Celiac Abstracts 4

© 2011

Update on the management of refractory coeliac disease

         (Al-Toma, Verbeek et al. 2007) Download

True Refractory Coeliac Disease (RCD) is being currently defined as persisting or recurring villous atrophy with crypt hyperplasia and increased intraepithelial lymphocytes in spite of a strict gluten free diet for more than 12 months or when severe persisting symptoms necessitate intervention independent of the duration of the dietary therapy. Currently two categories of RCD are being recognized: type I without aberrant T-cells and type II with aberrant T-cells detected by immunophenotyping by flowcytometric analysis or immunohistology of the intestinal mucosa. Establishing the diagnosis of RCD requires exclusion of other causes of villous atrophy and malignancies that may complicate coeliac disease. In contrast to patients with a high percentage of aberrant T cells, patients with RCD type I seem to profit from an immunosuppressive treatment. In cases of RCD II with persistent clinical symptoms and/or high percentage of aberrant T cells in intestinal biopsies in spite of a corticosteroid treatment, more aggressive therapeutic schemes should be considered. However, no therapy seems to be curative in RCD II. Cladribine (2-CDA) seems to have some role in the management of these patients. More recently, high dose chemotherapy followed by autologous stem cell transplantation has been used in patients resulting in a dramatic improvement in the clinical, laboratory, histopathological and immunological parameters. This review provides an overview of the currently available diagnostic and therapeutic methods in a complicated form of coeliac disease.

Celiac disease and autoimmunity in the gut and elsewhere

            (Barton and Murray 2008) Download

This review focuses on the autoimmune connective tissue diseases, endocrine, and dermatologic conditions associated with celiac disease, as well as the related gut inflammatory disorders of refractory celiac disease, autoimmune enteropathy, collagenous enteritis, and collagenous colitis.


Parallels between pathogens and gluten peptides in celiac sprue

            (Bethune and Khosla 2008) Download

Pathogens are exogenous agents capable of causing disease in susceptible organisms. In celiac sprue, a disease triggered by partially hydrolyzed gluten peptides in the small intestine, the offending immunotoxins cannot replicate, but otherwise have many hallmarks of classical pathogens. First, dietary gluten and its peptide metabolites are ubiquitous components of the modern diet, yet only a small, genetically susceptible fraction of the human population contracts celiac sprue. Second, immunotoxic gluten peptides have certain unusual structural features that allow them to survive the harsh proteolytic conditions of the gastrointestinal tract and thereby interact extensively with the mucosal lining of the small intestine. Third, they invade across epithelial barriers intact to access the underlying gut-associated lymphoid tissue. Fourth, they possess recognition sequences for selective modification by an endogenous enzyme, transglutaminase 2, allowing for in situ activation to a more immunotoxic form via host subversion. Fifth, they precipitate a T cell-mediated immune reaction comprising both innate and adaptive responses that causes chronic inflammation of the small intestine. Sixth, complete elimination of immunotoxic gluten peptides from the celiac diet results in remission, whereas reintroduction of gluten in the diet causes relapse. Therefore, in analogy with antibiotics, orally administered proteases that reduce the host's exposure to the immunotoxin by accelerating gluten peptide destruction have considerable therapeutic potential. Last but not least, notwithstanding the power of in vitro methods to reconstitute the essence of the immune response to gluten in a celiac patient, animal models for the disease, while elusive, are likely to yield fundamentally new systems-level insights.

The impact of misdiagnosing celiac disease at a referral centre

            (Biagi, Bianchi et al. 2009) Download

In the past few years, the number of celiac disease diagnoses not confirmed at the Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, a tertiary referral centre, was particularly high. Therefore, a decision was made to investigate the reasons why these diagnoses were wrong and by whom they had been made. The clinical histories of all celiac patients referred to the centre were re-evaluated. Between December 1998 and January 2007, 614 patients who were diagnosed at other institutions and presumed to be affected by celiac disease attended the tertiary referral outpatient clinic. The histological and serological results allowed for confirmation the diagnosis in 434 patients. In the remaining 180 patients, the initial diagnosis of celiac disease could not be confirmed; therefore, the patients were re-investigated. After re-evaluation, the diagnosis of celiac disease was confirmed in only 61 of these 180 cases. The reasons for incorrect initial diagnosis were analyzed. A mere 80% correct diagnosis rate is a very disappointing result. Although it should be obvious that celiac disease must be investigated with duodenal biopsies and celiac antibody testing, this well-known strategy is not always followed, probably resulting in an incorrect diagnosis.

Autoantibody frequency in celiac disease

         (Caglar, Ugurlu et al. 2009) Download

AIM: In our study, we investigated the levels of glutamic acid decarboxylase antibody (anti-GAD), islet cell antibody (ICA), thyroperoxidase antibody (anti-TPO), thyroglobulin antibody (anti-TG), antinuclear antibodies (FANA), antibodies to double-stranded DNA (anti-ds DNA), antibody to Sjogren syndrome A antigen (anti-SSA), antibody to Sjogren syndrome B antigen (anti-SSB), Smith antibody (anti-Sm), smooth muscle antibodies (ASMA), and antimitochondrial antibody liver-kidney microsome (AMA-LKM) in patients with celiac disease as compared to healthy controls and autoimmune hypothyroid patients. MATERIALS AND METHODS: A total of 31 patients with celiac disease, 34 patients with autoimmune hypothyroidism and 29 healthy subjects were included in this study. Anti-SSA, anti-SSB, anti-Sm, anti-ds DNA, anti-GAD, anti-TPO and anti-TG were studied by Enzyme-Linked Immunosorbent Assay (ELISA), and AMA-LKM, ASMA, ANA and ICA were studied by immunofluorescence. Clinical data and the results of free thyroxine-thyroid stimulating hormone (FT4-TSH) were collected from the patients' files by retrospective analysis. SPSS ver 13.0 was used for data analysis, and the chi(2) method was used for comparisons within groups. RESULTS: The frequency of anti-SSA, anti-SSB, anti-GAD, anti-Sm, anti-ds DNA, AMA-LKM, ASMA, ANA and ICA were not significantly different between the groups. Levels of anti-TPO and anti-TG antibodies were found to be significantly higher (<0.001) in autoimmune hypothyroid patients when compared with other groups. CONCLUSION: In previous studies, an increased frequency of autoimmune diseases of other systems has been reported in patients with celiac disease. We found that the frequency of autoimmune antibodies specific for other autoimmune diseases was not higher in celiac disease.

Role of intestinal bacteria in gliadin-induced changes in intestinal mucosa: study in germ-free rats

            (Cinova, De Palma et al. 2011) Download

BACKGROUND AND AIMS: Celiac disease (CD) is a chronic inflammatory disorder of the small intestine that is induced by dietary wheat gluten proteins (gliadins) in genetically predisposed individuals. The overgrowth of potentially pathogenic bacteria and infections has been suggested to contribute to CD pathogenesis. We aimed to study the effects of gliadin and various intestinal bacterial strains on mucosal barrier integrity, gliadin translocation, and cytokine production. METHODOLOGY/PRINCIPAL FINDINGS: Changes in gut mucosa were assessed in the intestinal loops of inbred Wistar-AVN rats that were reared under germ-free conditions in the presence of various intestinal bacteria (enterobacteria and bifidobacteria isolated from CD patients and healthy children, respectively) and CD-triggering agents (gliadin and IFN-gamma) by histology, scanning electron microscopy, immunofluorescence, and a rat cytokine antibody array. Adhesion of the bacterial strains to the IEC-6 rat cell line was evaluated in vitro. Gliadin fragments alone or together with the proinflammatory cytokine interferon (IFN)-gamma significantly decreased the number of goblet cells in the small intestine; this effect was more pronounced in the presence of Escherichia coli CBL2 and Shigella CBD8. Shigella CBD8 and IFN-gamma induced the highest mucin secretion and greatest impairment in tight junctions and, consequently, translocation of gliadin fragments into the lamina propria. Shigella CBD8 and E. coli CBL2 strongly adhered to IEC-6 epithelial cells. The number of goblet cells in small intestine increased by the simultaneous incubation of Bifidobacterium bifidum IATA-ES2 with gliadin, IFN-gamma and enterobacteria. B. bifidum IATA-ES2 also enhanced the production of chemotactic factors and inhibitors of metalloproteinases, which can contribute to gut mucosal protection. CONCLUSIONS: Our results suggest that the composition of the intestinal microbiota affects the permeability of the intestinal mucosa and, consequently, could be involved in the early stages of CD pathogenesis.

Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells

            (de Kauwe, Chen et al. 2009) Download

Celiac disease is a chronic inflammatory enteropathy caused by cellular immunity to dietary gluten. More than 90% of patients carry HLA-DQ2 encoded by HLA-DQA1*05 and DQB1*02, and gluten-specific CD4(+) T cells from intestinal biopsies of these patients are HLA-DQ2-restricted, produce Th1 cytokines and preferentially recognize gluten peptides deamidated by tissue transglutaminase. We generated mice lacking murine MHC class II genes that are transgenic for human CD4 and the autoimmunity and celiac disease-associated HLA-DR3-DQ2 haplotype. Immunization with the alpha-gliadin 17-mer that incorporates the overlapping DQ2-alpha-I and DQ2-alpha-II epitopes immunodominant in human celiac disease generates peptide-specific HLA-DQ2-restricted CD4(+) T cells. When exposed to dietary gluten, naive or gliadin-primed mice do not develop pathology. Coincident introduction of dietary gluten and intestinal inflammation resulted in low-penetrance enteropathy and tissue transglutaminase-specific IgA. Two further strains of transgenic mice expressing HLA-DR3-DQ2 and human CD4, one with a NOD background and another TCR transgenic having over 90% of CD4(+) T cells specific for the DQ2-alpha-II epitope with a Th1 phenotype, were also healthy when consuming gluten. These humanized mouse models indicate that gluten ingestion can be tolerated without intestinal pathology even when HLA-DQ2-restricted CD4(+) T cell immunity to gluten is established, thereby implicating additional factors in controlling the penetrance of celiac disease.

Celiac Disease and Autoimmune Thyroid Disease in Children with Type 1 Diabetes Mellitus: Clinical and HLA-Genotyping Results

            (Ergur, Ocal et al. 2011) Download

Objective: Increased prevalence of celiac disease (CD) and autoimmune thyroid disorders (ATD) in patients with Type 1 diabetes mellitus (T1D) has been widely reported. Such an association may lead to adverse effects on the growth, bone metabolism and fertility, and response to therapy may become difficult. The aim of this study was to evaluate the clinical findings and HLA typing results in patients with T1D associated with CD or ATD.Methods: The association of CD and ATD was evaluated in 38 children with T1D aged 1.5-16.8 years who had been followed for 48.3+/-28 months. Diagnosis of CD was based on positivity for serum endomysial IgA antibody and histopathological findings of intestinal biopsy specimens. Thyroid autoimmunity was assessed by antithyroglobulin and antithyroid peroxidase antibodies and with diagnostic ultrasonographic findings.Results: ATD was detected in 31.5%, and CD-in 7.8% of T1D patients. Subjects with CD showed either no symptoms or suggestive problems such as short stature, hepatosteatosis, pubertal delay and difficulties in the control of diabetes. Patients with ATD had no clinical symptoms. DQ8 was the most prominent finding in CD.Conclusions: It is essential that patients with T1D, regardless of presence or absence of symptoms, should be investigated for CD and ATD.Conflict of interest:None declared.

Diagnosis and treatment of coeliac disease

         (Geboes and Geboes 2009) Download

It is now clearly established that coeliac disease is much more common than originally considered. While in the past it was taught that coeliac disease was mainly a disease of children, it is clear now that it may be diagnosed at any age. The clinical presentation of adolescents and adults is, however, less typical. Recent evidence suggests that coeliac disease is a multi-organ disease. The diagnostic techniques involving histology and serologic testing have been improved and the involvement of environmental and genetic factors in the pathogenesis of this immune disorder has been clarified, although the pathogenesis is not yet completely understood. Complications are now better identified, and new treatment strategies are under consideration.

Comparative analysis of organ-specific autoantibodies and celiac disease--associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects

            (Jaeger, Hatziagelaki et al. 2001) Download

OBJECTIVE: In type 1 diabetes the coexistence with other endocrine diseases and organ-specific autoantibodies has been frequently reported leading to the concept of autoimmune polyendocrine syndrome (APS). In addition, an association of type 1 diabetes with celiac disease has been described. These disorders share a similar genetic background, and first-degree relatives of type 1 diabetic patients may also be affected significantly. Screening for specific antibodies allows early diagnosis of these disorders. RESEARCH DESIGN AND METHODS: In the present cross-sectional study, we analyzed sera from 197 recent-onset type 1 diabetic patients at the time of diagnosis, 882 first-degree relatives, and sera of 150 healthy control subjects for prevalence and co-occurence of the following antibodies (method): insulin autoantibodies (radioimmunoassay); GAD and IA-2 antibodies (radioligand assay); islet cell antibody, anti-adrenal cortex antibodies, and anti-gastric parietal cell antibodies (indirect immunofluorescence); anti-thyroglobulin and anti-thyroid peroxidase antibodies; and gliadin IgG/A and tissue-transglutaminase IgA (enzyme-linked immunosorbent assay). RESULTS: The overall frequency of gastric patietal cell antibodies and adrenal antibodies did not differ significantly among groups. In contrast, type 1 diabetes-associated antibodies and thyroid antibodies were significantly more frequent both in recent-onset type 1 diabetic patients and in the group of first-degree relatives (P < 0.05). The prevalence of gliadin IgG/IgA and transglutaminase IgA was significantly higher in the group of recent-onset type 1 diabetic patients (P < 0.05), but the difference between first-degree relatives and control subjects did not reach statistical significance. Focusing on the coexistence of antibodies, the group of recentonset type 1 diabetic patients presented with 27.4% of the subjects testing antibody-positive-specific for two or more of the envisaged disorders (i.e., type 1 diabetes, autoimmune thyroiditis, and celiac disease) compared with 3.1% in the group of first-degree relatives and 0 of 150 in the control population (P < 0.05). CONCLUSIONS: We conclude that, in an active case-finding strategy, recent-onset type 1 diabetic patients should be routinely screened at least for concomitant autoimmune thyroid disease and additionally for celiac disease. Screening in their first-degree relatives should include at a minimum the search for thyroid autoimmunity in addition to screening for pre-type 1 diabetes.


Patterns of clinical presentation of adult coeliac disease in a rural setting

         (Jones, D'Souza et al. 2006) Download

BACKGROUND: In recent years there has been increasing recognition that the pattern of presentation of coeliac disease may be changing. The classic sprue syndrome with diarrhoea and weight loss may be less common than the more subtle presentations of coeliac disease such as an isolated iron deficiency anaemia. As a result, the diagnosis of this treatable condition is often delayed or missed. Recent serologic screening tests allow non-invasive screening to identify most patients with the disease and can be applied in patients with even subtle symptoms indicative of coeliac disease. Both benign and malignant complications of coeliac disease can be avoided by early diagnosis and a strict compliance with a gluten free diet. AIM: The aim of this study is to evaluate the trends in clinical presentation of patients diagnosed with adult coeliac disease. In addition, we studied the biochemical and serological features and the prevalence of associated conditions in patients with adult coeliac disease. METHODS: This is an observational, retrospective, cross-sectional review of the medical notes of 32 adult patients attending the specialist coeliac clinic in a district general hospital. RESULTS: Anaemia was the most common mode of presentation accounting for 66% of patients. Less than half of the patients had any of the classical symptoms of coeliac disease and 25% had none of the classical symptoms at presentation. Anti-gliadin antibodies, anti-endomysial antibody and anti-tissue transglutaminase showed 75%, 68% and 90% sensitivity respectively. In combination, serology results were 100% sensitive as screening tests for adult coeliac disease. Fifty nine percent patients had either osteoporosis or osteopenia. There were no malignant complications observed during the follow up of our patients. CONCLUSION: Most adults with coeliac disease have a sub clinical form of the disease and iron deficiency anaemia may be its sole presenting symptom. Only a minority of adult coeliac disease patients present with classical mal-absorption symptoms of diarrhoea and weight loss. Patients with atypical form of disease often present initially to hospital specialists other than a gastro-enterologist. An awareness of the broad spectrum of presentations of adult coeliac disease, among doctors both in primary care and by the various hospital specialists in secondary care, is necessary to avoid delays in diagnosis. It is important to include serological screening tests for coeliac disease systematically in the evaluation of adult patients with unexplained iron deficiency anaemia or unexplained gastro-intestinal symptoms and in those who are considered to be at increased risk for coeliac disease.


A Brazilian experience of the self transglutaminase-based test for celiac disease case finding and diet monitoring

            (Kotze, Brambila Rodrigues et al. 2009) Download

AIM: To evaluate the effectiveness of a rapid and easy fingertip whole blood point-of-care test for celiac disease (CD) case finding and diet monitoring. METHODS: Three hundred individuals, 206 females (68.7%) and 94 males (31.3%), were submitted to a rapid and easy immunoglobulin-A-class fingertip whole blood point-of-care test in the doctor's office in order to make immediate clinical decisions: 13 healthy controls, 6 with CD suspicion, 46 treated celiacs, 84 relatives of the celiac patients, 69 patients with dyspepsia, 64 with irritable bowel syndrome (IBS), 8 with Crohn's disease and 9 with other causes of diarrhea. RESULTS: Upper gastrointestinal endoscopy with duodenal biopsies was performed in patients with CD suspicion and in individuals with positive test outcome: in 83.3% (5/6) of the patients with CD suspicion, in 100% of the patients that admitted gluten-free diet transgressions (6/6), in 3.8% of first-degree relatives (3/79) and in 2.9% of patients with dyspepsia (2/69). In all these individuals duodenal biopsies confirmed CD (Marsh's histological classification). The studied test showed good correlation with serologic antibodies, endoscopic and histological findings. CONCLUSION: The point-of-care test was as reliable as conventional serological tests in detecting CD cases and in CD diet monitoring.

Coeliac disease

            (Leeds, Hopper et al. 2008) Download

INTRODUCTION: Coeliac disease is a common but often under diagnosed condition with important complications. It is due to immune-mediated gluten intolerance and may present in a number of ways. It has become more frequently diagnosed due to the recognition of the atypical presentations. In recent years, more sensitive and specific serological markers have been developed but the gold standard of diagnosis remains duodenal biopsy. Compliance with a strict, lifelong gluten-free diet is the cornerstone of management, improving symptoms and reducing complications of the disease. SOURCES OF DATA: For this review, we focused on papers published on coeliac disease in recent years. Particular emphasis was given to clinical papers examining new methods for the diagnosis of coeliac disease or newer therapies for managing complications. The main source was PubMed and the major gastroenterology journals. AREAS OF AGREEMENT: Coeliac disease is more common than once thought with a prevalence of around 1%. Diagnosis should always be confirmed with a duodenal biopsy. Management of coeliac disease with a gluten-free diet remains the cornerstone of treatment. AREAS OF CONTROVERSY: Some complications of coeliac disease, especially neurological, are not widely accepted despite growing support from the literature. Management of enteropathy-associated lymphoma has been difficult, and the optimal therapy is not known. GROWING POINTS: Current understanding is such that coeliac disease is the most widely understood autoimmune condition. 'Atypical' presentations are becoming the most common presenting features of coeliac disease. AREAS TIMELY FOR DEVELOPING RESEARCH: Alternatives to the gluten-free diet are about to go into clinical studies. Similarly, better serological screening tests may obviate the need for duodenal biopsy. This review will try to summarize the current understanding of coeliac disease with regard to diagnosis, management, complications and future perspectives.

A universal approach to eliminate antigenic properties of alpha-gliadin peptides in celiac disease

            (Mitea, Salentijn et al. 2011) Download

Celiac disease is caused by an uncontrolled immune response to gluten, a heterogeneous mixture of wheat storage proteins, including the alpha-gliadins. It has been shown that alpha-gliadins harbor several major epitopes involved in the disease pathogenesis. A major step towards elimination of gluten toxicity for celiac disease patients would thus be the elimination of such epitopes from alpha-gliadins. We have analyzed over 3,000 expressed alpha-gliadin sequences from 11 bread wheat cultivars to determine whether they encode for peptides potentially involved in celiac disease. All identified epitope variants were synthesized as peptides and tested for binding to the disease-associated HLA-DQ2 and HLA-DQ8 molecules and for recognition by patient-derived alpha-gliadin specific T cell clones. Several specific naturally occurring amino acid substitutions were identified for each of the alpha-gliadin derived peptides involved in celiac disease that eliminate the antigenic properties of the epitope variants. Finally, we provide proof of principle at the peptide level that through the systematic introduction of such naturally occurring variations alpha-gliadins genes can be generated that no longer encode antigenic peptides. This forms a crucial step in the development of strategies to modify gluten genes in wheat so that it becomes safe for celiac disease patients. It also provides the information to design and introduce safe gluten genes in other cereals, which would exhibit improved quality while remaining safe for consumption by celiac disease patients.

Autoantibody profiles in two patients with non-autoimmune muscle disease implicate a role for gliadin autoreactivity

            (Olsen, Prather et al. 2011) Download

The objective of this case study was to characterize autoreactivity in two patients with non-autoimmune forms of muscle disease who had positivity for antinuclear antibodies (ANA) and Ro (SSA) autoantibodies. Serum samples from these two patients were applied to an autoantigen protein array with more than 70 specificities and were compared to samples from healthy controls and patients with systemic lupus erythematosus. Both myopathy patients had high levels of gliadin autoreactivity in serum and one patient had an overall autoantibody profile with lupus-like features. The findings suggest that some disorders of muscle that are considered non-autoimmune, may in fact have autoimmune features. Further examination of the role of subclinical gluten autoreactivity in the pathogenesis of myopathy syndromes has the potential to suggest improved approaches to diagnosis and treatment of these conditions.

Anti-microbial antibodies in celiac disease: trick or treat?

            (Papp, Foldi et al. 2009) Download

AIM: To determine the prevalence of a new set of anti-glycan and anti-outer membrane protein (anti-OMP) antibodies in a Hungarian cohort of adult Celiac disease (CD) patients. METHODS: 190 consecutive CD patients [M/F: 71/119, age:39.9 (SD:14.1) years], 100 healthy, and 48 gastrointestinal controls were tested for glycan anti-Saccharomyces cerevisiae (gASCA), anti-laminaribioside (ALCA), anti-chitobioside, anti-mannobioside, anti-OMP antibodies and major NOD2/CARD15 mutations. Thirty out of 82 CD patients enrolled at the time of diagnosis were re-evaluated for the same antibodies after longstanding gluten-free diet (GFD). RESULTS: 65.9% of the CD patients were positive for at least one of the tested antibodies at the time of the diagnosis. Except anti-OMP and ALCA, anti-microbial antibodies were exclusively seen in untreated CD; however, the overall sensitivity was low. Any glycan positivity (LR+: 3.13; 95% CI: 2.08-4.73) was associated with an increased likelihood ratio for diagnosing CD. Significant correlation was found between the levels of anti-glycan and anti-endomysial or anti-transglutaminase antibodies. Anti-glycan positivity was lost after longstanding GFD. Anti-glycan antibody titers were associated with symptoms at presentation, but not the presence of NOD2/CARD15 mutations. Patients with severe malabsorption more frequently had multiple antibodies at diagnosis (P = 0.019). CONCLUSION: The presence of anti-glycan antibodies in CD seems to be secondary to the impaired small bowel mucosa which can lead to increased antigen presentation. Furthermore, anti-glycan positivity may be considered an additional marker of CD and dietary adherence.

The changing clinical presentation of coeliac disease

         (Ravikumara, Tuthill et al. 2006) Download

BACKGROUND: There has been a growing recognition that coeliac disease is much more common than previously recognised, and this has coincided with the increasingly widespread use of serological testing. AIM: To determine whether the age at presentation and the clinical presentation of coeliac disease have changed with the advent of serological testing. METHODS: A 21-year review of prospectively recorded data on the mode of presentation of biopsy confirmed coeliac disease in a single regional centre. Presenting features over the past 5 years were compared with those of the previous 16 years. Between 1983 and 1989 (inclusive), no serological testing was undertaken; between 1990 and 1998, antigliadin antibody was used with occasional use of antiendomysial antibody and antireticulin antibody. From 1999 onwards, anti-tissue transglutaminase was used. RESULTS: 86 patients were diagnosed over the 21-year period: 50 children between 1999 and 2004 compared with 25 children between 1990 and 1998 and 11 children between 1983 and 1989. The median age at presentation has risen over the years. Gastrointestinal manifestations as presenting features have decreased dramatically. In the past 5 years, almost one in four children with coeliac disease was diagnosed by targeted screening. CONCLUSION: This study reports considerable changes in the presentation of coeliac disease-namely, a decreased proportion presenting with gastrointestinal manifestations and a rise in the number of patients without symptoms picked up by targeted screening. Almost one in four children with coeliac disease is now diagnosed by targeted screening. Most children with coeliac disease remain undiagnosed. Paediatricians and primary care physicians should keep the possibility of coeliac disease in mind and have a low threshold for testing, so that the potential long-term problems associated with untreated coeliac disease can be prevented.

Celiac disease

            (Rubio-Tapia and Murray 2010) Download

PURPOSE OF REVIEW: To summarize recent advances in celiac disease published between August 2008 and July 2009. RECENT FINDINGS: Celiac disease affects nearly 1% of most populations but remains largely unrecognized. In the last year, work has shown that the prevalence of celiac disease has increased dramatically, not simply due to increased detection. Also, undiagnosed celiac disease may be associated with increased mortality. Significant progress has been made in understanding how gliadin peptides can cross the intestinal border and access the immune system. New genetic loci and candidate genes that may contribute to the risk of celiac disease and its overlap with type 1 diabetes mellitus have been identified. Novel deamidated gliadin peptides antibodies have better diagnostic accuracy over native gliadin-based tests. The inclusion of duodenal bulb biopsy specimens may increase the rate of celiac disease detection. The spectrum of celiac disease likely includes a minority of patients with mild enteropathy. A practical seven-item instrument may facilitate standardized evaluation of gluten-free diet adherence. Finally, refractory celiac disease, although rare, is associated with a poor prognosis. SUMMARY: Celiac disease is a global health problem that requires a multidisciplinary and increasingly cooperative multinational research effort.

Classification and management of refractory coeliac disease

         (Rubio-Tapia and Murray 2010) Download

Refractory coeliac disease (RCD) is defined by persistent or recurrent malabsorptive symptoms and villous atrophy despite strict adherence to a gluten-free diet (GFD) for at least 6-12 months in the absence of other causes of non-responsive treated coeliac disease and overt malignancy. Symptoms are often severe and require additional therapeutic intervention besides a GFD. RCD can be classified as type 1 (normal intraepithelial lymphocyte phenotype), or type 2 (defined by the presence of abnormal (clonal) intraepithelial lymphocyte phenotype). Patients with RCD may never have responded to a GFD or may have relapsed despite adherence and initial response to the GFD. RCD type 1 usually improves after treatment with a combination of aggressive nutritional support, adherence to a GFD, and alternative pharmacological therapies. By contrast, clinical response to alternative therapies in RCD type 2 is less certain and the prognosis is poor. Severe complications such as ulcerative jejunitis and enteropathy-associated T cell lymphoma may occur in a subgroup of patients with RCD. The aims of this article are to (1) review recent advances in the diagnosis and management of patients with RCD, and (2) describe current and novel methods for classification of patients with RCD into categories that are useful to predict outcome and direct treatment.

Novel immune response to gluten in individuals with schizophrenia

         (Samaroo, Dickerson et al. 2010) Download

A link between celiac disease and schizophrenia has been postulated for several years, based primarily on reports of elevated levels of antibody to gliadin in patients. We sought to examine the proposed connection between schizophrenia and celiac disease by characterizing the molecular specificity and mechanism of the anti-gliadin immune response in a subset of individuals with schizophrenia. Blood samples from individuals with schizophrenia and elevated anti-gliadin antibody titer were examined for celiac disease-associated biomarkers, including antibodies to transglutaminase 2 (TG2) enzyme and deamidated gliadin peptides, as well as the HLA-DQ2 and -DQ8 MHC genes. The anti-gliadin antibody response was further characterized through examination of reactivity towards chromatographically separated gluten proteins. Target proteins of interest were identified by peptide mass mapping. In contrast to celiac disease patients, an association between the anti-gliadin immune response and anti-TG2 antibody or HLA-DQ2 and -DQ8 markers was not found in individuals with schizophrenia. In addition, the majority of individuals with schizophrenia and anti-gliadin antibody did not exhibit antibody reactivity to deamidated gliadin peptides. Further characterization of the antibody specificity revealed preferential reactivity towards different gluten proteins in the schizophrenia and celiac disease groups. These findings indicate that the anti-gliadin immune response in schizophrenia has a different antigenic specificity from that in celiac disease and is independent of the action of transglutaminase enzyme and HLA-DQ2/DQ8. Meanwhile, the presence of elevated levels of antibodies to specific gluten proteins points to shared immunologic abnormalities in a subset of schizophrenia patients. Further characterization and understanding of the immune response to gluten in schizophrenia may provide novel insights into the etiopathogenesis of specific disease phenotypes.

Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease

            (Sapone, Lammers et al. 2010) Download

BACKGROUND: The immune-mediated enteropathy, celiac disease (CD), and gluten sensitivity (GS) are two distinct clinical conditions that are both triggered by the ingestion of wheat gliadin. CD, but not GS, is associated with and possibly mediated by an autoimmune process. Recent studies show that gliadin may induce the activation of IL-17-producing T cells and that IL-17 expression in the CD mucosa correlates with gluten intake. METHODS: The small-intestinal mucosa of patients with CD and GS and dyspeptic controls was analyzed for expression of IL-17A mRNA by quantitative RT-PCR. The number of CD3+ and TCR-gammadelta lymphocytes and the proportion of CD3+ cells coexpressing the Th17 marker CCR6 were examined by in situ small-intestinal immunohistochemistry. RESULTS: Mucosal expression of IL-17A was significantly increased in CD but not in GS patients, compared to controls. This difference was due to enhanced IL-17A levels in >50% of CD patients, with the remainder expressing levels similar to GS patients or controls, and was paralleled by a trend toward increased proportions of CD3+CCR6+ cells in intestinal mucosal specimens from these subjects. CONCLUSION: We conclude that GS, albeit gluten-induced, is different from CD not only with respect to the genetic makeup and clinical and functional parameters, but also with respect to the nature of the immune response. Our findings also suggest that two subgroups of CD, IL-17-dependent and IL-17-independent, may be identified based on differential mucosal expression of this cytokine.

Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity

            (Sapone, Lammers et al. 2011) Download

BACKGROUND: Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten. Gluten-sensitive individuals (GS) cannot tolerate gluten and may develop gastrointestinal symptoms similar to those in CD, but the overall clinical picture is generally less severe and is not accompanied by the concurrence of tissue transglutaminase autoantibodies or autoimmune comorbidities. By studying and comparing mucosal expression of genes associated with intestinal barrier function, as well as innate and adaptive immunity in CD compared with GS, we sought to better understand the similarities and differences between these two gluten-associated disorders. METHODS: CD, GS and healthy, gluten-tolerant individuals were enrolled in this study. Intestinal permeability was evaluated using a lactulose and mannitol probe, and mucosal biopsy specimens were collected to study the expression of genes involved in barrier function and immunity. RESULTS: Unlike CD, GS is not associated with increased intestinal permeability. In fact, this was significantly reduced in GS compared with controls (P = 0.0308), paralleled by significantly increased expression of claudin (CLDN) 4 (P = 0.0286). Relative to controls, adaptive immunity markers interleukin (IL)-6 (P = 0.0124) and IL-21 (P = 0.0572) were expressed at higher levels in CD but not in GS, while expression of the innate immunity marker Toll-like receptor (TLR) 2 was increased in GS but not in CD (P = 0.0295). Finally, expression of the T-regulatory cell marker FOXP3 was significantly reduced in GS relative to controls (P = 0.0325) and CD patients (P = 0.0293). CONCLUSIONS: This study shows that the two gluten-associated disorders, CD and GS, are different clinical entities, and it contributes to the characterization of GS as a condition associated with prevalent gluten-induced activation of innate, rather than adaptive, immune responses in the absence of detectable changes in mucosal barrier function.

Improved Xenobiotic Metabolism and Reduced Susceptibility to Cancer in Gluten-Sensitive Macaques upon Introduction of a Gluten-Free Diet

            (Sestak, Conroy et al. 2011) Download

BACKGROUND: A non-human primate (NHP) model of gluten sensitivity was employed to study the gene perturbations associated with dietary gluten changes in small intestinal tissues from gluten-sensitive rhesus macaques (Macaca mulatta). METHODOLOGY: Stages of remission and relapse were accomplished in gluten-sensitive animals by administration of gluten-free (GFD) and gluten-containing (GD) diets, as described previously. Pin-head-sized biopsies, obtained non-invasively by pediatric endoscope from duodenum while on GFD or GD, were used for preparation of total RNA and gene profiling, using the commercial Rhesus Macaque Microarray (Agilent Technologies),targeting expression of over 20,000 genes. PRINCIPAL FINDINGS: When compared with normal healthy control, gluten-sensitive macaques showed differential gene expressions induced by GD. While observed gene perturbations were classified into one of 12 overlapping categories - cancer, metabolism, digestive tract function, immune response, cell growth, signal transduction, autoimmunity, detoxification of xenobiotics, apoptosis, actin-collagen deposition, neuronal and unknown function - this study focused on cancer-related gene networks such as cytochrome P450 family (detoxification function) and actin-collagen-matrix metalloproteinases (MMP) genes. CONCLUSIONS/SIGNIFICANCE: A loss of detoxification function paralleled with necessity to metabolize carcinogens was revealed in gluten-sensitive animals while on GD. An increase in cancer-promoting factors and a simultaneous decrease in cancer-preventing factors associated with altered expression of actin-collagen-MMP gene network were noted. In addition, gluten-sensitive macaques showed reduced number of differentially expressed genes including the cancer-associated ones upon withdrawal of dietary gluten. Taken together, these findings indicate potentially expanded utility of gluten-sensitive rhesus macaques in cancer research.

Effect of the timing of gluten introduction on the development of celiac disease

         (Silano, Agostoni et al. 2010) Download

Celiac disease (CD) is a permanent auto-immune enteropathy, triggered in genetically predisposed individuals by the ingestion of dietary gluten. Gluten is the alcohol-soluble protein component of the cereals wheat, rye and barley. CD is a multifactorial condition, originating from the interplay of genetic and environmental factors. The necessary environmental trigger is gluten, while the genetic predisposition has been identified in the major histocompatibility complex region on chromosome 6p21, with over 90% of CD patients expressing HLA DQ2 and the remaining celiac patients express DQ8. The fact that only about 4% of DQ2/8-positive individuals exposed to gluten develop CD, has led to the recognition that other genetic and environmental factors are also necessary. In the last few years, several epidemiological studies have suggested that the timing of the introduction of gluten, as well as the pattern of breastfeeding, may play an important role in the subsequent development of CD. Here, we present and review the most recent evidences regarding the effect of timing of gluten introduction during weaning, the amount of gluten introduced and simultaneous breastfeeding, on the development of CD.

PPAR signaling pathway and cancer-related proteins are involved in celiac disease-associated tissue damage

            (Simula, Cannizzaro et al. 2010) Download

Celiac disease (CD) is an immune-mediated disorder triggered by the ingestion of wheat gliadin and related proteins in genetically predisposed individuals. To find a proteomic CD diagnostic signature and to gain a better understanding of pathogenetic mechanisms associated with CD, we analyzed the intestinal mucosa proteome alterations using two dimensional difference gel electrophoresis (2D-DIGE) coupled with matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF ms) of CD patients with varying degrees of histological abnormalities defined by Marsh criteria and controls. Our results clearly evidenced the presence of two groups of patients: Group A, including controls and Marsh 0-I CD patients; and Group B, consisting of CD subjects with grade II-III Oberhuber-Marsh classification. Differentially expressed proteins were involved mainly in lipid, protein and sugar metabolism. Interestingly, in Group B, several downregulated proteins (FABP1, FABP2, APOC3, HMGCS2, ACADM and PEPCK) were implicated directly in the peroxisome proliferator-activated receptor (PPAR) signaling pathway. Moreover, Group B patients presented a deregulation of some proteins involved in apoptosis/survival pathways: phosphatidylethanolamine-binding protein 1 (PEBP1), Ras-related nuclear protein (Ran) and peroxiredoxin 4 (PRDX4). PEBP1 downregulation and RAN and PRDX4 upregulation were associated with more severe tissue damage. Likewise, IgMs were found strongly upregulated in Group B. In conclusion, our results indicate that a downregulation of proteins involved in PPAR signaling and the modulation of several cancer-related proteins are associated with the highest CD histological score according to Oberhuber-Marsh classification.

Capsule endoscopy in celiac disease

         (Spada, Riccioni et al. 2008) Download

Video capsule endoscopy is an attractive and patient-friendly tool that provides high quality images of the small bowel. Obscure gastrointestinal bleeding is the primary and most evaluated indication to capsule endoscopy; however, indications are expanding and a small number of preliminary reports have been presented concerning the role of video capsule endoscopy in the diagnosis of celiac disease. The purpose of this review is to update the current knowledge and to hypothesize on future perspectives of the use of video capsule endoscopy in patients with celiac disease.

Evaluation of Cladribine treatment in refractory celiac disease type II

            (Tack, Verbeek et al. 2011) Download

AIM: To evaluate cladribine [2-chlorodeoxyadenosine (2-CdA)] therapy in refractory celiac disease (RCD) II. METHODS: An open-label cohort-study of RCD II patients treated with 2-CdA was performed between 2000 and 2010. Survival rate, enteropathy associated T-cell lymphoma (EATL) occurrence, clinical course, and histological and immunological response rates were evaluated. RESULTS: Overall, 32 patients were included with a median follow-up of 31 mo. Eighteen patients responded well to 2-CdA. Patients responsive to 2-CdA had a statistically significant increased survival compared to those who were unresponsive. The overall 3- and 5-year survival was 83% in the responder and 63% and 22% in the non-responder group, respectively. The overall 2-year clinical, histological and immunological response rates were 81%, 47% and 41%, respectively. Progression into EATL was reported in 16%, all of these patients died. CONCLUSION: Treatment of RCD II with 2-CdA holds promise, showing excellent clinical and histological response rates, and probably less frequent transition into EATL.

Antibodies to the wheat storage globulin Glo-3A in children before and at diagnosis of celiac disease

            (Taplin, Mojibian et al. 2011) Download

OBJECTIVE: Celiac disease (CD) is an autoimmune disease triggered by exposure to gluten-containing foods. IgA autoantibodies to tissue transglutaminase (TTG) are elevated in CD, but little is known about the gastrointestinal state before the appearance of TTG. Antibodies to wheat storage globulin Glo-3A have been studied in type 1 diabetes, and may be a marker of altered mucosal barrier and/or immune function. In the present study, we investigated antibody responses to Glo-3A in CD. PATIENTS AND METHODS: In the Diabetes Autoimmunity Study in the Young, children were studied prospectively from birth for the appearance of TTG and CD. Fifty cases of CD were frequency matched with 50 controls on age (of TTG seroconversion in the case), sex, ethnicity, presence of a first-degree relative with type 1 diabetes mellitus, and human leukocyte antigen -DR3 genotype. In cases and controls, IgG antibodies to Glo-3A were analyzed in a blinded manner in the sample collected at the time of seroconversion to TTG positivity (or the matched sample in controls) and in all of the previous samples since birth (mean 4.5 samples). The association between Glo-3A antibody levels and CD case status was explored using t tests at the TTG-positive visit and when Glo-3A levels were highest, and mixed modeling to describe Glo-3A over time. RESULTS: At the time of first elevated TTG (mean 4.9 years), patients with CD had higher Glo-3A antibody levels than controls (13.3 +/- 17.2 vs 7.6 +/- 11.7, P = 0.005). In both cases and controls, Glo-3A antibodies appear to peak at a mean age of 2.9 years, before mean age of initial TTG seroconversion. The peak Glo-3A antibody levels were higher in cases than controls (25.5 +/- 21.8 vs 14.9 +/- 18.3 P = 0.0007). Using mixed modeling to account for multiple visits per person, cases had higher levels of Glo-3A antibodies than controls at all ages from birth to TTG seroconversion (beta = 0.53, P = 0.002). CONCLUSIONS: Compared with controls, CD cases have higher Glo-3A antibody responses in the beginning years, before initial detection of TTG.

Celiac disease: how complicated can it get?

            (Tjon, van Bergen et al. 2011) Download

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.

Presence of celiac disease epitopes in modern and old hexaploid wheat varieties: wheat breeding may have contributed to increased prevalence of celiac disease

            (van den Broeck, de Jong et al. 2010) Download

Gluten proteins from wheat can induce celiac disease (CD) in genetically susceptible individuals. Specific gluten peptides can be presented by antigen presenting cells to gluten-sensitive T-cell lymphocytes leading to CD. During the last decades, a significant increase has been observed in the prevalence of CD. This may partly be attributed to an increase in awareness and to improved diagnostic techniques, but increased wheat and gluten consumption is also considered a major cause. To analyze whether wheat breeding contributed to the increase of the prevalence of CD, we have compared the genetic diversity of gluten proteins for the presence of two CD epitopes (Glia-alpha9 and Glia-alpha20) in 36 modern European wheat varieties and in 50 landraces representing the wheat varieties grown up to around a century ago. Glia-alpha9 is a major (immunodominant) epitope that is recognized by the majority of CD patients. The minor Glia-alpha20 was included as a technical reference. Overall, the presence of the Glia-alpha9 epitope was higher in the modern varieties, whereas the presence of the Glia-alpha20 epitope was lower, as compared to the landraces. This suggests that modern wheat breeding practices may have led to an increased exposure to CD epitopes. On the other hand, some modern varieties and landraces have been identified that have relatively low contents of both epitopes. Such selected lines may serve as a start to breed wheat for the introduction of 'low CD toxic' as a new breeding trait. Large-scale culture and consumption of such varieties would considerably aid in decreasing the prevalence of CD.

Alpha-gliadin genes from the A, B, and D genomes of wheat contain different sets of celiac disease epitopes

            (van Herpen, Goryunova et al. 2006) Download

BACKGROUND: Bread wheat (Triticum aestivum) is an important staple food. However, wheat gluten proteins cause celiac disease (CD) in 0.5 to 1% of the general population. Among these proteins, the alpha-gliadins contain several peptides that are associated to the disease. RESULTS: We obtained 230 distinct alpha-gliadin gene sequences from severaldiploid wheat species representing the ancestral A, B, and D genomes of the hexaploid bread wheat. The large majority of these sequences (87%) contained an internal stop codon. All alpha-gliadin sequences could be distinguished according to the genome of origin on the basis of sequence similarity, of the average length of the polyglutamine repeats, and of the differences in the presence of four peptides that have been identified as T cell stimulatory epitopes in CD patients through binding to HLA-DQ2/8. By sequence similarity, alpha-gliadins from the public database of hexaploid T. aestivum could be assigned directly to chromosome 6A, 6B, or 6D. T. monococcum (A genome) sequences, as well as those from chromosome 6A of bread wheat, almost invariably contained epitope glia-alpha9 and glia-alpha20, but never the intact epitopes glia-alpha and glia-alpha2. A number of sequences from T. speltoides, as well as a number of sequences fromchromosome 6B of bread wheat, did not contain any of the four T cell epitopes screened for. The sequences from T. tauschii (D genome), as well as those from chromosome 6D of bread wheat, were found to contain all of these T cell epitopes in variable combinations per gene. The differences in epitope composition resulted mainly from point mutations. These substitutions appeared to be genome specific. CONCLUSION: Our analysis shows that alpha-gliadin sequences from the three genomes of bread wheat form distinct groups. The four known T cell stimulatory epitopes are distributed non-randomly across the sequences, indicating that the three genomes contribute differently to epitope content. A systematic analysis of all known epitopes in gliadins and glutenins will lead to better understanding of the differences in toxicity among wheat varieties. On the basis of such insight, breeding strategies can be designed to generate less toxic varieties of wheat which may be tolerated by at least part of the CD patient population.


Lymphocytic duodenosis and the spectrum of celiac disease

            (Vande Voort, Murray et al. 2009) Download

OBJECTIVES: Celiac disease (CD) is a chronic inflammatory disease of the small bowel that is characterized by increased intraepithelial lymphocytes (IELs) and villous atrophy of the mucosa. It is unclear how often intraepithelial lymphocytosis in the absence of atrophy is a manifestation of gluten sensitive enteropathy. The objective of this study was to identify factors that discriminate patients with CD from those with lymphocytic duodenosis (LD, intraepithelial lymphocytosis without villous atrophy). We compared Class 2 HLA type, presenting symptoms, and serology in patients with LD and CD. METHODS: Retrospective review of 124 systematically assessed patients with LD compared with 454 CD patients with villous atrophy. All patients had duodenal biopsies and Class 2 HLA typing performed. HLA type, symptoms, serology pattern, and response to a gluten-free diet were analyzed using univariate logistic regression modeling, adjusted for age and gender. RESULTS: Half of the (63 (51%)) LD patients lack the Class 2 HLA genotypes encoding DQ2 or DQ8 whereas only 11 (2%) CD patients had neither DQ2 nor DQ8, P<0.001. The genes encoding DQ2 were much more prevalent in CD (91%) than that in LD (37%, P<0.001), however, the rate of carriage of DQ8 did not differ between the two groups (15% vs. 15%, P=0.9). Although diarrhea and weight loss were equally frequent in LD and CD patients, LD patients were less likely to be associated with anemia (P=0.007), malaise (P=0.006), skin disorder (P=0.007), or a family history of CD (P<0.001). The LD subjects were much less likely to have tissue transglutaminase or endomysial antibodies than were CD subjects (12% or 0% vs. 87% and 87%; P<0.001, respectively). CONCLUSIONS: The LD cohort differs significantly in terms of HLA type, serology, and clinical features, suggesting that the majority of patients with LD do not belong in the spectrum of CD.

Increasing prevalence and high incidence of celiac disease in elderly people: a population-based study

            (Vilppula, Kaukinen et al. 2009) Download

BACKGROUND: Celiac disease may emerge at any age, but little is known of its appearance in elderly people. We evaluated the prevalence of the condition in individuals over 55 years of age, and determined the incidence of biopsy-proven celiac disease (CDb) and celiac disease including seropositive subjects for anti-tissue transglutaminase antibodies (CDb+s). METHODS: The study based on prevalence figures in 2815 randomly selected subjects who had undergone a clinical examination and serologic screening for celiac disease in 2002. A second screening in the same population was carried out in 2005, comprising now 2216 individuals. Positive tissue transglutaminase antibodies were confirmed with small bowel biopsy. RESULTS: Within three years the prevalence of CDb increased from 2.13 to 2.34%, and that of CDb+s from 2.45 to 2.70%. Five new cases were found among patients previously seronegative; two had minor abdominal symptoms and three were asymptomatic. The incidence of celiac disease in 2002-2005 was 0.23%, giving an annual incidence of 0.08% in this population. CONCLUSION: The prevalence of celiac disease was high in elderly people, but the symptoms were subtle. Repeated screening detected five biopsy-proven cases in three years, indicating that the disorder may develop even in the elderly. Increased alertness to the disorder is therefore warranted.

Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms

            (Visser, Rozing et al. 2009) Download

Autoimmune diseases are characterized by tissue damage and loss of function due to an immune response that is directed against specific organs. This review is focused on celiac disease (CD), an autoimmune enteropathy, and type 1 diabetes (T1D), a hyperglycosaemia caused by a destructive autoimmune process targeting the insulin-producing pancreatic islet cells. Even if environmental factors and genetic susceptibility are clearly involved in the pathogenesis of autoimmunity, for most autoimmune disorders there is no or little knowledge about the causing agent or genetic makeup underlying the disease. In this respect, CD represents a unique autoimmune disorder because a close genetic association with HLA-DQ2 or HLA-DQ8 haplotypes and, more importantly, the environmental trigger (the gliadin fraction of gluten-containing grains wheat, barley, and rye) are known. Conversely, the trigger for autoimmune destruction of pancreatic ss cells in T1D is unclear. Interestingly, recent data suggest that gliadin is also involved in the pathogenesis of T1D. There is growing evidence that increased intestinal permeability plays a pathogenic role in various autoimmune diseases including CD and T1D. Therefore, we hypothesize that besides genetic and environmental factors, loss of intestinal barrier function is necessary to develop autoimmunity. In this review, each of these components will be briefly reviewed.


References

Al-Toma, A., W. H. Verbeek, et al. (2007). "Update on the management of refractory coeliac disease." J Gastrointestin Liver Dis 16(1): 57-63.

Barton, S. H. and J. A. Murray (2008). "Celiac disease and autoimmunity in the gut and elsewhere." Gastroenterol Clin North Am 37(2): 411-28, vii.

Bethune, M. T. and C. Khosla (2008). "Parallels between pathogens and gluten peptides in celiac sprue." PLoS Pathog 4(2): e34.

Biagi, F., P. I. Bianchi, et al. (2009). "The impact of misdiagnosing celiac disease at a referral centre." Can J Gastroenterol 23(8): 543-5.

Caglar, E., S. Ugurlu, et al. (2009). "Autoantibody frequency in celiac disease." Clinics (Sao Paulo) 64(12): 1195-200.

Cinova, J., G. De Palma, et al. (2011). "Role of intestinal bacteria in gliadin-induced changes in intestinal mucosa: study in germ-free rats." PLoS One 6(1): e16169.

de Kauwe, A. L., Z. Chen, et al. (2009). "Resistance to celiac disease in humanized HLA-DR3-DQ2-transgenic mice expressing specific anti-gliadin CD4+ T cells." J Immunol 182(12): 7440-50.

Ergur, A. T., G. Ocal, et al. (2011). "Celiac Disease and Autoimmune Thyroid Disease in Children with Type 1 Diabetes Mellitus: Clinical and HLA-Genotyping Results." J Clin Res Pediatr Endocrinol 2(4): 151-4.

Geboes, K. and K. P. Geboes (2009). "Diagnosis and treatment of coeliac disease." F1000 Med Rep 1.

Jaeger, C., E. Hatziagelaki, et al. (2001). "Comparative analysis of organ-specific autoantibodies and celiac disease--associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects." Diabetes Care 24(1): 27-32.

Jones, S., C. D'Souza, et al. (2006). "Patterns of clinical presentation of adult coeliac disease in a rural setting." Nutr J 5: 24.

Kotze, L. M., A. P. Brambila Rodrigues, et al. (2009). "A Brazilian experience of the self transglutaminase-based test for celiac disease case finding and diet monitoring." World J Gastroenterol 15(35): 4423-8.

Leeds, J. S., A. D. Hopper, et al. (2008). "Coeliac disease." Br Med Bull 88(1): 157-70.

Mitea, C., E. M. Salentijn, et al. (2011). "A universal approach to eliminate antigenic properties of alpha-gliadin peptides in celiac disease." PLoS One 5(12): e15637.

Olsen, N. J., H. Prather, et al. (2011). "Autoantibody profiles in two patients with non-autoimmune muscle disease implicate a role for gliadin autoreactivity." Neuromuscul Disord 20(3): 188-91.

Papp, M., I. Foldi, et al. (2009). "Anti-microbial antibodies in celiac disease: trick or treat?" World J Gastroenterol 15(31): 3891-900.

Ravikumara, M., D. P. Tuthill, et al. (2006). "The changing clinical presentation of coeliac disease." Arch Dis Child 91(12): 969-71.

Rubio-Tapia, A. and J. A. Murray (2010). "Celiac disease." Curr Opin Gastroenterol 26(2): 116-22.

Rubio-Tapia, A. and J. A. Murray (2010). "Classification and management of refractory coeliac disease." Gut 59(4): 547-57.

Samaroo, D., F. Dickerson, et al. (2010). "Novel immune response to gluten in individuals with schizophrenia." Schizophr Res 118(1-3): 248-55.

Sapone, A., K. M. Lammers, et al. (2011). "Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity." BMC Med 9: 23.

Sapone, A., K. M. Lammers, et al. (2010). "Differential mucosal IL-17 expression in two gliadin-induced disorders: gluten sensitivity and the autoimmune enteropathy celiac disease." Int Arch Allergy Immunol 152(1): 75-80.

Sestak, K., L. Conroy, et al. (2011). "Improved Xenobiotic Metabolism and Reduced Susceptibility to Cancer in Gluten-Sensitive Macaques upon Introduction of a Gluten-Free Diet." PLoS One 6(4): e18648.

Silano, M., C. Agostoni, et al. (2010). "Effect of the timing of gluten introduction on the development of celiac disease." World J Gastroenterol 16(16): 1939-42.

Simula, M. P., R. Cannizzaro, et al. (2010). "PPAR signaling pathway and cancer-related proteins are involved in celiac disease-associated tissue damage." Mol Med 16(5-6): 199-209.

Spada, C., M. E. Riccioni, et al. (2008). "Capsule endoscopy in celiac disease." World J Gastroenterol 14(26): 4146-51.

Tack, G. J., W. H. Verbeek, et al. (2011). "Evaluation of Cladribine treatment in refractory celiac disease type II." World J Gastroenterol 17(4): 506-13.

Taplin, C. E., M. Mojibian, et al. (2011). "Antibodies to the wheat storage globulin Glo-3A in children before and at diagnosis of celiac disease." J Pediatr Gastroenterol Nutr 52(1): 21-5.

Tjon, J. M., J. van Bergen, et al. (2011). "Celiac disease: how complicated can it get?" Immunogenetics 62(10): 641-51.

van den Broeck, H. C., H. C. de Jong, et al. (2010). "Presence of celiac disease epitopes in modern and old hexaploid wheat varieties: wheat breeding may have contributed to increased prevalence of celiac disease." Theor Appl Genet 121(8): 1527-39.

van Herpen, T. W., S. V. Goryunova, et al. (2006). "Alpha-gliadin genes from the A, B, and D genomes of wheat contain different sets of celiac disease epitopes." BMC Genomics 7: 1.

Vande Voort, J. L., J. A. Murray, et al. (2009). "Lymphocytic duodenosis and the spectrum of celiac disease." Am J Gastroenterol 104(1): 142-8.

Vilppula, A., K. Kaukinen, et al. (2009). "Increasing prevalence and high incidence of celiac disease in elderly people: a population-based study." BMC Gastroenterol 9: 49.

Visser, J., J. Rozing, et al. (2009). "Tight junctions, intestinal permeability, and autoimmunity: celiac disease and type 1 diabetes paradigms." Ann N Y Acad Sci 1165: 195-205.