The toxicity of certain cereal proteins in coeliac disease

Cornell, Hugh J.; Townley, R. R. W.

doi:10.1136/gut.15.11.862

Cited by 46 publications

(15 citation statements)

References 11 publications

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“…These latter studies have pointed to the possibility of an enzyme deficiency in the small intestine of patients with coeliac disease and this is linked to evidence that fraction 9 of this digest contains a large proportion of the toxic components of gluten. This is supported by the results of similar experiments with rye gliadin and by the ability of fraction 9 to cause significant reduction in D-xylose absorption in coeliac patients in remission (Cornell and Townley, 1974 (Townley et al, 1973) provides further evidence that fraction 9 contains the causative agents in coeliac disease.…”

supporting

confidence: 53%

Further evidence of a primary mucosal defect in coeliac disease: In vitro mucosal digestion studies in coeliac patients in remission, their relatives, and control subjects

Cornell¹,

Rolles²

1978

Gut

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SUMMARY Subfractions of fraction 9, obtained from a peptic-tryptic-pancreatinic digest of wheat gliadin, were subjected to in vitro mucosal digestion and the filtrates examined for residual peptides. Small-intestinal mucosa from four groups of individuals were studied-eight patients with coeliac disease in remission; eight healthy controls; nine first degree relatives of patients with coeliac disease, and six children with recurrent diarrhoea investigated for possible coeliac disease, but in whom the diagnosis was excluded. The highest amounts of residual peptides (measured by scanning densitometer) were detected after digestion with mucosa from patients with coeliac disease and the lowest amounts with the control groups. The results obtained with the group of relatives fell between those of the coeliac disease and control groups, while the recurrent diarrhoea group overlapped the relatives and controls. The residual peptides were derived chiefly from the B-type subfractions of subfractions 1 and 2, obtained by ion-exchange chromatography of fraction 9. These subfractions are rich in glutamine/glutamic acid and proline and have a molecular weight (apparent) of not greater than 1500 Daltons. The results lend further support to the hypothesis of an enzyme deficiency in coeliac disease. A partial enzyme deficiency may exist in some first-degree relatives and in some children with recurrent diarrhoea but with histology of the small intestine within normal limits. HLA-B8 antigen is not correlated with this deficiency, but, when the two factors are associated, they could be related to the manifestation and severity of coeliac disease.The demonstration that an ultrafiltrate of a peptictryptic-pancreatinic digest of wheat gliadin was toxic to patients with coeliac disease (Bronstein et al., 1966) has led to mucosal digestion studies in vitro on fractions of this digest in an attempt to define the toxic substances (Cornell and Townley, 1973a). These latter studies have pointed to the possibility of an enzyme deficiency in the small intestine of patients with coeliac disease and this is linked to evidence that fraction 9 of this digest contains a large proportion of the toxic components of gluten. This is supported by the results of similar experiments with rye gliadin and by the ability of fraction 9 to cause significant reduction in D-xylose absorption in coeliac patients in remission (Cornell and Townley, 1974). Organ culture of small intestinal mucosa "Present address and address for reprints: Royal Melbourne

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supporting

confidence: 53%

Further evidence of a primary mucosal defect in coeliac disease: In vitro mucosal digestion studies in coeliac patients in remission, their relatives, and control subjects

Cornell¹,

Rolles²

1978

Gut

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“…Fraction 9 has been shown to be toxic in vivo to patients with celiac disease (Cornell and Townley, 1974). Separation of the peptides present in fraction 9 using HPLC (Cornell et al, 1992) and subsequent synthesis of peptides corresponding to those present in the subfractions has focused attention on two celiac-active peptides.…”

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In vitro mucosal digestion of synthetic gliadin-derived peptides in celiac disease

Cornell

Rivett

1995

J Protein Chem

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Two celiac-active synthetic peptides derived from the A-gliadin structure corresponding to residues 8-19 (LQPQNPSQQQPQ) and to 11-19 were digested in vitro with small intestinal mucosa from children with celiac disease in remission and from normal children. The products of digestion were separated into two fractions on the basis of M(r) < 400 and M(r) > 400 by gel permeation chromatography and subjected to amino acid analysis. After digestion of the dodecapeptide with celiac mucosa, 71 +/- 14% (molar) of the total digestion products remained in the M(r) > 400 fraction. Glutamine, proline, serine, and asparagine were the major amino acids present. Glutamine, proline, and leucine were the major amino acids in the M(r) < 400 fraction. The M(r) > 400 fraction from the celiac mucosal digestion of the nonapeptide was of similar composition to the corresponding fraction from the dodecapeptide and represented 78 +/- 15% of the total products. Digestion of the two peptides with normal mucosa gave lower amounts of products in the M(r) > 400 fraction, but they were of similar composition to the corresponding fractions from the celiac mucosal digestion. Peptides such as NPSQQP and QNPSQQQ may be present in the M(r) > 400 fractions since glutamine and proline are present in the approximate ratio of 2:1, respectively. The results indicate a defect in the mucosal digestion of peptides which are active in an animal model of celiac disease.

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“…cultures in the presence of barley peptides, and in two cultures in the presence of sorghum peptides. Columnar epithelium was observed in 13 culture segments in the presence of rye prolamine DISCUSSION peptides, in eight segments in the presence of oat peptides, in 14 Toxicity in celiac diseuse of cereals other than wheat. If the segments in the presence of barley peptides, and in 10 cultured results described in Table 1 are compared with those previously segments in the presence of sorghum prolamine peptides.…”

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confidence: 99%

An in Vitro Animal Model for the Study of Cereal Components Toxic in Celiac Disease

Auricchio¹,

Cardelli

Ritis³

et al. 1984

Pediatr Res

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ABSTRACT. Peptic-tryptic-Cotazym (PTC) digests were obtained, simulating in vivo protein digestion, from rice, maize, rye, oats, barley, and sorghum prolamines and tested on small intestine cultures from rat fetus. The PTC digests of the prolamine fractions from rice and maize, even when tested at a concentration as high as 0.5 mg/ml, did not affect in vitro differentiation and maturation of fetal rat jejunum that took place in vitro in a way comparable to what happens in vivo. On the contrary, the PTC digests of prolamines from rye, oats, barley, and sorghum were very active in slowing down in vitro development of fetal rat intestine. These results further strengthen earlier findings and all together show that there is a strong correlation between toxicity results of cereal and/or cereal components assessed with clinical trials or in vitro systems based on bioptic specimens of intestinal mucosa from celiac patients and with the culture of rat fetal intestine. Therefore, the rat fetal intestine culture is considered to be an adequate model for screening and investigating cereal peptides which are toxic for the celiac small intestinal mucosa. 18:1372-1378, 1984) Abbreviations PTC, peptic-tryptic-cotazym GP, gliadin peptides Celiac disease is an enteropathy occumng in genetically predisposed individuals (about 0.5/1000 of the general population) when wheat is a component of the diet. Under such circumstances, diarrhea and several malabsorption symptoms are observed in association with intestinal mucosa atrophy. Soon after the discovery that wheat is the environmental factor triggering the appearance of malabsorption symptoms, it was demonstrated that wheat toxicitv resulted from the gliadin protein fraction and that the other w h a t protein fractions, i.e. albumins, globulins, and glutenins, were harmless (6, 64, 65, 67). Later on it was shown (27, 28) that the ingestion of peptide mixtures obtained from wheat gluten after in vitro sequential digestion with proteolytic enzymes also induces the typical symptoms in patients affected by celiac disease. Moreover, clinical trials have shown Received July 29. 1983; February 7. 1984. Address correspondence to Salvatore Auricchio. Clinica Pediatrica, I1 Facolti di Medicina e Chirugia. Via Sergio Pansini 5 , 8013 1 Naples, Italy. This paper is dedicated by the authors to Professor Francesco Pocchiari on the occasion of his 60th birthday. (Pediatr Resthat, in addition to wheat, rye, barley, and probably oats also have toxicity (7, 41), whereas rice and maize are considered nontoxic and are usually used as wheat substitutes in the diet of celiac patients. It is presumed, but not demonstrated, that toxicity of cereals other than wheat is associated with prolamine fractions equivalent to gliadins in the grain of these other species.The detection and characterization of cereal components that are toxic in celiac disease are very difficult because no animal models exist for this disease. Falchuk et al. (19,20) have proposed the organ culture of human small intestinal biopsie...

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The toxicity of certain cereal proteins in coeliac disease

Cited by 46 publications

References 11 publications

Further evidence of a primary mucosal defect in coeliac disease: In vitro mucosal digestion studies in coeliac patients in remission, their relatives, and control subjects

Further evidence of a primary mucosal defect in coeliac disease: In vitro mucosal digestion studies in coeliac patients in remission, their relatives, and control subjects

In vitro mucosal digestion of synthetic gliadin-derived peptides in celiac disease

An in Vitro Animal Model for the Study of Cereal Components Toxic in Celiac Disease

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