Disruption of positive selection of thymocytes causes autoimmunity.
To differentiate into T cells, immature thymocytes must engage, through their antigen-specific T-cell receptor, peptides derived from self proteins presented by cortical epithelial cells in the thymus, a process called positive selection. Despite this requirement for self-recognition during development, mature T cells do not normally show autoreactivity. Mice injected in the thymus with procainamide-hydroxylamine, a metabolite of procainamide, develop autoimmune features resembling drug-induced lupus. Here, we show that when thymocytes undergo positive selection in the presence of procainamide-hydroxylamine, they fail to establish unresponsiveness to low affinity selecting self antigens, resulting in systemic autoimmunity.
Kretz-Rommel
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W.M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM 131, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Rubin
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RL
D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D000938:Antigen-Presenting Cells / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D015551:Autoimmunity; D010856:Columbidae; D003574:Cytochrome c Group / Q000737:chemistry / Q000276:immunology*; D007108:Immune Tolerance; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011342:Procainamide / Q000031:analogs & derivatives / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*
D003574:Cytochrome c Group; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; C051948:procainamide 4-hydroxylamine; D011342:Procainamide