title: Tolerance: a case of self/not-self discrimination maintained by clonal deletion?
abstract: The clonal selection theory of immune reactivity is based on a metaphor of self/not-self discrimination and considers self-tolerance to result from clonal deletion. There is evidence that a deletional mechanism is responsible for negative selection of self MHC-reactive T-cells in the thymus. Bretscher/Cohn theory builds on this concept and provides a model which allows self/not-self discrimination to occur at any time throughout the life of the individual. However, modern concepts of antigen presentation in which MHC-peptide co-presentation is the unit recognised by the T-cell receptor have abandoned the Bretscher/Cohn requirement for associative recognition of antigen. For this reason, such models of APC function cannot use Bretscher/Cohn theory to explain self/not-self discrimination. Matzinger's 'danger' metaphor for the immune system provides a theoretical way forward by moving the emphasis away from an immune system based on self/not-self discrimination. These theoretical developments lead to a novel approach to the control of autoimmunity that is based on the strengthening of immune regulation by the use of adjuvant therapy.
authors.affiliation: Division of Molecular Medicine, John Curtin School of Medical Research, Australian National University, Canberra.
authors.forename: K J
authors.initials: KJ
authors.lastname: Lafferty
authors.forename: L S
authors.initials: LS
authors.lastname: Gazda
mesh_terms: D000486:Allergy and Immunology / Q000266:history; D000818:Animals; D017951:Antigen Presentation; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology / Q000276:immunology; D049672:History, 19th Century; D049673:History, 20th Century; D006801:Humans; D008285:Major Histocompatibility Complex; D051379:Mice; D016688:Mice, Inbred NOD; D008954:Models, Biological; D017634:Self Tolerance; D013601:T-Lymphocytes / Q000276:immunology