Peripheral T cell response to A-gliadin in celiac disease: differential processing and presentation capacities of Epstein-Barr-transformed B cells and fibroblasts.
Celiac disease (CD) is a small intestinal disorder characterized by the malabsorption of most nutrients. Disease pathogenesis appears to be associated with immune-mediated pathology. Susceptibility is associated with genes coding for DQw2 class II molecules. In the present report we investigated T cell responses to A-gliadin (AGL), a major alpha-gliadin component known to activate disease. Gliadin-specific lines were generated from a CD patient and a normal donor. Three major points were revealed by the analysis of these T cells: (1) On the basis of mapping experiments using Epstein-Barr virus (EBV) lines and DR-transfected fibroblasts and DR-, DP-, and DQ-specific monoclonal antibodies (mAb), all responses appeared to be DR-restricted. Thus, in contrast to the strong association of disease susceptibility with DQ molecules, no DQ-restricted, gliadin-specific response was detectable. (2) Fine specificity analysis, using a panel of synthetic peptides spanning the entire alpha-gliadin component molecule, revealed that the clones derived from the normal donor were DR53-restricted and AGL 21-40-specific, while clones derived from the CD patient were DR7-restricted and peptide 1-20-specific. (3) Both whole AGL and AGL 1-20 were presented to the patient-derived clones with much higher efficiency by DDR-transfected fibroblasts than by EBV lines. These data suggested that fibroblasts processed this determinant efficiently, while EBV lines were unable to do so. Indeed, analysis of a panel of truncated AGL 1-20 analogs revealed that peptide AGL 1-8, which contained the minimal T cell epitope, was presented with equal efficiency by fixed or irradiated EBV and irradiated DR7-transfected fibroblasts.
Franco
A
A
Cytel, San Diego, California 92121.
Appella
E
E
Kagnoff
M F
MF
Chowers
Y
Y
Sakaguchi
K
K
Grey
H M
HM
Sette
A
A
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000938:Antigen-Presenting Cells / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology; D002446:Celiac Disease / Q000097:blood*; D002461:Cell Line, Transformed; D002472:Cell Transformation, Viral; D002999:Clone Cells; D000939:Epitopes / Q000032:analysis; D005260:Female; D005903:Gliadin / Q000097:blood / Q000276:immunology*; D004854:Herpesvirus 4, Human / Q000502:physiology; D006801:Humans; D008285:Major Histocompatibility Complex; D008297:Male; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*
D000939:Epitopes; D005903:Gliadin