The toxicity of high molecular weight glutenin subunits of wheat to patients with coeliac disease.
OBJECTIVE
The ability of the gliadin fraction of wheat gluten to exacerbate coeliac disease is well documented. We investigated the possible toxicity of high molecular weight glutenin subunits (HMW-GS) in coeliac disease in vitro using gluten-sensitive T cells, and in vivo with challenge studies in patient volunteers.


METHODS
A mixture of four HMW-GS was chemically separated from wheat flour and checked for purity by HPLC, SDS-PAGE and ELISA. T-cell lines, grown up from small intestinal biopsies from coeliac patients (n=17), were tested for their reactivity to HMW-GS. Adults with coeliac disease and who were on a gluten-free diet (n=3) underwent in-vivo challenges with HMW-GS. Duodenal biopsies, taken prior to the challenge and at intervals up to 6 h afterwards, were assessed for morphology, intra-epithelial lymphocyte count, and interleukin 15 (IL-15) expression, by immunohistochemistry.


RESULTS
T-cell lines from 11 of 17 patients were stimulated by HMW-GS. There was a significant change in small intestinal morphology 4 h after commencing infusions with HMW-GS in all three subjects. For example villus height to crypt depth ratios were reduced in the three patients from 3.0+/-0.5 to 1.29+/-0.2, 2.53+/-0.7 to 0.81+/-0.6 and 3.0+/-0.7 to 1.85+/-0.3, P<0.0001 in all cases. There was increased expression of IL-15 in the small intestine from 2 h after the HMW-GS challenges.


CONCLUSIONS
Mixed HMW-GS stimulate T-cell lines from some coeliac patients and exacerbate coeliac disease in vivo, inducing expression, within 2 h, of IL-15. This suggests an innate immune response to these proteins.
Dewar
David H
DH
Rayne Institute (KCL Division of Nutrition), St Thomas' Hospital, Lambeth Palace Road, London, UK.
Amato
Massimo
M
Ellis
H Julia
HJ
Pollock
Emma L
EL
Gonzalez-Cinca
Nuria
N
Wieser
Herbert
H
Ciclitira
Paul J
PJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D002446:Celiac Disease / Q000276:immunology / Q000473:pathology*; D002460:Cell Line; D018753:Diet, Protein-Restricted; D000939:Epitopes / Q000276:immunology; D005260:Female; D005983:Glutens / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology / Q000302:isolation & purification; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D019409:Interleukin-15 / Q000032:analysis; D007413:Intestinal Mucosa / Q000276:immunology / Q000473:pathology; D007421:Intestine, Small / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008970:Molecular Weight; D013601:T-Lymphocytes / Q000276:immunology; D014908:Triticum / Q000737:chemistry*
D000939:Epitopes; D019409:Interleukin-15; D005983:Glutens; D007371:Interferon-gamma; C037302:glutenin