Celiac disease: how complicated can it get?
- First Online:
In the small intestine of celiac disease patients, dietary wheat gluten and similar proteins in barley and rye trigger an inflammatory response. While strict adherence to a gluten-free diet induces full recovery in most patients, a small percentage of patients fail to recover. In a subset of these refractory celiac disease patients, an (aberrant) oligoclonal intraepithelial lymphocyte population develops into overt lymphoma. Celiac disease is strongly associated with HLA-DQ2 and/or HLA-DQ8, as both genotypes predispose for disease development. This association can be explained by the fact that gluten peptides can be presented in HLA-DQ2 and HLA-DQ8 molecules on antigen presenting cells. Gluten-specific CD4+ T cells in the lamina propria respond to these peptides, and this likely enhances cytotoxicity of intraepithelial lymphocytes against the intestinal epithelium. We propose a threshold model for the development of celiac disease, in which the efficiency of gluten presentation to CD4+ T cells determines the likelihood of developing celiac disease and its complications. Key factors that influence the efficiency of gluten presentation include: (1) the level of gluten intake, (2) the enzyme tissue transglutaminase 2 which modifies gluten into high affinity binding peptides for HLA-DQ2 and HLA-DQ8, (3) the HLA-DQ type, as HLA-DQ2 binds a wider range of gluten peptides than HLA-DQ8, (4) the gene dose of HLA-DQ2 and HLA-DQ8, and finally,(5) additional genetic polymorphisms that may influence T cell reactivity. This threshold model might also help to understand the development of refractory celiac disease and lymphoma.
KeywordsCeliac disease Refractory celiac disease T cell reactivity HLA
With a prevalence of 1% in western populations, celiac disease (CD) is one of the most common inflammatory disorders of the small intestine (Green and Cellier 2007). CD is often assumed to have its onset in childhood, but it has recently been suggested that adults can also develop CD (Vilppula et al. 2009). Clinical manifestations vary according to age group: infants and young children present with diarrhea, abdominal distention, and failure to thrive, whereas adults that develop CD not only present with diarrhea, but also with silent manifestations such as anemia, osteoporosis, or neurological symptoms (Green and Cellier 2007). Immunohistochemistry of the small intestine of patients shows villous atrophy, crypt hyperplasia, and elevated levels of intraepithelial lymphocytes (IELs). The only therapy until now is a gluten-free diet, which will normalize the clinical and histological manifestations and allows the patients to live an otherwise normal life.
The development of CD is determined by both environmental and genetic factors. In the 1950s, ingestion of wheat products was described to cause malabsorption symptoms in patients (Dicke et al. 1953). Later on, it was established that gluten, the storage proteins in wheat, barley and rye, caused a cell-mediated immune response in the small intestine (Ferguson et al. 1975). In addition to this environmental factor, CD development involves genetic predisposition, as the vast majority of the CD patients possess human leukocyte antigen (HLA)-DQ2 and/or HLA-DQ8 (Spurkland et al. 1997). HLA-DQ2 is a genotype that is present in roughly 25% of the European population (Bourgey et al. 2007; Fig. 1). Yet, only ~4% of all HLA-DQ2+ individuals develop CD (Fig. 1) (Wolters and Wijmenga 2008). CD development in HLA-DQ2- and HLA-DQ8-negative individuals is extremely rare (Karell et al. 2003). These findings came together with the observation that CD4+ T cell lines from duodenal biopsies of CD patients specifically respond to gluten peptides presented by HLA-DQ2 and/or HLA-DQ8 (Lundin et al. 1993, 1994). The etiology of RCD is much less clear, but seems to be associated with HLA-DQ2 (Al-Toma et al. 2006).
In short, the complex interplay of multiple genetic and environmental factors will determine the development of CD and its complications. This review describes current knowledge on gluten, HLA-DQ, and the immunopathogenesis of CD and its complications. In addition, we present a likely sequence of events in the development of CD and discuss the factors that may influence the risk of CD development.
Gluten: the disease-inducing environmental trigger
The visco-elastic properties of gluten are essential for dough formation of wheat flour and give bread its unique texture and taste. Because of its unique properties, gluten is widely used in the food industry: not only in products that are readily associated with wheat, like bread, cookies and pasta, but also as a hidden ingredient in sauces, instant soups, and even medication. Consequently, the daily gluten intake on a gluten-containing diet in Western Europe and the United States is high, between 15 and 20 g per day. The omnipresence of gluten makes adherence to a gluten-free diet challenging for CD patients.
Gluten is a heterogeneous mixture of gliadins and glutenins in wheat or similar proteins in barley and rye. Each wheat variety expresses multiple α-, γ-, and ω-gliadins in addition to low- and high-molecular weight glutenins. Gluten has a very high content of the amino acids glutamine (30%) and proline (15%). By virtue of its high glutamine content, gluten is rich in nitrogen, an essential factor for seed germination. The high proline content renders gluten highly resistant to degradation by gastrointestinal enzymes, making it possible for large immunogenic gluten peptides to reach the mucosal surface (Shan et al. 2002, 2005). As modern wheat varieties contain three complete genomes encoding gliadins and glutenins, up to 100 different gluten proteins may be present in a single wheat variety, and many of these are implicated in the pathogenesis of CD.
HLA-DQ: the strongest disease-associated gene locus by far
The strong genetic influence in CD is apparent, as the concordance between monozygotic twins is 80%, whereas in dizygotic twins, this is only 11% (Nistico et al. 2006), which is approximately the same as the risk for first-degree relatives (Dube et al. 2005). The main genetic influence in CD is HLA, which was first indicated by studies describing the predominance of HLA-B8 and HLA-DR3 serotypes in CD patients (Falchuk et al. 1972; Keuning et al. 1976). Later studies established that the strongest association is with HLA-DQ2 (DQA*0501, DQB*0201, termed HLA-DQ2.5 hereafter) (Sollid et al. 1989), which is encoded together with HLA-B8 and HLA-DR3 on the highly conserved ancestral haplotype 8.1 (Price et al. 1999). CD is associated, to a lesser extent, with HLA-DQ8 (DQA*03, DQB*0302) (Spurkland et al. 1997). The strong association between HLA-DQ2.5 and CD is further illustrated by the observation that individuals homozygous for HLA-DQ2.5 have a fivefold increased risk for development of CD compared to individuals heterozygous for HLA-DQ2.5 (Mearin et al. 1983). Similarly, HLA-DQ 2.5 homozygosity is associated with the development of RCD II and RCD-associated lymphoma, whereas this association is less clear for HLA-DQ2.5 heterozygosity and HLA-DQ8 (Al-Toma et al. 2006). Another HLA-DQ2 variant exists: HLA-DQ2.2 (DQA*0201, DQB*0202), which has a peptide-binding motif that is almost identical to that of HLA-DQ2.5 (van de Wal et al. 1997). Whereas HLA-DQ2.5 predisposes to CD, HLA-DQ2.2 does not. This difference is related to the peptide-binding properties of these HLA-DQ2 variants (see below). The estimated risk effect of HLA-DQ2 and HLA-DQ8 on CD development is estimated to be ~35% (Hunt et al. 2008).
Non-HLA genes associated with CD
Candidate gene association study: Candidate genes, selected on the basis of current understanding of CD immunopathology, were tested for association with CD. Genes studied with this approach include, among others, IFN-γ, FAS, TCR, and TG2 (van Heel et al. 2005). No convincing association with CD was found.
Genetic linkage study: This approach is aimed at the identification of chromosomal regions that likely contain disease-causing genes in families with a high prevalence of CD. The genomic region 2q33 showed linkage to celiac disease in multiple populations. This region contains the genes CD28, CTLA4, and ICOS which all control different aspects of the T cell response (van Heel et al. 2005). Linkage was also found for chromosome 5q31-33 (Greco et al. 2001) and chromosome 19p13.1 (van Belzen et al. 2003). Linkage to these regions, however, could not always be replicated in other populations.
Genome-wide association study: In recent years, it has become possible to perform large-scale case control-based association studies using single nucleotide polymorphisms. With this approach, it is possible to identify common variants in the genome that predispose to disease. Until now, ten non-HLA loci associated with CD have been identified and linkage to 2q33 has been confirmed (Table 1) (Hunt et al. 2008;Trynka et al. 2009;van Heel et al. 2007). Recently, 13 additional true risk variants and 13 suggestive risk variants were identified (Dubois et al. 2010). Although causality has only been proven for the risk allele SH2B3 (Zhernakova et al. 2010), it is clear that nearly all associated regions contain genes involved in immune response.
Loci associated with CD development
Subunit of IL12, regulates Th1 differentation
CCR1, CCR2, CCR3 and CCR5
Recruitment of immune cells to the site of inflammation
Possible role in maintaining cell shape
Inhibits NFκB activation and TNF-mediated apoptosis
Adaptor molecule involved in signaling in T cells
IL18R1 and IL18RAP
Respectively the α and β-chain of IL18 receptor, IL18 is a pro-inflammatory cytokine
Role in modulating cytoskeletal changes
Component of NFκB transcription complex
Inhibitory effect on the T cell response
Stimulating effect on the T cell response
Stimulating effect on the T cell response
Acts as GTPase activating protein, thereby regulating cell signating
Stimulating proliferation of T cells
Regulates the function of T and NK cells
The adaptive immune response: gluten, HLA-DQ, and CD4+ T cells
TG2 is mostly retained intracellularly in an inactive form and is activated upon its release during tissue damage (Lorand and Graham 2003; Siegel et al. 2008). Therefore, something should trigger tissue damage which initiates TG2 release, allowing the modification of gluten peptides. Whereas CD4+ T cell responses against native gluten peptides are relatively rare, they could represent the first breach in oral tolerance to gluten. The presentation of native gluten peptides by HLA-DQ2 or HLA-DQ8 to CD4+ T cells will lead to the production of IFN-γ (Fig. 2). IFN-γ will in turn lead to higher expression of the HLA-DQ molecules and thereby, to increased gluten peptide presentation (Fig. 2). In the presence of gluten, this could become a self-amplifying loop that could cause limited tissue damage locally. This tissue damage would lead to the release of TG2 that will modify native gluten peptides into high affinity ligands for HLA-DQ2 and/or HLA-DQ8, thereby expanding the gluten-specific CD4+ T cell responses and leading to additional tissue damage: the initiation of a second self-amplifying loop (Fig. 2). Alternatively, infections occurring in the gastrointestinal tract would generate a pro-inflammatory milieu that might lead to loss of tolerance to native gluten peptides and generate tissue damage simultaneously and thus, initiate deamidation by TG2.
Activated intraepithelial lymphocytes damage the intestinal epithelium
Intraepithelial lymphocytes are localized between intestinal epithelial cells at the basolateral side of the epithelium and are thought to play an important role in immunosurveillance of the epithelium. The IEL population in the small intestine is a mixed population of TCRαβ+ T cells, TCRγδ+ T cells, and NK cells, although the vast majority of the IELs are CD8+ TCRαβ+ T cells (Jabri and Ebert 2007). Furthermore, most of these TCR+ IELs express a variety of NK cell receptors that is distinct from the NK cell receptors expressed on blood T cells (Jabri et al. 2000). The NK cell receptors are thought to act mainly as T cell co-stimulators, lowering the threshold for T cell activation in stressful times (Bauer et al. 1999).
IL-15 is a cytokine that, just as IL-2, is able to induce T cell proliferation, IFN-γ production, and cytotoxicity. Furthermore, IL-15 is known to play an important role in NK cell development and activation (Fehniger and Caligiuri 2001). Under normal circumstances, IL-15 expression is strictly regulated at the level of transcription, translation, and secretion (Budagian et al. 2006). In CD, this regulation is disrupted, which results in massive upregulation of IL-15 in the epithelium and lamina propria. The abnormal availability of IL-15 results in chronic inflammation by survival, proliferation, and activation of IELs (Di Sabatino et al. 2006;Ebert 1998). Furthermore, IL-15 can exert an inhibitory effect on TGF-β, a negative regulator of the immune response (Benahmed et al. 2007). Recently, it has been shown that IL-15 can synergize with IL-21, a cytokine expressed on CD4+ T cells and a stimulator of IFN-γ production and cytolytic activity of CD8+ T cells and NK cells (Ebert 2009;Parrish-Novak et al. 2000).
In RCD, the survival, expansion, and acquisition of an NK cell-like phenotype by IELs is even more pronounced than in CD, possibly as a result of the presence of larger amounts of IL-15. RCD II patients have an aberrant clonal IEL population that lacks surface TCR-CD3 expression. Studies on aberrant TCR-CD3- IEL lines from RCD II patients showed that, upon stimulation with IL-15, these cell lines express granzyme B and lyse the intestinal epithelial cell line HT29, suggesting a role for aberrant IELs in perpetuating epithelial damage in RCD II (Mention et al. 2003). Therefore, IL-15-dependent NK cell-like transformation of IELs may be an essential step in the immunopathology of RCD.
A threshold model for the risk of CD development
The expansion of the presentable gluten peptide repertoire due to the release and activity of TG2 is a critical step in the pathogenesis of full-blown CD. Several lines of evidence support the notion that the level of gluten presentation to T cells critically influences the risk of disease development.
First, HLA-DQ2.5 homozygous individuals have a fivefold higher risk of CD development than HLA-DQ2.5 heterozygous individuals (Mearin et al. 1983). This gene dose effect directly correlates with the magnitude of the CD4+ T cell response: antigen presenting cells (APC) from HLA-DQ2.5 homozygous individuals induce very strong proliferative T cell responses and IFN-γ production, while APC from HLA-DQ2.5/DQX heterozygous individuals induce much weaker responses (Vader et al. 2003b). These data indicate that the number of HLA-DQ2.5 molecules capable of presenting gluten peptides on the surface of APC will define the magnitude of the CD4+ T cell response.
Second, whereas HLA-DQ2.5 is associated with CD development, the homologous HLA-DQ2.2 is not. Although these two variants have almost identical peptide-binding motifs, HLA-DQ2.2 can only bind a subset of the gluten peptides that can bind to HLA-DQ2.5. This difference is explained by the fact that a proline at position 3 in peptides has an adverse effect on peptide binding to HLA-DQ2.2 (van de Wal et al. 1997). As gluten epitopes cluster in proline-rich regions (Arentz-Hansen et al. 2002), many gluten peptides have a proline at position 3 and do not bind to HLA-DQ2.2 (Vader et al. 2003b). Consequently, HLA-DQ2.5 is able to present a much broader repertoire of gluten peptides than HLA-DQ2.2. In addition, HLA-DQ2.5 is better at retaining gluten peptides in its binding groove compared to HLA-DQ2.2 (Fallang et al. 2009). As a result, gluten peptide presentation by HLA-DQ2.5 is protracted compared to presentation by HLA-DQ2.2, which will increase the chance for productive CD4+ T cell stimulation.
Third, CD is associated mainly with HLA-DQ2.5 and, to a lesser extent, with HLA-DQ8. Although a variety of gluten peptides has been identified that can stimulate HLA-DQ8 restricted T cells from CD patients, one α-gliadin peptide in particular appears to be immunodominant, as this peptide invariably induces specific T cell responses in HLA-DQ8+ CD patients (Henderson et al. 2007; Tollefsen et al. 2006; van de Wal et al. 1998b, 1999; Kooy et al. unpublished data). In contrast to the HLA-DQ2.5 restricted α-gliadin peptides, the HLA-DQ8 peptide is not derived from a proline-rich region of the α-gliadin protein, and therefore likely susceptible to degradation in the gastrointestinal tract. Furthermore, whereas for HLA-DQ2 a single deamidation in a gluten peptide is sufficient to evoke a CD4+ T cell response, for HLA-DQ8, deamidation at two positions is preferred (Henderson et al. 2007), which may limit the generation of strong antigenic gluten peptides. The fact that the immunodominant HLA-DQ8 peptide is more readily degraded and requires more deamidation steps, limits the availability for antigen presentation and may therefore limit the risk to develop CD.
Fourth, further evidence that the level of gluten presentation is a critical parameter comes from a totally different angle: most CD patients tolerate oat even though it has been shown that the gluten-like molecules in oat can elicit CD4+ T cell responses in CD patients (Arentz-Hansen et al. 2004; Vader et al. 2003a) There are two striking differences between the relatively safe oat and the disease-inducing cereals wheat, barley, and rye: (1) while the gluten-like molecules in oat contain only two antigenic sequences, dozens are found in gluten and the gluten-like molecules of barley and rye, (2) the “gluten” content of oat is much lower compared to the other cereals. Consumption of oat thus results in a much lower exposure to antigenic peptides, in comparison with the other cereals, and this is apparently tolerated, as it does not lead to disease in the majority of patients.
Collectively, these data indicate the presence of a threshold to develop CD. Initiation of CD becomes more likely with increased T cell exposure to gluten antigens. This exposure is influenced by the type and amount of HLA-DQ, as this determines the efficiency of gluten peptide presentation to CD4+ T cells. For HLA-DQ2.5 homozygous individuals, the threshold to develop CD is most easily exceeded, whereas for HLA-DQ2.2+ and HLA-DQ8+ individuals, the threshold is much higher.
CD development: a series of unfortunate events
The development of full-blown CD is most likely the result of an unfortunate series of events which, in isolation, would not lead to disease, but, combined, have a detrimental outcome. It is important to note that exposure to gluten, frequent enteroviral infections, and occasional TG2 activation likely occur in every individual, but usually do not result in CD development, even in HLA-DQ2+ and/or HLA-DQ8+ individuals (Fig. 1). It has now become clear that the presence of a higher number of additional non-HLA risk alleles (Table 1) is directly correlated with an increase in the risk to develop CD (Romanos et al. 2009). This suggests that the influence of non-HLA genes lowers the threshold to develop CD and could skew the balance towards disease development (Fig. 4). It is plausible that non-HLA genes also increase the risk to develop complicated CD, although this hypothesis will be difficult to test as this patient population is very small. Thus, even though key pieces of the celiac puzzle have been collected and assembled, the picture is not yet complete.
Although the molecular basis for the involvement of HLA-DQ in CD is now well established, a number of issues remain unclear.
First, it is still controversial how immunogenic gluten peptides from the intestinal lumen reach the lamina propria where they can prime gluten-specific T cells. It has been suggested that gluten peptides can be transported during transient increased intestinal permeability during enteroviral infections (Stene et al. 2006) or by IgA-mediated retrotranscytosis (Matysiak-Budnik et al. 2008). Yet, this issue is far from resolved.
Direct effects of gluten
The role of gluten in the adaptive immune response in CD is well established. In addition, a direct (innate) effect of gluten on the intestinal mucosa has been suggested. One of the first indications for the potential of gluten to elicit a response in the epithelium came from in vivo challenges where administration of gliadin caused villous atrophy and increase of IELs within 2–3h after gluten ingestion (Ciclitira et al. 1984). This effect was later attributed to the non-immunodominant peptide p31-49 from alpha-gliadin (Sturgess et al. 1994). In vitro studies with p31-49 showed that epithelial alterations were independent of CD4+ T cell activation. Furthermore, p31-49 stimulated IL-15 production in the lamina propria of cultured biopsies from CD patients (Maiuri et al. 2003). The fact that p31-49 could activate the local immune system implied that a receptor for p31-49 should exist. A transcellular transport pathway was proposed where anti-gliadin IgA antibodies were able to bind p31-49. This complex would then bind the transferrin receptor CD71 which would provide protected trafficking across the intestinal epithelium (Matysiak-Budnik et al. 2008). However, this mechanism would not function in all CD patients, as a relatively large fraction of them is IgA-deficient (McGowan et al. 2008).
We also assessed the hypothesis that a receptor for p31-49 is present on intestinal epithelial cells. Binding of p31-49 to intestinal epithelial cell lines, however, could not be detected, neither directly nor by either UV-crosslinking or TG2-induced transamidation (Tjon et al. unpublished data). In the absence of a receptor through which p31-43 could exert its activity, the molecular mechanism underlying the biological effects observed with this peptide remains unclear.
Third, TG2 is a crucial factor in expanding the presentable gluten peptide repertoire. In steady state conditions, TG2 is present in an inactive form intracellular and on the cell surface. An intriguing question is, therefore, how TG2 is activated and released in CD. We propose that TG2 is released upon tissue damage induced by the initial CD4+ T cell response to native gluten peptides (Figs. 2 and 3). Alternatively, a recent study proposed a role for TLR3 ligands released during enteroviral infections that, upon ligation with TLR3, could result in TG2 activation (Siegel et al. 2008). These two possibilities are not mutually exclusive.
Fourth, in active CD, disrupted IL-15 regulation results in massive overexpression of IL-15. It remains unclear what causes this disruption. As on a gluten-free diet, the adaptive CD4+ T cell response and IL-15 expression both decrease (Mention et al. 2003); it is possible that the adaptive CD4+ T cell response has a direct effect on IL-15 expression (Fig. 3). Alternatively, innate signals delivered through TLRs may be responsible for elevated IL-15 levels.
Finally, the events leading from uncomplicated CD to RCD II and subsequent lymphoma development are still poorly understood. Lymphoma cells develop from the aberrant IELs in RCD II. One view is that aberrant IELs derive from mature TCR+ IELs that have undergone oligoclonal expansion and lost surface TCR-CD3 expression due to overstimulation (Cellier et al. 1998). Alternatively, aberrant IELs could derive from a distinct population of CD3− CD7+ precursor cells that can develop into T cells and NK cells (Gunther et al. 2005). In favor of the first hypothesis: although aberrant IELs lack surface TCR-CD3 expression, they do express CD3 intracellularly and display TCR-γ-gene rearrangements (Malamut et al. 2009). Furthermore, microarray analysis in one study on TCR-CD3+ IEL lines from CD patients revealed a significant decrease in the transcript levels of TCRα- and TCRβ-chains (Meresse et al. 2006), indicating that IELs may lower TCR expression in CD. We found that aberrant IELs not only express CD3ε intracellularly, but also have intracellular expression of the CD3γ, CD3δ, and ζ-chains (Tjon et al. 2008). In favor of the second hypothesis: the TCR chains were not always present (Tjon et al. 2008), and TCR rearrangements were often incomplete (Tjon et al. unpublished data). Furthermore, the full complement of CD3 chains and incomplete TCR rearrangements have also been observed in NK cell precursors, and even mature NK cells can carry partially rearranged TCRs. A recent study indicated that extrathymic TCR-gene rearrangement is an ongoing event in the human small intestine throughout life (Bas et al. 2009). This raises the possibility that aberrant IELs derive from cells in an early stage of extrathymic lymphocyte development.
Life used to be simple: CD was a rare disease, diagnosed in 1 in 1,000 individuals. Patients were HLA-DQ2+ of HLA-DQ8+ and could be treated effectively with a gluten-free diet. That was about it.
Now we know that CD affects ~1% of the population in Western Europe and the USA, most of which remain undiagnosed. Although good insight has been gained on the immunopathology of CD—inflammation in both lamina propria and epithelium—it remains unclear what triggers the development of CD and why not every patient is equally affected. In addition, with the recognition of RCD and RCD-associated lymphoma that do not respond to a gluten-free diet, CD has become a far more complicated disease.
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
- Cellier C, Patey N, Mauvieux L, Jabri B, Delabesse E, Cervoni JP, Burtin ML, Guy-Grand D, Bouhnik Y, Modigliani R, Barbier JP, Macintyre E, Brousse N, Cerf-Bensussan N (1998) Abnormal intestinal intraepithelial lymphocytes in refractory sprue. Gastroenterology 114:471–481CrossRefPubMedGoogle Scholar
- Deleeuw RJ, Zettl A, Klinker E, Haralambieva E, Trottier M, Chari R, Ge Y, Gascoyne RD, Chott A, Muller-Hermelink HK, Lam WL (2007) Whole-genome analysis and HLA genotyping of enteropathy-type T-cell lymphoma reveals 2 distinct lymphoma subtypes. Gastroenterology 132:1902–1911CrossRefPubMedGoogle Scholar
- Di Sabatino A, Ciccocioppo R, Cupelli F, Cinque B, Millimaggi D, Clarkson MM, Paulli M, Cifone MG, Corazza GR (2006) Epithelium derived interleukin 15 regulates intraepithelial lymphocyte Th1 cytokine production, cytotoxicity, and survival in coeliac disease. Gut 55:469–477CrossRefPubMedGoogle Scholar
- Dube C, Rostom A, Sy R, Cranney A, Saloojee N, Garritty C, Sampson M, Zhang L, Yazdi F, Mamaladze V, Pan I, Macneil J, Mack D, Patel D, Moher D (2005) The prevalence of celiac disease in average-risk and at-risk Western European populations: a systematic review. Gastroenterology 128:S57–S67CrossRefPubMedGoogle Scholar
- Dubois PC, Trynka G, Franke L, Hunt KA, Romanos J, Curtotti A, Zhernakova A, Heap GA, Adany R, Aromaa A, Bardella MT, van den Berg LH, Bockett NA, de la Concha EG, Dema B, Fehrmann RS, Fernandez-Arquero M, Fiatal S, Grandone E, Green PM, Groen HJ, Gwilliam R, Houwen RH, Hunt SE, Kaukinen K, Kelleher D, Korponay-Szabo I, Kurppa K, Macmathuna P, Maki M, Mazzilli MC, McCann OT, Mearin ML, Mein CA, Mirza MM, Mistry V, Mora B, Morley KI, Mulder CJ, Murray JA, Nunez C, Oosterom E, Ophoff RA, Polanco I, Peltonen L, Platteel M, Rybak A, Salomaa V, Schweizer JJ, Sperandeo MP, Tack GJ, Turner G, Veldink JH, Verbeek WH, Weersma RK, Wolters VM, Urcelay E, Cukrowska B, Greco L, Neuhausen SL, McManus R, Barisani D, Deloukas P, Barrett JC, Saavalainen P, Wijmenga C, van Heel DA (2010) Multiple common variants for celiac disease influencing immune gene expression. Nat Genet 42:295–302CrossRefPubMedGoogle Scholar
- Greco L, Babron MC, Corazza GR, Percopo S, Sica R, Clot F, Fulchignoni-Lataud MC, Zavattari P, Momigliano-Richiardi P, Casari G, Gasparini P, Tosi R, Mantovani V, De VS, Iacono G, D'Alfonso A, Selinger-Leneman H, Lemainque A, Serre JL, Clerget-Darpoux F (2001) Existence of a genetic risk factor on chromosome 5q in Italian coeliac disease families. Ann Hum Genet 65:35–41CrossRefPubMedGoogle Scholar
- Gunther U, Holloway JA, Gordon JN, Knight A, Chance V, Hanley NA, Wilson DI, French R, Spencer J, Steer H, Anderson G, Macdonald TT (2005) Phenotypic characterization of CD3-7+ cells in developing human intestine and an analysis of their ability to differentiate into T cells. J Immunol 174:5414–5422PubMedGoogle Scholar
- Henderson KN, Tye-Din JA, Reid HH, Chen Z, Borg NA, Beissbarth T, Tatham A, Mannering SI, Purcell AW, Dudek NL, van Heel DA, McCluskey J, Rossjohn J, Anderson RP (2007) A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease. Immunity 27:23–34CrossRefPubMedGoogle Scholar
- Hunt KA, Zhernakova A, Turner G, Heap GA, Franke L, Bruinenberg M, Romanos J, Dinesen LC, Ryan AW, Panesar D, Gwilliam R, Takeuchi F, McLaren WM, Holmes GK, Howdle PD, Walters JR, Sanders DS, Playford RJ, Trynka G, Mulder CJ, Mearin ML, Verbeek WH, Trimble V, Stevens FM, O'Morain C, Kennedy NP, Kelleher D, Pennington DJ, Strachan DP, McArdle WL, Mein CA, Wapenaar MC, Deloukas P, McGinnis R, McManus R, Wijmenga C, van Heel DA (2008) Newly identified genetic risk variants for celiac disease related to the immune response. Nat Genet 40:395–402CrossRefPubMedGoogle Scholar
- Jabri B, de Serre NP, Cellier C, Evans K, Gache C, Carvalho C, Mougenot JF, Allez M, Jian R, Desreumaux P, Colombel JF, Matuchansky C, Cugnenc H, Lopez-Botet M, Vivier E, Moretta A, Roberts AI, Ebert EC, Guy-Grand D, Brousse N, Schmitz J, Cerf-Bensussan N (2000) Selective expansion of intraepithelial lymphocytes expressing the HLA-E-specific natural killer receptor CD94 in celiac disease. Gastroenterology 118:867–879CrossRefPubMedGoogle Scholar
- Karell K, Louka AS, Moodie SJ, Ascher H, Clot F, Greco L, Ciclitira PJ, Sollid LM, Partanen J (2003) HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol 64:469–477CrossRefPubMedGoogle Scholar
- Malamut G, Afchain P, Verkarre V, Lecomte T, Amiot A, Damotte D, Bouhnik Y, Colombel JF, Delchier JC, Allez M, Cosnes J, Lavergne-Slove A, Meresse B, Trinquart L, Macintyre E, Radford-Weiss I, Hermine O, Brousse N, Cerf-Bensussan N, Cellier C (2009) Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. Gastroenterology 136:81–90CrossRefPubMedGoogle Scholar
- Matysiak-Budnik T, Moura IC, Arcos-Fajardo M, Lebreton C, Menard S, Candalh C, Ben-Khalifa K, Dugave C, Tamouza H, van NG, Bouhnik Y, Lamarque D, Chaussade S, Malamut G, Cellier C, Cerf-Bensussan N, Monteiro RC, Heyman M (2008) Secretory IgA mediates retrotranscytosis of intact gliadin peptides via the transferrin receptor in celiac disease. J Exp Med 205:143–54CrossRefPubMedGoogle Scholar
- Mention JJ, Ben AM, Begue B, Barbe U, Verkarre V, Asnafi V, Colombel JF, Cugnenc PH, Ruemmele FM, McIntyre E, Brousse N, Cellier C, Cerf-Bensussan N (2003) Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125:730–745CrossRefPubMedGoogle Scholar
- Meresse B, Chen Z, Ciszewski C, Tretiakova M, Bhagat G, Krausz TN, Raulet DH, Lanier LL, Groh V, Spies T, Ebert EC, Green PH, Jabri B (2004) Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease. Immunity 21:357–366CrossRefPubMedGoogle Scholar
- Meresse B, Curran SA, Ciszewski C, Orbelyan G, Setty M, Bhagat G, Lee L, Tretiakova M, Semrad C, Kistner E, Winchester RJ, Braud V, Lanier LL, Geraghty DE, Green PH, Guandalini S, Jabri B (2006) Reprogramming of CTLs into natural killer-like cells in celiac disease. J Exp Med 203:1343–1355CrossRefPubMedGoogle Scholar
- Molberg O, McAdam SN, Korner R, Quarsten H, Kristiansen C, Madsen L, Fugger L, Scott H, Noren O, Roepstorff P, Lundin KE, Sjostrom H, Sollid LM (1998) Tissue transglutaminase selectively modifies gliadin peptides that are recognized by gut-derived T cells in celiac disease. Nat Med 4:713–717CrossRefPubMedGoogle Scholar
- Nistico L, Fagnani C, Coto I, Percopo S, Cotichini R, Limongelli MG, Paparo F, D'Alfonso S, Giordano M, Sferlazzas C, Magazzu G, Momigliano-Richiardi P, Greco L, Stazi MA (2006) Concordance, disease progression, and heritability of coeliac disease in Italian twins. Gut 55:803–808CrossRefPubMedGoogle Scholar
- Parrish-Novak J, Dillon SR, Nelson A, Hammond A, Sprecher C, Gross JA, Johnston J, Madden K, Xu W, West J, Schrader S, Burkhead S, Heipel M, Brandt C, Kuijper JL, Kramer J, Conklin D, Presnell SR, Berry J, Shiota F, Bort S, Hambly K, Mudri S, Clegg C, Moore M, Grant FJ, Lofton-Day C, Gilbert T, Rayond F, Ching A, Yao L, Smith D, Webster P, Whitmore T, Maurer M, Kaushansky K, Holly RD, Foster D (2000) Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408:57–63CrossRefPubMedGoogle Scholar
- Romanos J, van Diemen CC, Nolte IM, Trynka G, Zhernakova A, Fu J, Bardella MT, Barisani D, McManus R, van Heel DA, Wijmenga C (2009) Analysis of HLA and non-HLA alleles can identify individuals at high risk for celiac disease. Gastroenterology 137(834–40):840Google Scholar
- Tjon JM, Verbeek WH, Kooy-Winkelaar YM, Nguyen BH, van der Slik AR, Thompson A, Heemskerk MH, Schreurs MW, Dekking LH, Mulder CJ, van Bergen J, Koning F (2008) Defective synthesis or association of T-cell receptor chains underlies loss of surface T-cell receptor-CD3 expression in enteropathy-associated T-cell lymphoma. Blood 112:5103–5110CrossRefPubMedGoogle Scholar
- Trynka G, Zhernakova A, Romanos J, Franke L, Hunt KA, Turner G, Bruinenberg M, Heap GA, Platteel M, Ryan AW, de KC H, GK HPD, Walters JR, Sanders DS, Mulder CJ, Mearin ML, Verbeek WH, Trimble V, Stevens FM, Kelleher D, Barisani D, Bardella MT, McManus R, van Heel DA, Wijmenga C (2009) Coeliac disease-associated risk variants in TNFAIP3 and REL implicate altered NF-kappaB signalling. Gut 58:1078–1083CrossRefPubMedGoogle Scholar
- van de Wal Y, Kooy YM, van Veelen PA, Pena SA, Mearin LM, Molberg O, Lundin KE, Sollid LM, Mutis T, Benckhuijsen WE, Drijfhout JW, Koning F (1998b) Small intestinal T cells of celiac disease patients recognize a natural pepsin fragment of gliadin. Proc Natl Acad Sci USA 95:10050–10054CrossRefPubMedGoogle Scholar
- van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M, Wapenaar MC, Barnardo MC, Bethel G, Holmes GK, Feighery C, Jewell D, Kelleher D, Kumar P, Travis S, Walters JR, Sanders DS, Howdle P, Swift J, Playford RJ, McLaren WM, Mearin ML, Mulder CJ, McManus R, McGinnis R, Cardon LR, Deloukas P, Wijmenga C (2007) A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. Nat Genet 39:827–829CrossRefPubMedGoogle Scholar
- Verkarre V, Romana SP, Cellier C, Asnafi V, Mention JJ, Barbe U, Nusbaum S, Hermine O, Macintyre E, Brousse N, Cerf-Bensussan N, Radford-Weiss I (2003) Recurrent partial trisomy 1q22-q44 in clonal intraepithelial lymphocytes in refractory celiac sprue. Gastroenterology 125:40–46CrossRefPubMedGoogle Scholar
- Zhernakova A, Elbers CC, Ferwerda B, Romanos J, Trynka G, Dubois PC, de Kovel CG, Franke L, Oosting M, Barisani D, Bardella MT, Joosten LA, Saavalainen P, van Heel DA, Catassi C, Netea MG, Wijmenga C (2010) Evolutionary and functional analysis of celiac risk loci reveals SH2B3 as a protective factor against bacterial infection. Am J Hum Genet 86:970–977CrossRefPubMedGoogle Scholar