Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 2, Issue 41, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3001012
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Funding
- National Health and Medical Research Council (NHMRC)
- Australian and New Zealand Coeliac Research Fund
- German National Genome Research Network by the Federal Ministry of Education and Research [PBF-S19T10]
- Wellcome Trust [GR068094MA]
- Juvenile Diabetes Research Foundation [10-2006-261]
- Australian Research Council
- Walter and Eliza Hall Institute
- Melbourne Health
- Lions Cancer Council
- NHMRC [406656]
- Coeliac UK Project
- Graham Bird Memorial Fund (Oxford)
- Oxford University College
- BTG International plc, Nexpep Pty Ltd.
- NHMRC Independent Research Institutes [361646]
- Victorian State Government Operational Infrastructure Support
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Celiac disease is a genetic condition that results in a debilitating immune reaction in the gut to antigens in grain. The antigenic peptides recognized by the T cells that cause this disease are incompletely defined. Our understanding of the epitopes of pathogenic CD4(+) T cells is based primarily on responses shown by intestinal T cells in vitro to hydrolysates or polypeptides of gluten, the causative antigen. A protease-resistant 33-amino acid peptide from wheat alpha-gliadin is the immunodominant antigen, but little is known about the spectrum of T cell epitopes in rye and barley or the hierarchy of immunodominance and consistency of recognition of T cell epitopes in vivo. We induced polyclonal gluten-specific T cells in the peripheral blood of celiac patients by feeding them cereal and performed a comprehensive, unbiased analysis of responses to all celiac toxic prolamins, a class of plant storage protein. The peptides that stimulated T cells were the same among patients who ate the same cereal, but were different after wheat, barley, and rye ingestion. Unexpectedly, a sequence from omega-gliadin (wheat) and C-hordein (barley) but not alpha-gliadin was immunodominant regardless of the grain consumed. Furthermore, T cells specific for just three peptides accounted for most gluten-specific T cells, and their recognition of gluten peptides was highly redundant. Our findings show that pathogenic T cells in celiac disease show limited diversity and therefore suggest that peptide-based therapeutics for this disease and potentially other strongly human leukocyte antigen-restricted immune diseases should be possible.
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