Theoretical aspects of termination of immune tolerance by cross-reacting antigens

Abstract

This theory accounts for the main experimental findings concerned with the termination of tolerance by injection of cross-reacting antigens (CRA). It also accounts, in part, for related phenomena such as cross-tolerance, heterogeneity of antibody, innumerable antibody specificities, and auto-immunity induced by exposure to autologous antigens. It is based on the assumption that there is an interaction of antigen with immunocompetent cells (ICC) analogous to the interaction of antigen with antibody. This is applied to teh concepts of complementary fit, reversibility, and cross-reactivity. it is assumed that the presence of immuno-competent cells capable of responding to both the tolerated and the cross-reacting antigens, but with a stronger affinity for the cross-reacting antigens, is essential tot he termination of tolerance by the latter antigens. The tolerated antigen will not produce a detectable response because the initial number of cells and the fraction of the specific immunocompetent cell population stimulated during each division period (the F-value) are too small for the generation of the minimal number of cells required for a detectable response. The cross-reacting antigen with a larger F-value will cause a larger increase in the number of early generation cells than the tolerated antigen. Tolerance will be terminated if this increase enabled the tolerated antigen to generate the minimal number of cells required for a detectable response. The assumption that identical determinants may cross-react with a variety of immunocompetent cell types (ICC-Spectrum) accounts for cross-tolerance. The assumption that operationally a single antibody is a molecular population which is the product of an ICC-Spectrum, can account for the heterogeneity of antibody, and for the fact that the number of different antibodies parallels the number of different antigens. Auto-immunity may result from the termination of natural tolerant states through conditions, e.g. antigen concentration, which increase the F-values of the autologous antigens.