Structural basis for gluten intolerance in celiac sprue.

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Science 2002 Sep 27;297(5590):2275-9

 

Structural basis for gluten intolerance in celiac sprue.

Shan L, Molberg O, Parrot I, Hausch F, Filiz F, Gray GM, Sollid LM, Khosla

C.

Department of Chemical Engineering, Department of Medicine, Department of

Chemistry, and, Department of Biochemistry, Stanford University, Stanford,

CA 94305-5025, USA., Institute of Immunology, Rikshospitalet, University of

Oslo, N-0027 Oslo, Norway.

Celiac Sprue, a widely prevalent autoimmune disease of the small intestine,

is induced in genetically susceptible individuals by exposure to dietary

gluten. A 33-mer peptide was identified that has several characteristics

suggesting it is the primary initiator of the inflammatory response to

gluten in Celiac Sprue patients. In vitro and in vivo studies in rats and

humans demonstrated that it is stable toward breakdown by all gastric,

pancreatic, and intestinal brush-border membrane proteases. The peptide

reacted with tissue transglutaminase, the major autoantigen in Celiac Sprue,

with substantially greater selectivity than known natural substrates of this

extracellular enzyme. It was a potent inducer of gut-derived human T cell

lines from 14 of 14 Celiac Sprue patients. Homologs of this peptide were

found in all food grains that are toxic to Celiac Sprue patients but are

absent from all nontoxic food grains. The peptide could be detoxified in in

vitro and in vivo assays by exposure to a bacterial prolyl endopeptidase,

suggesting a strategy for oral peptidase supplement therapy for Celiac

Sprue.

PMID: 12351792 [PubMed - in process]