Background-Villus atrophy is the most distinctive sign of untreated coeliac
disease (CD) and epithelial apoptosis is considered to be involved in this
stage of the coeliac lesion. The extent of villus atrophy is, however, not
homogeneous and patients with patchy or mild lesions have been described.
Aims-To address: (a) the degree of "patchiness" in untreated CD patients; a
nd (b) to clarify if apoptosis, and eventually which trigger drives it, cau
ses epithelial damage.
Patients-Twenty of 40 untreated, 14 treated coeliac patients, and 15 contro
ls received five or more multiple duodenal biopsies; the remaining 20 untre
ated CD patients had no more than three biopsies. Methods-All biopsies were
analysed to monitor the presence of a ((flat)) mucosa. Biopsies of 14 untr
eated, 10 treated coeliacs, and seven controls were cultured with or withou
t gliadin. DNA fragmentation was studied by terminal deoxynucleotidyl trans
ferase (TdT) mediated dUTP digoxigenin nick end labelling (TUNEL), and FAS
and Ki67 expression by immunohistochemistry. Antiendomysium antibodies (EMA
) were surveyed in biopsy culture supernatants.
Results-A pattern of patchy duodenal lesions was observed in all untreated
CD patients biopsied up to five times. High enterocyte FAS expression, and
a high number of TUNEL+ and Ki67+ enterocytes were detected in areas with v
illus atrophy but not in those with a normal morphology (p<0.001). Converse
ly, EMA in culture supernatants and signs of immunological activation were
present in all untreated CD biopsies. In vitro gliadin challenge increased
the number of TUNEL+ and Ki67+ enterocytes (p<0.001 v cultures with medium
alone) only in "flat" biopsies. Neutralising anti-FAS monoclonal antibodies
were found to control gliadin induced enterocyte apoptosis (p>0.01) while
agonist anti-FAS monoclonal antibody increased it (p<0.001).
Conclusions-Patchy lesions are observed in untreated CD mucosa and epitheli
al FAS engagement is a key trigger in driving villus atrophy in CD.