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Rheum Dis Clin North Am. 2001 May;27(2):305-15.

The role of the DR4 shared epitope in selection and commitment of autoreactive T cells in rheumatoid arthritis.

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Virginia Mason Research Center, Seattle, Washington, USA.


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.

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