The role of the DR4 shared epitope in selection and commitment of autoreactive T cells in rheumatoid arthritis.
The mechanistic basis for HLA associations with RA is still unknown in spite of 20 years of disease association studies and a detailed characterization of HLA class II alleles associated with disease. Analysis of the structural interactions between DR4 susceptibility molecules and T cells specific for the peptide-MHC complex suggests a mechanism for directed T-cell selection and amplification in which RA-associated genetic polymorphisms bias intermolecular recognition. New immunologic models for illustrating the importance of regulated thresholds for T-cell activation based on avidity between the TCR, MHC, and peptide offer insight into a potential mechanism in which the disease-associated HLA molecules create an autoimmune-prone individual by virtue of a biased TCR selection and T-cell amplification process. New tools such as the use of HLA-DR4 tetramers provide the ability to identify and monitor the presence of such autoreactive T cells in the periphery of individuals and patients and should assist in further testing of the multistep model for RA pathways presented in this article.
Nepom
G T
GT
Virginia Mason Research Center, Seattle, Washington, USA. nepom@vmresearch.org
D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000276:immunology*; D006801:Humans; D013601:T-Lymphocytes / Q000276:immunology*
D000939:Epitopes; D015804:HLA-DR4 Antigen