Gluten-sensitive Enteropathy

Falchuk, Z. Myron; Nelson, David L.; Katz, Aubrey J.; Bernardin, John E.; Kasarda, Donald D.; Hague, Norma E.; Strober, Warren

doi:10.1172/jci109848

Cited by 42 publications

(6 citation statements)

References 16 publications

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“…In vivo and in vitro studies have identified α-gliadins as a major source of toxicity for CD patients 26272829. Our study confirms that these proteins are also a major focus of the intestinal T cell response to gluten.…”

Section: Discussionsupporting

confidence: 79%

The Intestinal T Cell Response to α-Gliadin in Adult Celiac Disease Is Focused on a Single Deamidated Glutamine Targeted by Tissue Transglutaminase

Arentz‐Hansen

Körner²,

Molberg

et al. 2000

The Journal of Experimental Medicine

609

485

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The great majority of patients that are intolerant of wheat gluten protein due to celiac disease (CD) are human histocompatibility leukocyte antigen (HLA)-DQ2+, and the remaining few normally express HLA-DQ8. These two class II molecules are chiefly responsible for the presentation of gluten peptides to the gluten-specific T cells that are found only in the gut of CD patients but not of controls. Interestingly, tissue transglutaminase (tTG)-mediated deamidation of gliadin plays an important role in recognition of this food antigen by intestinal T cells. Here we have used recombinant antigens to demonstrate that the intestinal T cell response to α-gliadin in adult CD is focused on two immunodominant, DQ2-restricted peptides that overlap by a seven-residue fragment of gliadin. We show that tTG converts a glutamine residue within this fragment into glutamic acid and that this process is critical for T cell recognition. Gluten-specific T cell lines from 16 different adult patients all responded to one or both of these deamidated peptides, indicating that these epitopes are highly relevant to disease pathology. Binding studies showed that the deamidated peptides displayed an increased affinity for DQ2, a molecule known to preferentially bind peptides containing negatively charged residues. Interestingly, the modified glutamine is accommodated in different pockets of DQ2 for the different epitopes. These results suggest modifications of anchor residues that lead to an improved affinity for major histocompatibility complex (MHC), and altered conformation of the peptide–MHC complex may be a critical factor leading to T cell responses to gliadin and the oral intolerance of gluten found in CD.

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Section: Discussionsupporting

confidence: 79%

The Intestinal T Cell Response to α-Gliadin in Adult Celiac Disease Is Focused on a Single Deamidated Glutamine Targeted by Tissue Transglutaminase

Arentz‐Hansen

Körner²,

Molberg

et al. 2000

The Journal of Experimental Medicine

609

485

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“…Cultured intestinal epithelial tissues from celiac patients have been tested also by Jos et al (36)(37)(38) who showed that peptides derived from purified gliadin fractions including a-, P-, 7-, and w-gliadins were toxic in celiac disease. These results were consistent with those by Hekkens et al (32) who demonstrated that an a-gliadin fraction, coded A-gliadin (10,49), was capable of producing changes in epithelial tissue characteristic of celiac disease when instilled directly into the small intestine of celiac patients and with those by Falchuk et al (19) showing that this fraction had adverse effects on biopsied intestinal epithelium. Huge and co-workers (24)(25)(26) have developed a morphological, morphometric, and biochemical assessment of human duodenal biopsies from celiac patients maintained in organ culture and have tested with this in vitro system several gliadin fractions including a-gliadin and Frazer's fraction I11 and subfractions.…”

supporting

confidence: 92%

“…Falchuk et al (19,20) have proposed the organ culture of human small intestinal biopsies as an in vitro model of celiac disease. Jejunal specimens obtained from patients with active enteropathy show morphological and biochemical improvement when cultured in a gliadin-free medium.…”

Section: (Pediatr Resmentioning

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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“…They have also shown that cortisol appears to provide some protection from the effects in vitro of GFIII on untreated coeliac mucosa, suggesting that cortisol is acting through its immunosuppressant effects [42]. They have more recently shown that the response of the untreated coeliac mucosa in vitro to GFIII is related to the HLA B8 status of the patients, once again providing a link with immunopathological mechanisms [43].…”

Section: Human Mucosamentioning

confidence: 98%

Organ Culture in the Study of the Gastrointestinal Tract in Health and Disease

Howdle

1983

Clinical Science

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Gluten-sensitive Enteropathy

Cited by 42 publications

References 16 publications

The Intestinal T Cell Response to α-Gliadin in Adult Celiac Disease Is Focused on a Single Deamidated Glutamine Targeted by Tissue Transglutaminase

The Intestinal T Cell Response to α-Gliadin in Adult Celiac Disease Is Focused on a Single Deamidated Glutamine Targeted by Tissue Transglutaminase

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

Organ Culture in the Study of the Gastrointestinal Tract in Health and Disease

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