Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation.
Celiac disease driven by an antigluten T cell response is strongly associated with the histocompatibility antigen HLA-DQ2.5 but is barely associated with HLA-DQ2.2. Yet these molecules have very similar peptide-binding motifs and both present gluten T cell epitopes. We found that DQ2.5(+) antigen-presenting cells (APCs) had greater stability of bound peptides and protracted gluten presentation relative to that of DQ2.2(+) cells. The improved ability of DQ2.5 to retain its peptide cargo can be ascribed to a polymorphism of DQalpha22 whereby DQ2.5 (tyrosine) can establish a hydrogen bond to the peptide main chain but DQ2.2 (phenylalanine) cannot. Our findings suggest that the kinetic stability of complexes of peptide and major histocompatibility complex (MHC) is of importance for the association of HLA with disease.
Fallang
Lars-Egil
LE
Centre for Immune Regulation, Institute of Immunology, University of Oslo and Oslo University Hospital Rikshospitalet, Oslo, Norway.
Bergseng
Elin
E
Hotta
Kinya
K
Berg-Larsen
Axel
A
Kim
Chu-Young
CY
Sollid
Ludvig M
LM
D017951:Antigen Presentation / Q000276:immunology*; D000938:Antigen-Presenting Cells / Q000276:immunology*; D002446:Celiac Disease / Q000235:genetics* / Q000276:immunology; D002460:Cell Line; D005434:Flow Cytometry; D020022:Genetic Predisposition to Disease; D005983:Glutens / Q000276:immunology*; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006801:Humans; D006860:Hydrogen Bonding; D008869:Microtubule-Associated Proteins / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000276:immunology; D012307:Risk Factors; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014162:Transfection
C497850:CLASP1 protein, human; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; D008869:Microtubule-Associated Proteins; D010455:Peptides; D005983:Glutens