg,M., Romanos, J., Dinesen, L.C., Ryan, A.W., Panesar, D., et al. (2008). Newlyidentified genetic risk variants for celiac disease related to the immuneresponse. Nat. Genet.40, 395402.

Ivarsson, A. (2005). The Swedish epidemic of coeliac disease explored usingan epidemiological approachsome lessons to be learnt. Best Pract. Res.Clin. Gastroenterol. 19, 425440.

Jabri, B., de Serre, N.P., Cellier, C., Evans, K., Gache, C., Carvalho, C., Mou-genot, J.F., Allez, M., Jian, R., Desreumaux, P., et al. (2000). Selective expan-sion of intraepithelial lymphocytes expressing the HLA-E-specific natural killerreceptor CD94 in celiac disease. Gastroenterology118, 867879.

Klock, C., Diraimondo, T.R., and Khosla, C. (2012). Role of transglutaminase 2in celiac disease pathogenesis. Semin. Immunopathol.

Kooy-Winkelaar, Y., van Lummel, M., Moustakas, A.K., Schweizer, J., Mearin,M.L., Mulder, C.J., Roep, B.O., Drijfhout, J.W., Papadopoulos, G.K., van Ber-

gen, J., and Koning, F. (2011). Gluten-specific T cells cross-react betweenHLA-DQ8 and the HLA-DQ2a/DQ8btransdimer. J. Immunol.187, 51235129.

Koskinen, O., Collin, P., Korponay-Szabo, I., Salmi, T., Iltanen, S., Haimila, K.,Partanen, J., Maki, M., and Kaukinen, K. (2008). Gluten-dependent smallbowel mucosal transglutaminase 2-specific IgA deposits in overt and mild

enteropathy coeliac disease. J. Pediatr. Gastroenterol. Nutr.47, 436442.

Kurts, C., Robinson,B.W., and Knolle, P.A. (2010). Cross-priming in health anddisease. Nat. Rev. Immunol. 10, 403414.

Lebreton, C., Menard, S., Abed, J., Cruz-Moura, I., Coppo, R., Dugave, C.,Monteiro, R., Fricot, A., Garfa Traore, M., Cellier, C., Malamut, G., Cerf-Ben-sussan, N., and Heyman, M. (2012). Permeability to gliadin peptides in celiacdisease is controlled by interactions between SIgA, CD71 and transglutami-nase. Gastroenterology, in press.

Lionetti, E., and Catassi, C. (2011). New clues in celiac disease epidemiology,pathogenesis, clinical manifestations, and treatment. Int. Rev. Immunol. 30,219231.

Ludvigsson, J.F., Leffler, D.A., Bai, J.C., Biagi, F., Fasano, A., Green, P.H.,Hadjivassiliou, M., Kaukinen, K., Kelly, C.P., Leonard, J.N., et al. (2012). TheOslo definitions for coeliac disease and related terms. Gut. Published onlineFebruary 16, 2012.

Lundin, K.E.A., Scott, H., Hansen, T., Paulsen,G., Halstensen, T.S.,Fausa, O.,Thorsby, E., and Sollid, L.M. (1993). Gliadin-specific, HLA-DQ(alpha1*0501,beta 1*0201) restricted T cells isolatedfrom thesmall intestinal mucosaof celiac disease patients. J. Exp. Med.178, 187196.

Maiuri, L., Ciacci, C., Ricciardelli, I., Vacca, L., Raia, V., Auricchio, S., Picard,J., Osman, M., Quaratino, S., and Londei, M. (2003). Association betweeninnate response to gliadin and activation of pathogenic T cells in coeliacdisease. Lancet 362, 3037.

Malamut, G., Afchain, P., Verkarre, V., Lecomte, T., Amiot, A., Damotte, D.,Bouhnik, Y., Colombel,J.F., Delchier, J.C., Allez, M.,et al. (2009). Presentationand long-term follow-up of refractory celiac disease: comparison of typeI withtype II. Gastroenterology136, 8190.

Malamut, G., El Machhour, R., Montcuquet, N., Martin-Lanneree, S., Dusan-ter-Fourt, I., Verkarre, V., Mention, J.J., Rahmi, G., Kiyono, H., Butz, E.A.,et al. (2010). IL-15 triggers an antiapoptotic pathway in human intraepitheliallymphocytes thatis a potentialnew target in celiac disease-associated inflam-

mation and lymphomagenesis. J. Clin. Invest.120, 21312143.

Marie, J.C., Liggitt,D., and Rudensky, A.Y.(2006).Cellularmechanismsof fatalearly-onset autoimmunity in mice with the T cell-specific targeting of trans-forming growth factor-beta receptor. Immunity25, 441454.

Marietta, E., Black, K., Camilleri, M., Krause, P., Rogers, R.S., 3rd, David, C.,Pittelkow, M.R., and Murray,J.A. (2004). A new model for dermatitis herpetifor-mis that uses HLA-DQ8 transgenic NOD mice. J. Clin. Invest.114, 10901097.

Markiewicz, M.A., Wise, E.L., Buchwald, Z.S., Pinto, A.K., Zafirova, B., Polic,B., and Shaw, A.S. (2012). RAE1 ligand expressed on pancreatic isletsrecruits NKG2D receptor-expressing cytotoxic T cells independent of T cellreceptor recognition. Immunity 36, 132141.

Matysiak-Budnik,T., Moura, I.C., Arcos-Fajardo, M.,Lebreton, C., Menard,S.,Candalh, C., Ben-Khalifa, K., Dugave, C., Tamouza, H., van Niel, G., et al.(2008). Secretory IgA mediates retrotranscytosis of intact gliadin peptidesvia the transferrin receptor in celiac disease. J. Exp. Med. 205, 143154.

Mazzarella, G., Stefanile, R., Camarca, A., Giliberti, P., Cosentini, E., Marano,C., Iaquinto, G., Giardullo, N., Auricchio, S., Sette, A., et al. (2008). Gliadin acti-vates HLA class I-restricted CD8+ T cells in celiac disease intestinal mucosaand induces the enterocyte apoptosis. Gastroenterology134, 10171027.

McGuire, H.M., Vogelzang, A., Ma, C.S., Hughes, W.E., Silveira, P.A., Tangye,S.G., Christ, D.,Fulcher, D., Falcone, M., andKing, C.(2011). A subsetof inter-leukin-21+ chemokine receptor CCR9+ T helper cells target accessory organsof the digestive system in autoimmunity. Immunity 34, 602615.

Mention, J.J., Ben Ahmed, M., Be` gue,B., Barbe, U., Verkarre, V., Asnafi, V.,Colombel, J.F., Cugnenc, P.H., Ruemmele, F.M., McIntyre, E., et al. (2003).Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis andlymphomagenesis in celiac disease. Gastroenterology125, 730745.

Mention, J.-J., Ben Ahmed, M., Verkarre, V., Brousse, N., Cellier, C., andCerf-Bensussan, N. (2004). Enterocyte-derived IL-15: a key to diruspted IELhomestasis and lymphomagenesis in coeliac disease. In Proceedings of the


Immunity

Review


12/13


13/13

Van de Kamer, J., Weijers, H., and Dicke, W. (1953). Coeliac disease V. Someexperiments on the cause of the harmful effect of wheat gliadin. Acta Paediatr.Scand.42, 223231.

van Lummel, M., van Veelen, P.A., Zaldumbide, A., de Ru, A., Janssen, G.M.,Moustakas, A.K., Papadopoulos, G.K., Drijfhout, J.W., Roep, B.O., and Kon-

ing, F. (2012). Type 1 diabetes-associated HLA-DQ8 transdimer accommo-dates a unique peptide repertoire. J. Biol. Chem. 287, 95149524.

Wang, C.H., Eng, H.L., Lin, K.H., Chang, C.H., Hsieh, C.A., Lin, Y.L., and Lin,T.M. (2011a). TLR7 and TLR8 gene variations and susceptibility to hepatitisC virus infection. PLoS ONE 6, e26235.

Wang, N., Shen, N., Vyse, T.J., Anand, V., Gunnarson, I., Sturfelt, G., Ranta-paa-Dahlqvist, S., Elvin, K., Truedsson, L., Andersson, B.A., et al. (2011b).Selective IgA deficiency in autoimmune diseases. Mol. Med. 17, 13831396.

Worbs, T., Bode, U., Yan, S., Hoffmann, M.W., Hintzen, G., Bernhardt, G.,Forster, R., and Pabst, O. (2006). Oral tolerance originates in the intestinalimmune system and relies on antigen carriage by dendritic cells. J. Exp.Med. 203, 519527.

Yang, X.,Letterio, J.J., Lechleider,R.J., Chen,L., Hayman, R.,Gu, H.,Roberts,A.B., and Deng, C. (1999). Targeted disruption of SMAD3 results in impairedmucosal immunity and diminished T cell responsiveness to TGF-beta.

EMBO J.18

, 12801291.

Yi, J.S., Cox, M.A., and Zajac, A.J. (2010). Interleukin-21: a multifunctionalregulator of immunity to infections. Microbes Infect. 12, 11111119.

Zanzi, D., Stefanile, R., Santagata, S., Iaffaldano, L., Iaquinto,G., Giardullo, N.,Lania, G., Vigliano, I., Vera, A.R., Ferrara, K., et al. (2011). IL-15 interferes with

suppressive activityof intestinal regulatory T cells expanded in Celiac disease.Am. J. Gastroenterol.106, 13081317.

Zeng, R., Spolski, R., Finkelstein, S.E., Oh, S., Kovanen, P.E., Hinrichs, C.S.,Pise-Masison, C.A., Radonovich, M.F., Brady, J.N., Restifo, N.P., et al.(2005). Synergy of IL-21 and IL-15 in regulating CD8+ T cell expansion andfunction. J. Exp. Med.201, 139148.

Zhernakova, A., Elbers, C.C., Ferwerda, B., Romanos, J., Trynka, G., Dubois,P.C., de Kovel, C.G., Franke, L., Oosting, M., Barisani, D., et al; Finnish CeliacDiseaseStudy Group. (2010). Evolutionaryand functional analysis of celiac riskloci reveals SH2B3 as a protective factor against bacterial infection. Am. J.Hum. Genet. 86, 970977.

Zone, J.J., Schmidt, L.A., Taylor, T.B., Hull, C.M., Sotiriou, M.C., Jaskowski,T.D., Hill, H.R., and Meyer, L.J. (2011). Dermatitis herpetiformis sera or goatanti-transglutaminase-3 transferred to human skin-grafted mice mimics

dermatitis herpetiformis immunopathology. J. Immunol.186

, 44744480.

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