Celiac Disease: Caught Between a Rock and a Hard Place

doi:10.1053/j.gastro.2005.07.030

Gastroenterology

Volume 129, Issue 4, October 2005, Pages 1294-1301

https://doi.org/10.1053/j.gastro.2005.07.030 Get rights and content

Celiac disease (CD) is an intestinal disorder caused by an intolerance to gluten, proteins in wheat. CD is an HLA-associated disease: virtually all patients express HLA-DQ2 or HLA-DQ8. Recent work has shown that these disease-predisposing HLA-DQ molecules bind enzymatically modified gluten peptides and these HLA-DQ peptide complexes trigger inflammatory T-cell responses in the small intestine that lead to disease. In addition, gluten induces innate immune responses that contribute to the tissue damage that is characteristic for CD. Thus, CD patients are caught between a rock and a hard place: the disease is caused by a combination of adaptive and innate immune responses that both are triggered by gluten. These findings explain the disease-inducing properties of gluten and provide valuable clues for the development of alternative treatment modalities for patients. They also may be of relevance for our understanding of other multifactorial disorders including IBD and HLA-associated autoimmune diseases.

Section snippets

Wheat Gluten Causes CD

In 1950, Dicke²¹ found that wheat was responsible for causing CD symptoms, which later was attributed to the gluten proteins in wheat. Because of the widespread use of wheat, gluten is found in various food products including many that are not associated directly with wheat. Other cereals, including barley, rye, and oats, contain gluten-like molecules. Gluten is a mixture of gliadin and glutenin proteins. In turn, the gliadins can be subdivided into α/β-gliadins, γ-gliadins, and ω-gliadins,

Gluten Triggers Adaptive, T-Cell–Mediated Immune Responses

The large majority of CD patients express HLA-DQ2 and the remainder usually are HLA-DQ8 positive. HLA-DQ2 and -DQ8 are HLA class II molecules that bind and present peptides to CD4⁺ T cells. HLA-DQ molecules are heterodimers consisting of an α and a β chain. Many different HLA-DQ α and β chains exist that can combine in various combinations to form functional heterodimers. Although the HLA-DQ8 dimer can be formed by only 1 particular αβ chain combination (α*03 and β*0302), HLA-DQ2 heterodimers

Impact of the HLA-DQ2 Gene Dose

It is well established that there is a strong HLA-DQ2 gene dose effect. HLA-DQ2 homozygous individuals have an at least 5-fold increased risk for disease development compared with HLA-DQ2 heterozygous individuals.²³ Because HLA-DQ2 heterozygotes express 2 distinct DQα and DQβ chains, they potentially can form 4 distinct HLA-DQ-dimers of which only 1 will be HLA-DQ2 (Figure 4A). In contrast, all HLA-DQ dimers in HLA-DQ2 homozygotes will be of the HLA-DQ2 type (Figure 4A). This has a strong

Gluten Triggers Innate IEL-Mediated Immune Responses

At least 1 additional gluten peptide now is thought to play an important role in CD. This peptide, amino acids 31–43 from α gliadin, is not the target of gluten-specific T cells but does induce changes associated with CD on administration in vivo and during biopsy challenges in vitro.39, 40, 41 It also has been found to stimulate cytokine production by a macrophage cell line.⁴² Moreover, it has been shown that preincubation of biopsy specimens of CD patients with the 31–43 peptide enabled

Antibody Response to tTG

The presence of endomysium-specific antibodies of the immunoglobulin A class in serum for a long time has been known to be a specific indicator of CD. In 1997, Dieterich et al¹⁷ showed that these antibodies were specific for tTG. Many studies now have shown that, especially in adults, the presence of tTG-specific antibodies in serum is a highly specific indication of active disease and that antibody titers decrease during a strict gluten-free diet.²⁰ An unresolved question is why these

Additional Factors Contribute to CD Development

Approximately 25%–30% of the population in the Western hemisphere expresses HLA-DQ2 and is exposed to high amounts of gluten daily but only a minority develops CD. Also, the α gliadin–derived 31–43 peptide exerts its effect in biopsy specimens of CD patients only.⁴³ This indicates that currently unknown factors must contribute to disease development. Some of those may be environmental. Infections, for example, can lead to interferon-γ production, which would enhance HLA-DQ2 expression and lower

Can We Prevent CD?

It is well established that oats are tolerated by most CD patients whereas cereals that contain larger numbers of T-cell–stimulatory peptides are not. Also, a double HLA-DQ2 gene dose leads to a 5-fold increased risk.²³ Finally, the Swedish epidemic has shown that an increase in gluten content in infant food resulted in a tripling of CD incidence.⁵⁷ These observations indicate that the level of gluten presentation is linked tightly to the probability of disease development. This may imply that

Conclusions

Gluten has unique properties that set it apart from other food proteins. It is a degradation-resistant mixture of proteins that is modified efficiently by the enzyme tTG. The result is the generation of a series of immunogenic peptides that can trigger T-cell responses (Figure 5). Clustering of these epitopes leads to multivalency, which enhances immunogenicity. Similar peptides are found in other cereals, in particular barley and rye. The likelihood of the initiation of a gluten-specific

References (61)

C. Catassi et al.
Coeliac disease in the year 2000exploring the iceberg
Lancet
(1994)
C.G.D.S. Csizmadia et al.
An iceberg of childhood coeliac disease in the Netherlands
Lancet
(1999)
K.A. Lundin et al.
T cells from the small intestinal mucosa of a DR4, DQ7/DR4, DQ8 celiac-disease patient preferentially recognize gliadin when presented by DQ8
Hum Immunol
(1994)
S. Hüe et al.
A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease
Immunity
(2004)
B. Meresse et al.
Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease
Immunity
(2004)
S. Reif et al.
Tissue transglutaminase—the key player in celiac diseasea review
Autoimmunity Rev
(2004)
B. Fleckenstein et al.
Gliadin T cell epitope selection by tissue transglutaminase in celiac diseaseRole of enzyme specificity and pH influence on the transamidation versus deamidation process
J Biol Chem
(2002)
W. Vader et al.
The gluten response in children with recent onset celiac diseaseA highly diverse response towards multiple gliadin and glutenin derived peptides
Gastroenterology
(2002)
Ø. Molberg et al.
Intestinal T-cell responses to high-molecular-weight glutenins in celiac disease
Gastroenterology
(2003)
H. Arentz-Hansen et al.
Celiac lesion T cells recognize epitopes that cluster in regions of gliadins rich in proline residues
Gastroenterology
(2002)

R. Sturgess et al.

Wheat peptide challenge in coeliac disease

Lancet

(1994)

L. Jelínková et al.

Gliadin stimulates human monocytes to production of IL-8 and TNF-α through a mechanism involving NF-κB

FEBS Lett

(2004)

L. Maiuri et al.

Association between innate response to gliadin and activation of pathogenic T cells in coeliac disease

Lancet

(2003)

L. Maiuri et al.

Interleukin 15 mediates epithelial changes in celiac disease

Gastroenterology

(2000)

M. Maki et al.

Coeliac disease

Lancet

(1997)

B. Fleckenstein et al.

Molecular characterization of covalent complexes between tissue transglutaminase and gliadin peptides

J Biol Chem

(2004)

G. Cammarota et al.

Onset of coeliac disease during treatment with interferon for chronic hepatitis C

Lancet

(2000)

L. Greco et al.

Genome search in celiac disease

Am J Hum Genet

(1998)

M.J. van Belzen et al.

A major non-HLA locus in celiac disease maps to chromosome 19

Gastroenterology

(2003)

K. Rostami et al.

High prevalence of celiac disease in apparently healthy blood donors suggests a high prevalence of undiagnosed celiac disease in the Dutch population

Scand J Gastroenterol

(1999)

A. Fasano et al.

Prevalence of celiac disease in at-risk and not-at-risk groups in the United Statesa large multicenter study

Arch Intern Med

(2003)

L.M. Sollid et al.

Evidence for a primary association of coeliac disease to a particular HLA-DQ alpha/beta heterodimer

J Exp Med

(1989)

A. Spurkland et al.

Dermatitis herpetiformis and celiac disease are both primarily associated with the HLA-DQ (alpha 10501, beta 102) or the HLA-DQ (alpha 103, beta 10302) heterodimers

Tissue Antigens

(1997)

K.E. Lundin et al.

Gliadin-specific, HLA-DQ(α10501,β10201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients

J Exp Med

(1993)

Y. van de Wal et al.

Small intestinal cells of celiac disease patients recognize a natural pepsin fragment of gliadin

Proc Natl Acad Sci U S A

(1998)

H. Sjostrom et al.

Identification of a gliadin T cell epitope in coeliac diseasegeneral importance of gliadin deamidation for intestinal T cell recognition

Scand J Immunol

(1998)

Y. van de Wal et al.

Glutenin is involved in the gluten-driven mucosal T cell response

Eur J Immunol

(2000)

H. Arentz-Hansen et al.

The intestinal T cell response to α-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase

J Exp Med

(2000)

R.P. Anderson et al.

In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope

Nat Med

(2000)

C.Y. Kim et al.

Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease

Proc Natl Acad Sci U S A

(2004)

Cited by (106)

Structural bases of T cell antigen receptor recognition in celiac disease
2022, Current Opinion in Structural Biology
Celiac disease (CeD) is a human leukocyte antigen (HLA)-linked autoimmune-like disorder that is triggered by the ingestion of gluten or related storage proteins. The majority of CeD patients are HLA-DQ2.5⁺, with the remainder being either HLA-DQ8⁺ or HLA-DQ2.2⁺. Structural studies have shown how deamidation of gluten epitopes engenders binding to HLA-DQ2.5/8, which then triggers an aberrant CD4⁺ T cell response. HLA tetramer studies, combined with structural investigations, have demonstrated that repeated patterns of TCR usage underpins the immune response to some HLADQ2.5/8 restricted gluten epitopes, with distinct TCR motifs representing common landing pads atop the HLA–gluten complexes. Structural studies have provided insight into TCR specificity and cross-reactivity towards gluten epitopes, as well as cross-reactivity to bacterial homologues of gluten epitopes, suggesting that environmental factors may directly play a role in CeD pathogenesis. Collectively, structural immunology-based studies in the CeD axis may lead to new therapeutics/diagnostics to treat CeD, and also serve as an exemplar for other T cell mediated autoimmune diseases.
Structural basis of T cell receptor specificity and cross-reactivity of two HLA-DQ2.5-restricted gluten epitopes in celiac disease
2022, Journal of Biological Chemistry
Celiac disease is a T cell-mediated chronic inflammatory condition often characterized by human leukocyte antigen (HLA)-DQ2.5 molecules presenting gluten epitopes derived from wheat, barley, and rye. Although some T cells exhibit cross-reactivity toward distinct gluten epitopes, the structural basis underpinning such cross-reactivity is unclear. Here, we investigated the T-cell receptor specificity and cross-reactivity of two immunodominant wheat gluten epitopes, DQ2.5-glia-α1a (PFPQPELPY) and DQ2.5-glia-ω1 (PFPQPEQPF). We show by surface plasmon resonance that a T-cell receptor alpha variable (TRAV) 4⁺-T-cell receptor beta variable (TRBV) 29-1⁺ TCR bound to HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1 with similar affinity, whereas a TRAV4^- (TRAV9-2⁺) TCR recognized HLA-DQ2.5-glia-ω1 only. We further determined the crystal structures of the TRAV4⁺-TRBV29-1⁺ TCR bound to HLA-DQ2.5-glia-α1a and HLA-DQ2.5-glia-ω1, as well as the structure of an epitope-specific TRAV9-2⁺-TRBV7-3⁺ TCR-HLA-DQ2.5-glia-ω1 complex. We found that position 7 (p7) of the DQ2.5-glia-α1a and DQ2.5-glia-ω1 epitopes made very limited contacts with the TRAV4⁺ TCR, thereby explaining the TCR cross-reactivity across these two epitopes. In contrast, within the TRAV9-2⁺ TCR-HLA-DQ2.5-glia-ω1 ternary complex, the p7-Gln was situated in an electrostatic pocket formed by the hypervariable CDR3β loop of the TCR and Arg70β from HLA-DQ2.5, a polar network which would not be supported by the p7-Leu residue of DQ2.5-glia-α1a. In conclusion, we provide additional insights into the molecular determinants of TCR specificity and cross-reactivity to two closely-related epitopes in celiac disease.
Twin and family studies on epigenetics of autoimmune diseases
2021, Twin and Family Studies of Epigenetics
Defining the etiology of a disease is important to provide the opportunity to develop optimized predictive, diagnostic, preventative and therapeutic methods. The etiopathology of autoimmune disorders is known to be multifactorial, including several environmental and genetical factors. Although the impact of these components may vary significantly in different disorders, in the recent decades, researchers discovered the increasing roles of epigenetic changes in the development of autoimmune diseases. We must study the precise mechanisms and how these factors determine the pathogenesis and the course of these diseases. The consideration of these aspects makes it obvious why autoimmune disorders are common subjects of twin researches worldwide. The most commonly studied areas include systemic, endocrine and gastrointestinal autoimmune diseases. The purpose of this chapter is to review and summarize the findings of twin and family-based studies considering autoimmune diseases and the epigenetic changes behind them.
New coeliac disease treatments and their complications
2018, Gastroenterologia y Hepatologia
El único tratamiento aceptado para la enfermedad celiaca es el seguimiento de forma estricta de la dieta sin gluten. Este tipo de dieta puede ocasionar una disminución de la calidad de vida de los pacientes, dificultades sociales y económicas. Por lo tanto, son frecuentes las transgresiones dietéticas que pueden perpetuar el daño intestinal. En los últimos años se han desarrollado numerosos tratamientos, dirigidos hacia diferentes dianas en la patogenia de la enfermedad celiaca: modificación del gluten para conseguir un gluten no inmunogénico, terapias endoluminales que degraden el gluten en la luz intestinal, favorecer la tolerancia al gluten, modulación de la permeabilidad intestinal o regulación de la respuesta inmune adaptativa. En esta revisión se evalúan estas líneas terapéuticas que se están investigando para la enfermedad celiaca y los tratamientos enfocados al control de las complicaciones de la enfermedad, como la enfermedad celiaca refractaria.
The only accepted treatment for coeliac disease is strict adherence to a gluten-free diet. This type of diet may give rise to reduced patient quality of life with economic and social repercussions. For this reason, dietary transgressions are common and may elicit intestinal damage. Several treatments aimed at different pathogenic targets of coeliac disease have been developed in recent years: modification of gluten to produce non-immunogenic gluten, endoluminal therapies to degrade gluten in the intestinal lumen, increased gluten tolerance, modulation of intestinal permeability and regulation of the adaptive immune response. This review evaluates these coeliac disease treatment lines that are being researched and the treatments that aim to control disease complications like refractory coeliac disease.
Cystic Fibrosis and Celiac Disease
2015, Diet and Exercise in Cystic Fibrosis
Cystic fibrosis (CF) is associated with malnutrition resulting from exocrine pancreatic insufficiency, bacterial overgrowth, and intestinal dysmotility as a consequence of hyperviscous intestinal contents. Celiac disease (CD) is an autoimmune disease associated with gluten exposure leading to such symptoms as malnutrition, abdominal pain, and diarrhea. CD is common in many countries, including the United States, and it should be considered in any patient that presents with malnutrition, abdominal pain, or diarrhea. Other autoimmune diseases, including type 1 diabetes mellitus, autoimmune thyroiditis, and autoimmune hepatitis can be associated with CD. Various serum antibody tests are available to diagnose CD, although the gold standard of CD diagnosis is esophagogastroduodenoscopy with multiple duodenal biopsies. Treatment of CD includes lifelong removal of dietary gluten, which leads to resolution of malnutrition symptoms and reduces the risk of developing other autoimmune diseases and small bowel lymphoma. The prevalence of CD in CF patients is higher than in the general population, and any CF patient showing continuing signs and symptoms of malabsorption should be screened for CD.
Evaluating diagnostic accuracy of anti-tissue Transglutaminase IgA antibodies as first screening for Celiac Disease in very young children
2015, Clinica Chimica Acta
Citation Excerpt :
Celiac Disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten-containing grains in genetically susceptible individuals [1,2], and it damages the small intestine mucosa leading to villous atrophy, crypt hyperplasia and intraepithelial lymphocytic infiltrate [3,4].
Small bowel biopsy is the gold standard for Celiac Disease (CD) diagnosis, nevertheless serum assays are the first step in ascertaining a diagnosis of CD. New ESPGHAN Criteria 2012 (European Society of Pediatric Gastroenterology Hepatology and Nutrition) suggest using exclusively anti-tissue Transglutaminase IgA antibodies (anti-tTGA) as initial approach to symptomatic subjects. The aim of our study was to evaluate the diagnostic accuracy of anti-tTGA as initial screening assay for CD in a large cohort of pediatric patients.
We selected 730 subjects aged between 6 months and 4 years (“Group A”) and 348 subjects younger than 2 years (which are part of the 730 subjects) (“Group B”). We performed anti-Deamidated Gliadin Peptides IgA and IgG antibodies (a-DGP IgA/IgG) and anti-tTGA assays by ELISA test. We evaluated the agreement between anti-tTGA and a-DGP IgA/IgG assays and compared the diagnostic accuracy of a-DGP IgA/IgG with that of anti-tTGA in both groups of patients.
There was a substantial agreement between anti-tTGA and a-DGP IgA in “Group A” and an almost perfect agreement in “Group B”; the strength of agreement between anti-tTGA and a-DGP IgG was moderate in “Group A” and substantial in “Group B”.
anti-tTGA were more sensitive and specific than a-DGP IgA/IgG in both groups.
anti-tTGA could be used as initial screening assay for CD in all subjects from 6 months of age according to ESPGHAN Criteria 2012.

View all citing articles on Scopus

: Supported by grants from the European Commission (BHM4-CT98-3087 and QLK1-2000-00657), the “Stimuleringsfonds Voedingsonderzoek Leiden University Medical Centre,” the Dutch Organization for Scientific Research (ZonMW grant 912-02-028), and the Celiac Disease Consortium, an Innovative Cluster approved by the Netherlands Genomics Initiative and partially funded by the Dutch Government (BSIK03009).

View full text

Special reports and reviewCeliac Disease: Caught Between a Rock and a Hard Place

Section snippets

Wheat Gluten Causes CD

Gluten Triggers Adaptive, T-Cell–Mediated Immune Responses

Impact of the HLA-DQ2 Gene Dose

Gluten Triggers Innate IEL-Mediated Immune Responses

Antibody Response to tTG

Additional Factors Contribute to CD Development

Can We Prevent CD?

Conclusions

Lancet

Lancet

Hum Immunol

Immunity

Immunity

Autoimmunity Rev

J Biol Chem

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

FEBS Lett

Lancet

Gastroenterology

Lancet

J Biol Chem

Lancet

Am J Hum Genet

Gastroenterology

High prevalence of celiac disease in apparently healthy blood donors suggests a high prevalence of undiagnosed celiac disease in the Dutch population

Scand J Gastroenterol

Prevalence of celiac disease in at-risk and not-at-risk groups in the United Statesa large multicenter study

Arch Intern Med

Evidence for a primary association of coeliac disease to a particular HLA-DQ alpha/beta heterodimer

J Exp Med

Dermatitis herpetiformis and celiac disease are both primarily associated with the HLA-DQ (alpha 1*0501, beta 1*02) or the HLA-DQ (alpha 1*03, beta 1*0302) heterodimers

Tissue Antigens

Gliadin-specific, HLA-DQ(α1*0501,β1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients

J Exp Med

Small intestinal cells of celiac disease patients recognize a natural pepsin fragment of gliadin

Proc Natl Acad Sci U S A

Identification of a gliadin T cell epitope in coeliac diseasegeneral importance of gliadin deamidation for intestinal T cell recognition

Scand J Immunol

Glutenin is involved in the gluten-driven mucosal T cell response

Eur J Immunol

The intestinal T cell response to α-gliadin in adult celiac disease is focused on a single deamidated glutamine targeted by tissue transglutaminase

J Exp Med

In vivo antigen challenge in celiac disease identifies a single transglutaminase-modified peptide as the dominant A-gliadin T-cell epitope

Nat Med

Structural basis for HLA-DQ2-mediated presentation of gluten epitopes in celiac disease

Proc Natl Acad Sci U S A

Special reports and review
Celiac Disease: Caught Between a Rock and a Hard Place

Dermatitis herpetiformis and celiac disease are both primarily associated with the HLA-DQ (alpha 10501, beta 102) or the HLA-DQ (alpha 103, beta 10302) heterodimers

Gliadin-specific, HLA-DQ(α10501,β10201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients