Celiac Disease Gluten Research Articles

S1263 Implications of Enzymatic Detoxification of Food Gluten in Coeliac Disease

S1263 Implications of Enzymatic Detoxification of Food Gluten in Coeliac Disease

A treatment that abolishes the immunotoxicity of gluten in celiac disease

A treatment that abolishes the immunotoxicity of gluten in celiac disease

Food questionnaire for assessment of infant gluten consumption

In light of the possibly preventive role of timing and amount of gluten in celiac disease, it would be helpful to have a questionnaire to assess the gluten intake in infants. Development and validation of a food questionnaire to assess gluten consumption in healthy infants aged 0-12 months (FQ-gluten). A food frequency questionnaire, previously developed for the Generation R study, was adapted for the assessment of gluten intake. The results of a 2-day food record (FR) were compared with the results of this FQ-gluten. Eighty-seven parents filled in the FR and the FQ-gluten. The number of children who consume gluten and who are breast-fed is higher, reported in the FQ-gluten. The amount of gluten is comparable from the age of 3 up to 10 months, but at 11 and 12 months a higher gluten intake is reported using the FR, probably due to a larger variety of food products not detectable by the FQ-gluten. However, there is a high agreement in the food groups (Cohens' kappa=0.6-0.8). This new, short, standardized, validated and easy to use FQ-gluten may be a useful instrument to assess gluten intake in infants, both at the individual and at the population level. The use of this method by investigators in other countries provides the opportunity for a better comparison of the results of gluten consumption in (co-operative) studies throughout different countries.

The immune recognition of gluten in coeliac disease.

Coeliac disease, the most common intestinal disorder of western populations, is an autoimmune enteropathy caused by an abnormal immune response to dietary gluten peptides that occurs in genetically susceptible individuals carrying the HLA-DQ2 or -DQ8 haplotype. Despite the recent progresses in understanding the molecular mechanisms of mucosal lesions, it remains unknown how increased amounts of gluten peptides can enter the intestinal mucosa to initiate the inflammatory cascade. Current knowledge indicates that different gluten peptides are involved in the disease process in a different manner, some fragments being 'toxic' and others 'immunogenic'. Those defined as 'toxic' are able to induce mucosal damage either when added in culture to duodenal endoscopic biopsy or when administered in vivo, while those defined as 'immunogenic' are able to specifically stimulate HLA-DQ2- or DQ8-restricted T cell clones isolated from jejunal mucosa or peripheral blood of coeliac patients. These peptides are able to trigger two immunological pathways: one is thought to be a rapid effect on the epithelium that involves the innate immune response and the other represents the adaptive immune response involving CD4+ T cells in the lamina propria that recognize gluten epitopes processed and presented by antigen presenting cells. These findings are the subject of the present review.

Coeliac disease—a meeting point for genetics, immunology, and protein chemistry

Coeliac disease is caused by a genetically determined, specific immune response to antigens present in wheat gluten. This immune response may be focused on a limited region of the alpha gliadin component of gluten, and previous studies have suggested that the generation of epitopes for recognition by CD4+ T cells requires deamidation of the protein by tissue transglutaminase. However, it had not previously been shown that candidate epitope peptides could be generated from gluten in vivo, or that these epitopes were selective products of physiological digestion of gluten by tissue transglutaminase. Lu Shan and colleagues (Science 2002; 297: 2275-79) have recently shown that a 33-mer peptide containing known peptide epitopes is generated by digestion with intestinal enzymes in vivo and in vitro, producing a highly stimulatory antigen for CD4+ T cells. The resulting peptide is resistant to further digestion of a gliadin by intestinal brush border enzymes and is a highly specific substrate for deamidation by tissue transglutaminase. Because the 33-mer peptide is not present in cereal proteins that do not cause coeliac disease, Shan and colleagues suggest that generation of this peptide in vivo underlies the specific association between gluten, immune responsiveness, and tissue transglutaminase in coeliac disease. In addition, the 33-mer peptide can also be produced by digestion of gluten by bacterial prolyl endopeptidases, suggesting possible future strategies for generating non-toxic varieties of gluten. WHERE NEXT? It is now important to determine whether this 33-mer peptide and this pathway accounts for all immune recognition of wheat gluten in coeliac disease, and to explore if the tissue transglutaminase homologues found in other organisms can be used to produce non-toxic preparations of wheat.

Analysis and clinical effects of gluten in coeliac disease.

The prolamin working group coordinates research on laboratory gluten analysis in food and on clinical evaluation of patient sensitivity to prolamins. As an observer organization to the Codex Alimentarius Commission, the group summarizes current data on analysis and effects of gluten in coeliac disease. All types of gliadin, the ethanol-soluble fraction of gluten, contain the coeliac-active factor. However, coeliac toxicity and immunogenicity (humoral and cellular) of various prolamins are not identical in coeliac patients. There are no conclusive data on the threshold of gluten sensitivity of coeliac patients. Information as to the long-term risk to coeliac patients exposed to small doses of gliadin is lacking. Therefore, every effort should be made to keep the diet of coeliac patients as gluten-free as possible. The prolamin group is currently evaluating a new enzyme-linked immunosorbent assay (ELISA) protocol for gluten analysis that could serve as a basis for further Codex regulations. The group recommends adherence to a single Codex limit for gluten-free foods. The current limit of 200 ppm gluten is questionable and requires reconsideration based on new information that will be available soon.

Intestinal lymphangiectasia associated with deep vein thrombosis. First results in treatment with octreotide

Background & Aim: Intolerance to dietary gluten in celiac disease has traditionally been considered to persist lifelong, although the possibility of transient intolerance has been proposed. Whether patients can 'grow out' of true celiac disease and the frequency with which this may occur, is unclear. We performed a detailed review of clinical, serologic and histologic evidence for gluten intolerance in adult subjects over two decades after they were diagnosed as celiac in childhood. Methods: 103 patients diagnosed with celiac disease in childhood in a pediatric unit with special interest in the condition were contacted and reviewed 23-39 years after their original diagnosis. Original diagnostic criteria used at the time were histologic evidence of celiac disease above the age of 24 months, a clinical response to a gluten-free diet, and proven clinical and histologic response to gluten exclusion. After reassessment in adulthood, we offered endoscopic distal duodenal re-biopsy to patients who were not adhering to a gluten-free diet and in whom endomysial antibodies were negative. Results: Six patients have been identified who initially fulfilled traditional criteria for celiac disease but now have no evidence for gluten sensitivity on reassessment in adulthood, while on a full gluten-containing diet. Each patient presented with malabsorption within the first 2 years of life and had a subsequent jejunal biopsy that showed moderate (l/6) to severe villous atrophy (5/6). Evidence for malabsorption resolved on a gluten-free diet, and each had a subsequent small bowel biopsy 1-11 years later which, although improved, was still abnormal (partial villous atrophy in 3 cases and increased intraepithelial lymphocytes in the other 3 cases). In adulthood, while taking a full gluten-containing diet, none of the patients now have evidence of malabsorption, serum endomysial antibodies are negative, and distal duodenal biopsies have been normal in all. Conclusion: The observations provide evidence in favor of the occurrence of true transient gluten intolerance in some patients with apparent classical childhood celiac disease. That each patient had two abnormal biopsies at different intervals during childhood (albeit with improvement on gluten restriction) supports the validity of the original diagnosis and suggests that the initial abnormality was not due to one of the mimics of celiac disease in childhood. The results also support the view that the requirement for rigid adherence to a gluten-free diet may diminish and resolve in adulthood in a proportion of patients.

A gastroenterological list for the millennium.

To determine the 10 most significant advances in gastroenterology during this century as we approach the millennium, the authors polled 50 distinguished active clinicians and leading researchers in the field, including workers in liver disease and the pathology of the gut and its associated glands. Forty-five persons (90%) responded and listed 58 different items. These were then organized into four groups: group A, with 10 categories that received between 42 and 11 votes; group B, with 10 categories that received between 10 and 3 votes; group C, with 3 items receiving 2 votes each; and group D, with the remaining 14 items receiving 1 vote each. The respondents did not indicate their choices in rank order. The top 10 leading choices (group A, containing between 42 and 11 votes) included Helicobacter pylori, fiberoptic endoscopy, gastrointestinal imaging by radiograph and computed tomographic scan, Australia antigen including vaccines for hepatitis A and B, the molecular basis of colon cancer, liver transplantation, laparoscopic-assisted surgery, therapy for peptic ulcer disease including H2-receptor antagonists and proton pump inhibitors, the discovery of gastrointestinal hormones beginning with secretin, and lastly the discovery of the role for gluten in celiac disease.

New Diagnostic Test for Celiac Disease

Source: Troncone R, Maurano F, Rossi M, Micillo M, Greco L, Auricchio R, Salerno G, Salvatore F, Sacchetti L. IgA Antibodies to tissue transglutaminase: An effective diagnostic test for celiac disease. J Pediatr. 1999;134(2):166–171.Troncone et al have developed and validated an ELISA to measure serum antibodies to tissue transglutaminase (tTG). tTG is an autoantigen recognized by endomysial antibodies which are synthesized in patients with celiac disease (CD). Endomysial antibodies were also assayed using indirect immunofluorescence techniques. The authors studied 111 Neapolitan patients with suspected CD (mean age 5.7 years). Forty-eight patients met defined criteria for the diagnosis of CD, while 63 others were symptom-matched controls. All patients underwent small bowel biopsy for diagnostic confirmation. Additionally, the sera of 33 confirmed CD patients, on a gluten-free diet for varying periods of time, were examined. Finally, the authors examined sera for tTG and antiendomysial antibodies in 10 of the 33 CD patients who were gluten challenged. Their results indicate that tTG has a high sensitivity and specificity in CD, comparable to antiendomysial antibodies. Furthermore, tTG appears to be a useful tool in monitoring dietary compliance to a gluten-free diet.Although the above article may, at first, appear to be of more interest to our bench research colleagues and laboratory workers, there are important “take home” lessons to be learned. This study has confirmed the work of Dieterich et al1 by concluding that tTG is very sensitive and specific in diagnosing celiac disease (CD) and monitoring dietary compliance to a gluten-free diet in a mixed population of children, adolescents, and adults.Currently, antiendomysial antibodies are the serological “gold standard” for CD, having greater than 98% sensitivity and specificity.2–3 However, the drawback to this particular test is that it is technically difficult to interpret and uses monkey esophagus as a substrate. The ELISA for tTG appears to be easier to interpret and a newly developed cloned human tTG may yield even more improved sensitivity and specificity.4Results of the study discussed above indicate that antibodies to tTG have a 98% specificity and a 92% sensitivity for CD. The concordance between antiendomysial antibody and tTG was 95%. Dietary challenge with gluten in CD resulted in a rise in tTG that was parallel to the rise in antiendomysial antibodies. In conclusion, the development of a new ELISA utilizing tTG appears to have considerable promise in the diagnosis and treatment of CD. Commercial testing is now available for tTG and, with anticipated improvements in the ELISA, it should soon become a routine part of a failure-to-thrive evaluation in children with appropriate symptoms. Utilization of this test, once it is validated in large-scale clinical trials, will avoid the necessity of testing for an antigliaden or antiendomysial antibody.The question, again, is one of cost/benefit and availability of this test compared to the now readily available gold standards of the antigliadin and antiendomysial antibodies and the 24-karat gold standard of the small bowel biopsy. Keep your eyes “glutened” for more information on this new diagnostic test.

Cytotoxicity of lectins on rat intestinal mucosa enhanced by neuraminidase.

The lectins wheat germ agglutinin (WGA) and Concanavalin A (ConA) were perfused into an isolated small intestinal segment alone or after prior perfusion with neuraminidase for a 10 day period in the rat. Intestinal morphometry, intraepithelial Lymphocyte (IEL) and round cell content as well as digestive capacity was measured in the loop and in the adjacent segments. Both lectins induce a mucosal transformation in all segments but ConA is more effective than WGA. Pre-incubation with neuraminidase enhances the action of ConA throughout, whereas only a partial enhancement of the effect of WGA is observed. The mucosal transformation after long term perfusion with the lectins resembles the hyperregenerative adaptation of the mucosa due to gluten in coeliac disease and may thus serve as an animal model for this disease.

Leucocyte migration inhibition test in coeliac disease - a reappraisal.

Results of the direct leucocyte migration inhibition (LMI) test using gluten fraction III as antigen were unaffected by incorporation of puromycin into the culture medium at concentrations shown to prevent lymphokine mediated inhibition. Results of the LMI test performed with purified polymorphs were similar to and correlated with results of the standard LMI test using mixed leucocytes in both coeliacs and controls. The addition of purified T lymphocytes did not increase migration inhibition. Normal leucocytes incubated with serum from coeliac patients and washed showed marked migration inhibition when incubated with gluten fraction III. This sensitisation of normal leucocytes was prevented by preincubation with aggregated human IgG. These results suggest that leucocyte migration inhibition by gluten in coeliac disease is not due to lymphokine production by sensitised lymphocytes but is caused by cytophilic antibody.

Positive Skin Reactions to Gluten in Coeliac Disease

Following intradermal challenge with a peptic-tryptic digest of gluten, visible Arthus-type skin reactions were observed in 33 per cent of a group of 55 adults with coeliac disease. Of the 23 with untreated disease positive skin reactions occurred in 52 per cent. There was an invariable association between serum gluten antibodies and the presence of a skin reaction to gluten, indicating that gluten antibody combination with gluten in the skin provides the basis of the skin response. Since no false positive reactions were found in 52 normal controls, skin testing with gluten may provide a useful adjunct to the diagnosis and management of coeliac disease, especially in the outpatient department.

Immunoglobulins and malabsorption.

SummarySome of the associations between abnormal metabolism of immunoglobulins and intestinal malabsorption have been reviewed. Particular attention has been drawn to the following:1. In immunoglobulin losing enteropathies associated with dilated intestinal lymphatics, malabsorption of long chain fatty acids may occur.2. Large amounts of the heavy chain of the IgA molecule (alpha chain) are present in the serum of patients with malabsorption due to the rare lymphoma of the small bowel known as alpha chain disease.3. In coeliac disease gluten challenge results in increased synthesis of IgA and IgM antibodies to gluten by the jejunal mucosa.4. In certain immunoglobulin deficiency syndromes, particularly those in which there is deficiency of IgA, there is often malabsorption and this may be associated with Giardia lamblia infection, small intestinal villous atrophy and nodular lymphoid hyperplasia.

Plasma food antibodies during withdrawal and reintroduction of dietary gluten in coeliac disease.

Plasma food antibodies during withdrawal and reintroduction of dietary gluten in coeliac disease.

Coproantibodies to Gluten in Celiac Disease

Coproantibodies to the peptic-tryptic digest of wheat (fraction III) were demonstrated in three patients with celiac disease but were not demonstrated in 14 control subjects with various diarrheal diseases nor in six normal subjects. This preliminary report suggests that the polypeptides of gluten may elicit the production of antibodies within the gut and that the intestine continues to secrete these antibodies for extended periods even in the apparent absence of ingested wheat proteins. These copro-antibody studies are being further evaluated as to their specificity in the diagnosis of celiac disease.

Coproantibodies to gluten in celiac disease

Coproantibodies to gluten in celiac disease

Studies on the mechanism of destruction of the toxic action of wheat gluten in coeliac disease by crude papain

The toxic action of wheat gluten on two patients was eliminated after predigestion of gluten by crude papain. This change is thought to be due to an enzyme which liberates...