Tolerance: Case of self/not-self discrimination maintained by clonal deletion?

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 cheery builds on this concept and provides a model which allows self/not-self discrimination to occur at any time throughout che 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. (C) American Society for Histocompatibility and Immunogenetics, 1997.