Current concepts of celiac disease pathogenesis

First Department of Medicine, University of Erlangen-Nuernberg, Erlangen, Germany.
Gastroenterology (Impact Factor: 16.72). 08/2000; 119(1):234-42. DOI: 10.1053/gast.2000.8521
Source: PubMed

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.

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Available from: Detlef Schuppan, Nov 26, 2014
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    • "It has been acknowledged that in the case of clinical symptoms of CD occurring in a patient together with the presence of anti-tissue transglutaminase antibodies (> 10 times the upper limit of normal), the presence of anti-endomysial antibodies and the presence of class II HLA-DQ2 and/or DQ8 haplotype, CD can be diagnosed without the necessity of small-bowel biopsy [16]. HLA-DQ2 is present in 90–95% of CD patients, whereas HLA-DQ8 is present in about 5–15% [17]. HLA-DQ2 and/or DQ8 allele is not found in only 1% of celiac patients. "
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    ABSTRACT: Introduction: Celiac disease (CD) is a permanent intolerance to gluten that occurs in genetically predisposed individuals and leads to small intestinal mucosa damage. According to ESPGHAN guidelines from 2012, CD can be diagnosed in a patient with characteristic clinical symptoms, in whom, anti-tissue transglutaminase antibodies (> 10 times the upper limit) are found, endomysial antibodies (EMA) is confirmed and a positive genetic test is obtained. In these conditions no small-bowel biopsies are required. Aim: Evaluation of the presence of HLA-DQ2 and HLA-DQ8 haplotypes in children with previously diagnosed CD, hospitalised in 2012 at the Department of Paediatrics and Immunology and/or the Gastroenterological Outpatient Clinic, and their relatives. Material and methods: Blood samples of 22 subjects, including 9 children with CD diagnosed on the basis of clinical symptoms, serological investigations and small-intestine biopsy, 7 diagnosed on the basis of clinical symptoms and serological investigations, 2 with the suspicion of CD on the basis of clinical symptoms and 4 relatives of a child with CD. Methods: HLA-DQ2/DQ8 test, automatic evaluation by EUROArrayScan. Results: The presence of HLA-DQ2 and/or HLA-DQ8 genotype was confirmed in 16 children with CD diagnosed on the basis of clinical symptoms and serological tests with/without intestinal biopsy, in 2 with the suspicion of CD and in 1 relative of a celiac child. Conclusions: The evaluation of HLA-DQ2/DQ8 haplotype confirms the genetic predisposition to CD in subjects with the disease diagnosed previously on the basis of clinical symptoms, serological tests or intestinal biopsy. Genetic testing is particularly indicated for the diagnosis of CD in infants consuming gluten for a short time and in small amounts.
    Przegląd Gastroenterologiczny 03/2014; 9(1):32-7. DOI:10.5114/pg.2014.40848 · 0.38 Impact Factor
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    • "CD- otherwise known as Gluten-sensitive enteropathy- is triggered by gluten-containing foods (wheat, barley and rye) in genetically predisposed individuals and can also be associated with other immunological diseases such as diabetes mellitus type 1 and IgA deficiency, suggesting immune dysregulation. Although patients are often asymptomatic, CD can manifest with cutaneous, mucosal, systemic or autoimmune features [3,4]. A variety of oral lesions such as atrophic glossitis and aphthous ulcers are quite common in patients with CD with A prevalence ranging from 3% to 61% in several studies. "
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    ABSTRACT: Celiac disease is a common autoimmune disease triggered by gluten-containing foods (wheat, barley and rye) in genetically predisposed individuals. We present a patient with celiac disease complicated by severe aphthous stomatitis resulting in impairing swallowing, chewing and speaking. This led to weight loss, psychosocial problems as well as inability to perform her work. A variety of topical and systemic medications used resulted in either no improvement or only partial alleviation of the patient's symptoms. After informed consent, etanercept was initiated and resulted in complete remission of aphthous stomatitis, decrease in arthralgia and fatigue and considerable improvement in her quality of life. The use of newer biological agents for selected and severe manifestations of celiac disease may lead to improved morbidity in these patients, but more studies are needed to determine long-term efficacy as well as safety of these drugs in the mucosal and/or systemic complications of this disease.
    Clinical and Molecular Allergy 12/2013; 11(1):6. DOI:10.1186/1476-7961-11-6 · 1.39 Impact Factor
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    • "IL-15, synthesized by activated IECs, stimulates the conversion of dendritic cells and monocytes into APCs with the definite histocompatibility complex DQ2/DQ8 (reaction #16) (see clause (6)). These APCs bind both native and deamidated gluten peptides as well as deamidated gluten peptides complexed to TG-2 [1] (reaction #18). As a result, TG-2 also becomes an antigen. "
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    ABSTRACT: Celiac disease (CD) is an autoimmune disorder that occurs in genetically predisposed people and is caused by a reaction to the gluten protein found in wheat, which leads to intestinal villous atrophy. Currently there is no drug for treatment of CD. The only known treatment is lifelong gluten-free diet. The main aim of this work is to develop a mathematical model of the immune response in CD patients and to predict the efficacy of a transglutaminase-2 (TG-2) inhibitor as a potential drug for treatment of CD. A thorough analysis of the developed model provided the following results:1.TG-2 inhibitor treatment leads to insignificant decrease in antibody levels, and hence remains higher than in healthy individuals.2.TG-2 inhibitor treatment does not lead to any significant increase in villous area.3.The model predicts that the most effective treatment of CD would be the use of gluten peptide analogs that antagonize the binding of immunogenic gluten peptides to APC. The model predicts that the treatment of CD by such gluten peptide analogs can lead to a decrease in antibody levels to those of normal healthy people, and to a significant increase in villous area. The developed mathematical model of immune response in CD allows prediction of the efficacy of TG-2 inhibitors and other possible drugs for the treatment of CD: their influence on the intestinal villous area and on the antibody levels. The model also allows to understand what processes in the immune response have the strongest influence on the efficacy of different drugs. This model could be applied in the pharmaceutical R&D arena for the design of drugs against autoimmune small intestine disorders and on the design of their corresponding clinical trials.
    BMC Systems Biology 07/2013; 7(1):56. DOI:10.1186/1752-0509-7-56 · 2.44 Impact Factor
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