Identification of a gliadin T-cell epitope in coeliac disease: general importance of gliadin deamidation for intestinal T-cell recognition.
Coeliac disease probably results from a T-cell response to wheat gliadin and is associated to HLA-DQ2. No gliadin epitopes recognized by intestinal T cells have yet been identified, limiting our understanding of the pathogenesis. Gut-lesion-derived DQ2-restricted T cells from coeliac disease patients were used to identify an epitope within a purified gamma-type gliadin. The structure of the epitope was characterized by mass spectrometry and verified by synthesis. The epitope (QPQQSFPEQQ) results from deamidation of a distinct glutamine in the native structure. This deamidation is important for binding to DQ2 and T-cell recognition. Other gut-derived T cells fail to recognize the epitope, although deamidation of unfractionated gliadin enhances the response of all gut-derived DQ2-restricted T cells isolated from several patients. Several DQ2-restricted T-cell epitopes exist, but for all of them deamidation of glutamine residues appears to be critical for creation of active epitopes. Native gliadin has few negatively charged residues but is very rich in glutamine. After deamidation gliadin becomes a rich source of DQ2 epitopes thus providing a link between DQ2, gliadin and coeliac disease. The necessity for modification may have general immunological relevance.
Department of Medical Biochemistry and Genetics, The Panum Institute, University of Copenhagen, Denmark.
H
H
Sjöström
K E
KE
Lundin
O
O
Molberg
R
R
Körner
S N
SN
McAdam
D
D
Anthonsen
H
H
Quarsten
O
O
Norén
P
P
Roepstorff
E
E
Thorsby
L M
LM
Sollid
D000577:Amides / Q000378:metabolism; D000595:Amino Acid Sequence; D002446:Celiac Disease / Q000276:immunology*; D000939:Epitopes; D005903:Gliadin / Q000276:immunology* / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism; D006683:HLA-DQ Antigens / Q000378:metabolism; D006801:Humans; D007422:Intestines / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D000577:Amides; D000939:Epitopes; D006683:HLA-DQ Antigens; D005973:Glutamine; D005903:Gliadin