Children with Celiac Disease Express Inducible Nitric Oxide Synthase in the Small Intestine during Gluten Challenge

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Abstract
Childhood celiac disease in Sweden is presently seen at an incidence of around 1/250 and is thus one of the commonest chronic diseases in children. It has recently been shown that children with untreated celiac disease have increased levels of nitrate/nitrite in the urine, most likely reflecting an increased production of nitric oxide in the inflamed mucosa. Nitric oxide is produced from L-arginine by an inducible or a constitutive nitric oxide synthase. The inducible nitric oxide synthase (iNOS) can be stimulated in various cells by, for instance, inflammatory mediators. The present study has been done to find a possible source of nitric oxide in the small intestine that could result in the increased levels of nitrate/nitrite in the urine in children with active celiac disease. Small-intestinal biopsy specimens from children with active celiac disease were labeled with rabbit-anti-human antibodies to iNOS and visualized with fluorescent pig anti-rabbit antibodies. The specimens were then analyzed with confocal microscopy to assess the labeling pattern. In all of seven specimens from children with increased levels of nitrate/nitrite in the urine, we detected antibodies to iNOS, whereas in five of six control specimens--that is, from children with normal nitrate/nitrite levels--we could not detect any iNOS. Children with active celiac disease have a gluten-induced nitric oxide production in the small intestine reflected by increased urine levels of nitrate/nitrite and iNOS expression in the intestine. We conclude that the increased production of nitric oxide could presumably, directly or indirectly, result in injury of the small-intestinal tissue.