Current concepts of celiac disease pathogenesis

doi:10.1053/gast.2000.8521

Gastroenterology

Volume 119, Issue 1, July 2000, Pages 234-242

https://doi.org/10.1053/gast.2000.8521 Get rights and content

Abstract

Our knowledge of celiac disease pathogenesis has recently made rapid progress. The disorder is now considered the result of a complex interplay of intrinsic (genetic) and variable extrinsic (environmental) factors that explain the wide spectrum of clinical manifestations ranging from asymptomatic to severe malabsorption. Gluten peptides are efficiently presented by celiac disease–specific HLA-DQ2– and HLA-DQ8–positive antigen-presenting cells, and thus drive the immune response, predominantly in the connective tissue of the lamina propria. Tissue transglutaminase, which has been identified as the highly specific endomysial autoantigen, is released from cells during inflammation. It may potentiate antigen presentation by HLA-DQ2 and HLA-DQ8 by deamidating or cross-linking gluten peptides. The result is lamina propria T-cell activation and mucosal transformation by activated intestinal fibroblasts. In the future, manipulation of the gut-associated lymphoid tissue may allow reduced sensitivity or even generate oral tolerance to gluten. Long-standing untreated celiac disease, even if clinically silent, predisposes for other autoimmune diseases. Therefore, population screening for immunoglobulin A antibodies to tissue transglutaminase seems justified.

GASTROENTEROLOGY 2000;119:234-242

Section snippets

Gluten as a trigger of celiac disease

Gluten is the protein fraction of wheat, rye, and barley that confers the properties of stickiness and thus allows the baking of bread. Gluten can be fractioned into the ethanol-soluble prolamines and ethanol-insoluble glutenins. Studies have been performed with more soluble prolamines, but recent data suggest that glutenins can also damage the intestinal mucosa.23, 24, 25 A common feature of the prolamines of wheat is a high content of glutamine (>30%) and proline (>15%), whereas the nontoxic

Histopathologic characteristics of the celiac lesion

On the basis of histologic follow-up of celiac patients who were in remission after a gluten-free diet and who were rechallenged with a peptic-tryptic gliadin digest (Frazer fraction III), Marsh¹⁷ was the first to suggest a sequence of progression of the celiac lesion. The initial event observed is an increase in intraepithelial lymphocyte count, followed by infiltration of the lamina propria with lymphocytes (stage 1). Crypt hyperplasia (stage 2) precedes villous atrophy (stage 3) and is only

Genetic association of celiac disease

Concordance for celiac disease in first-degree relatives ranges between 8% and 18% and reaches 70% in monozygotic twins. Based on family studies, McDonald et al.⁹ were the first to suggest an autosomal dominant inheritance of celiac disease with incomplete penetrance. Later Greenberg and Lange³¹ found evidence for 2 unlinked recessive celiac disease genes, 1 associated with an HLA-locus. HLA-DQ2 is found in 95% and the related HLA-DQ8 in most of the remaining patients with celiac disease.14, 15

Autoimmunity in celiac disease

Gliadin and related cereal proteins are the undisputed triggers of celiac disease. Their elimination from the diet leads to histologic and clinical improvement in most patients. Active celiac disease is accompanied by mucosal (especially immunoglobulin [Ig] A) autoantibodies to reticulin, a common constituent of the extracellular matrix. Antireticulin autoantibodies are identical to antiendomysial, antijejunal or anti–umbilical cord antibodies.19, 20, 21 IgA antiendomysial autoantibodies (EMA)

Tissue transglutaminase as autoantigen

Immunoprecipitation of proteins extracted from metabolically labeled fibrosarcoma cells with IgA from celiac disease patients led to the identification of tissue transglutaminase (tTG) as the prominent, if not sole, endomysial autoantigen.²² tTG is a calcium-dependent ubiquitous intracellular enzyme that belongs to a family with 3 epidermal and 2 extracellular transglutaminases (prostate transglutaminase and factor XIII).39, 40 The transglutaminases catalyse the covalent and irreversible

Gliadins as preferred substrates for tTG

Gliadins that are glutamine- and proline-rich proteins (Table 2) are excellent glutamyl donor substrates for tTG, giving rise to gliadin-gliadin cross-links and even the covalent incorporation of tTG itself into high-molecular-weight complexes.22, 41 These observations were already made several years ago, yet without having identified tTG as the celiac disease autoantigen.42, 43 Furthermore, IgA antibodies of patients with celiac disease are also directed to cross-linked neoepitopes and their

Deamidation by tTG can create more potent T-cell epitopes

Apart from cross-linking a variety of proteins, tTG can also deamidate glutamyl donor substrates, especially when no acceptor protein is available. This deamidation converts certain peptide-bound glutamine residues into a negatively charged glutamic acid. Microsequencing of peptides eluted from HLA-DQ2 has revealed so-called anchor amino acid residues that are required for optimal binding to the HLA, including a negative charge at positions 4, 6, and 9 of the nonapeptide recognition groove.⁴⁴

Gliadin-reactive T cells and mucosal destruction

The isolation of T-cell clones from the intestinal mucosa of patients with celiac disease that can be stimulated with gliadin peptides presented in the context of HLA-DQ2 and -DQ8 supports a central role of gliadin in the initiation and maintenance of the celiac lesion. However, it does not explain the highly specific antibody response to tTG as the celiac disease autoantigen. A model was recently proposed based on the ability of B cells to present antigen in the context of HLA-DQ2.⁴⁷ In this

Autoantibodies block tTG bioactivity

The autoantibodies to tTG circulating in patients with celiac disease may have a biological role. This was suggested by an in vitro study that used T84 crypt epithelial cell differentiation in a fibroblast coculture model.⁵¹ This differentiation, which is dependent on transforming growth factor (TGF)-β,⁵² can be prevented either by addition of a blocking antibody to TGF-β or of IgA autoantibodies to tTG. tTG and plasmin are required to generate active TGF-β from the inactive (latent) TGF-β

γ/δ T cells as mucosal guardians

γ/δ T cells are considered a hallmark of celiac disease. They populate mucosal surfaces, particularly in the airways and the gut, residing within the epithelial lining. Recent data have advanced our understanding of the role of γ/δ T cells (Figure 7).16, 54, 55, 56

. Potential role of γ/δ T cells. Residing in the epithelium, γ/δ T cells are pathognomonic for celiac disease. They recognize bacterial nonpeptide antigens and stress-related proteins. Localized at the interface between the external and

Screening for detection of oligosymptomatic or silent celiac disease

Given the high positive predictive value of EMA testing by an experienced laboratory,36, 37 the availability of an observer-independent test system based on guinea pig tTG,58, 59 and recently human recombinant tTG,⁶⁰ makes population screening for clinically silent celiac disease possible. The usefulness of such an approach that might create unnecessary morbidity in previously healthy individuals has been questioned, but recent evidence is clearly in favor of identifying celiac disease patients

Future directions

Celiac disease is now considered the result of a complex interplay of intrinsic (genetic) and extrinsic factors. Given the undisputable role of gliadin in driving inflammation and autoimmunity, celiac disease can serve as a model disease with autoimmune features for which, in contrast to most other autoimmune diseases, the trigger (gliadin), a close genetic association (with HLA-DQ2 or -DQ8), and a highly specific humoral autoimmune response (autoantibodies to tTG) are known. Yet, full

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Celiac disease and other types of gluten intolerance significantly affect the life quality of patients making them restrict the diet removing all food produced from wheat, rye, oat, and barley flour, and some other products. These disorders arise from protease resistance of poorly soluble proteins prolamins, contained in gluten. Enhanced proteolytic digestion of gliadins might be considered as a prospective approach for the treatment of celiac disease and other types of gluten intolerance. Herein, we tested a range of sulfated polymers (kappa-carrageenan, dextran sulfate and different polysaccharides from brown seaweeds, and a synthetic polystyrene sulfonate) for the ability to activate gliadin digestion by human digestive proteases, pepsin and trypsin. Sulfated polysaccharide from Fucus evanescens enhanced proteolytic digestion of gliadins from wheat flour and reduced its cytotoxicity on intestinal epithelial Caco-2 cell culture. Regarding the non-toxic nature of fucoidans, the results provide a basis for polymer-based drugs or additives for the symptomatic treatment of gluten intolerance.
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Improving the diagnostic approach to celiac disease: Experience from a regional network
2022, Digestive and Liver Disease
Celiac disease (CD) is still underestimated. To close this diagnostic gap, the Health Sicilian Authorities have constituted the “Sicilian Network for CD”.
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We retrospectively evaluated the data collection forms of 369 patients with CD from three Centers within the Sicilian Network. All the Centers used a standard data collection form.
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The regional data sheets allowed an assessment of the diagnostic delay. We recorded a frequent use of unrecommended tests prescribed before referring patients to the regional Centers. Updating the education of physicians regarding CD is necessary to avoid unwarranted health expenditure.
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^☆: Address requests for reprints to: Detlef Schuppan, M.D., Ph.D., First Department of Medicine, University of Erlangen-Nuernberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. e-mail: [email protected]; fax: (49) 9131-85-36003.

^☆☆: Supported by Deutsche Forschungsgemeinschaft (grant Schu 646/11-1) and a grant from the German Celiac Foundation.

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Special Reports and ReviewsCurrent concepts of celiac disease pathogenesis☆,☆☆

Abstract

Section snippets

Gluten as a trigger of celiac disease

Histopathologic characteristics of the celiac lesion

Genetic association of celiac disease

Autoimmunity in celiac disease

Tissue transglutaminase as autoantigen

Gliadins as preferred substrates for tTG

Deamidation by tTG can create more potent T-cell epitopes

Gliadin-reactive T cells and mucosal destruction

Autoantibodies block tTG bioactivity

γ/δ T cells as mucosal guardians

Screening for detection of oligosymptomatic or silent celiac disease

Future directions

Lancet

Am J Med

Lancet

Lancet

Gastroenterology

Lancet

Clin Chim Acta

Baillieres Clin Gastroenterol

Am J Hum Genet

Lancet

Gastroenterology

Immunol Today

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Lancet

Immunol Today

On the coeliac affection

On the coeliac affection

St Bartholomews Hosp Rep

Ueber die Spruekrankheit (Aphthae tropicae)

Verh Dtsch Ges Pathol

Celiac disease, its specific treatment and cure without nutritional relapse

JAMA

Investigation of the harmful effects of certain types of cereal on patients with coeliac disease [doctoral thesis]

Coeliac disease IV. An investigation into the injurious constituents of wheat in connection with their action on patients with coeliac disease

Acta Paediatr Scand

Observations on the aetiology of idiopathic steatorrhoea

Br Med J

Studies of celiac disease. Part I. The apparent identical and specific nature of the duodenal and proximal jejunal lesion in celiac disease and idiopathic sprue

Gastroenterology

Studies of the familial nature of celiac sprue using biopsy of the small intestine

N Engl J Med

An HLA-D region restriction length polymorphism associated with celiac disease

J Exp Med

Evidence for a primary association of celiac disease to a particular HLA-DQ-α/β heterodimer

J Exp Med

Expression of disulfide-linked and non–disulfide-linked forms of the T cell receptor gamma/delta heterodimer in human intestinal intraepithelial lymphocytes

Eur J Immunol

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

J Exp Med

IgA class endomysium antibodies in dermatitis herpetiformis and coeliac disease

Ann N Y Acad Sci

Special Reports and Reviews
Current concepts of celiac disease pathogenesis☆,☆☆

Gliadin-specific, HLA-DQ (alpha0501, beta0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients