Celiac.com 06/20/2014 - Celiac disease is a T cell–mediated disease triggered by the protein in wheat gluten. More than 9 out of 10 of people with celiac disease carry human leukocyte antigen (HLA)-DQ2 locus.
The researchers included Jan Petersen, Veronica Montserrat, Jorge R Mujico, Khai Lee Loh, Dennis X Beringer, Menno van Lummel, Allan Thompson, M Luisa Mearin, Joachim Schweizer, Yvonne Kooy-Winkelaar, Jeroen van Bergen, Jan W Drijfhout, Wan-Ting Kan, Nicole L La Gruta, Robert P Anderson, Hugh H Reid, Frits Koning, and Jamie Ross.
They are variously affiliated with the Department of Biochemistry and Molecular Biology at the School of Biomedical Sciences, and the Australian Research Council Centre of Excellence in Advanced Molecular Imaging at Monash University in Clayton, Victoria, Australia, the Department of Pediatrics, and the Department of Immunohematology and Blood Transfusion at Leiden University Medical Center in Leiden, The Netherlands, the Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, at the University of Melbourne in Parkville, Victoria, Australia, ImmusanT, Inc., in Cambridge, Massachusetts, USA, and the Institute of Infection and Immunity at Cardiff University School of Medicine in Heath Park, Cardiff, UK.
The team first determined T-cell receptor (TCR) usage and fine specificity of patient-derived T-cell clones specific for two epitopes from wheat gliadin, DQ2.5-glia-α1a and DQ2.5-glia-α2.
They also determined the ternary structures of four distinct biased TCRs specific for those epitopes. They were able to establish a basis for the biased TCR usage through mutagenesis and affinity measurements, together with the fact that all three TCRs specific for DQ2.5-glia-α2 docked centrally above HLA-DQ2. They found that a non–germline–encoded arginine residue within the CDR3β loop served as key of this common docking footprint.
Although the TCRs specific for DQ2.5-glia-α1a and DQ2.5-glia-α2 docked similarly, their interactions with the respective gliadin determinants differed markedly, thereby providing a basis for epitope specificity.
This is the first time a research team has determined that T-cell receptor recognition of HLA-DQ2–gliadin complexes was connected with celiac disease. Further study is needed to better understand the nature of their relationship.