title: Death, adaptation and regulation: the three pillars of immune tolerance restrict the risk of autoimmune disease caused by molecular mimicry.
abstract: Extensive cross-reactivity in T cell receptor (TCR) recognition of peptide-MHC (pMHC) complexes seems to be essential to give sufficient immune surveillance against invading pathogens. This carries with it an inherent risk that T cells activated during a response to clear an infection can, perhaps years later, respond to a self pMHC of sufficient similarity. This lies at the heart of the molecular mimicry theory. Here we discuss our studies on the disease-causing potential of altered peptide ligands (APL) based on the sequence of a single autoantigenic epitope, the Ac1-9 peptide of myelin basic protein that induces experimental autoimmune encephalomyelitis in mice. These show that the window of similarity to self for induction of disease by cross-reactive non-self peptides is actually quite restricted. We show that each of the three pillars of immune tolerance (death, anergy/adaptation and regulation) has a role in limiting the risk of molecular mimicry by maintaining a threshold for harm.
authors.affiliation: University of Edinburgh, Institute of Immunology and Infection Research, School of Biological Sciences, Kings Buildings, West Mains Road, Edinburgh, EH9 3JT, UK.
authors.forename: Kelli R
authors.initials: KR
authors.lastname: Ryan
authors.forename: Sarju D
authors.initials: SD
authors.lastname: Patel
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Stephens
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
mesh_terms: D000222:Adaptation, Physiological / Q000276:immunology*; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D001327:Autoimmune Diseases; D015551:Autoimmunity; D016923:Cell Death; D006801:Humans; D007108:Immune Tolerance; D007239:Infections / Q000276:immunology; D018716:Molecular Mimicry; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D011948:Receptors, Antigen, T-Cell