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Structural Basis for Gluten Intolerance in Celiac Sprue
Lu Shan,1Øyvind Molberg,5Isabelle Parrot,1Felix Hausch,1Ferda Filiz,1Gary M. Gray,2Ludvig M. Sollid,5Chaitan Khosla134*
Celiac Sprue, a widely prevalent autoimmune disease of
the small intestine, is induced in genetically susceptible individualsby exposure to dietary gluten. A 33-mer peptide was identifiedthat has
several characteristics suggesting it is the primaryinitiator of the
inflammatory response to gluten in Celiac Spruepatients. In vitro and
in vivo studies in rats and humans demonstratedthat it is stable
toward breakdown by all gastric, pancreatic,and intestinal
brush-border membrane proteases. The peptide reactedwith tissue
transglutaminase, the major autoantigen in CeliacSprue, with
substantially greater selectivity than known naturalsubstrates of this
extracellular enzyme. It was a potent inducerof gut-derived human T
cell lines from 14 of 14 Celiac Sprue patients.Homologs of this
peptide were found in all food grains that aretoxic to Celiac Sprue
patients but are absent from all nontoxicfood grains. The peptide
could be detoxified in in vitro and invivo assays by exposure to a
bacterial prolyl endopeptidase, suggestinga strategy for oral
peptidase supplement therapy for Celiac Sprue.
1 Department of Chemical Engineering,
2 Department of Medicine,
3 Department of Chemistry, and
4 Department of Biochemistry, Stanford University,
Stanford, CA 94305-5025, USA.
5 Institute of
Immunology, Rikshospitalet, University of Oslo, N-0027 Oslo,
Norway.
*
To whom correspondence should be addressed. E-mail:
ck{at}chemeng.stanford.edu
The editors suggest the following Related Resources on Science sites:
In Science Magazine
LETTERS
Frits Koning, Willemijn Vader;, Lu Shan, Øyvind Molberg, Gary M. Gray, Ludvig M. Sollid, and Chaitan Khosla (24 January 2003) Science299 (5606), 513.
[DOI: 10.1126/science.299.5606.513] |Full Text »|PDF »
PERSPECTIVES
Detlef Schuppan and Eckhart G. Hahn (27 September 2002) Science297 (5590), 2218.
[DOI: 10.1126/science.1077572] |Summary »|Full Text »|PDF »
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