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Receptor Cross-Linking and Histamine Release

I. The Quantitative Dependence of Basophil Degranulation on the Number of Receptor Doublets

From the Laboratory of Theoretical Biology, National Cancer Institute, Bethesda, Maryland 20014 and the Laboratory of Microbiology and Immunology, National Institute of Dental Research, Bethesda, Maryland 20014

Abstract

We develop and apply a mathematical method for relating the number of antigen-induced IgE clusters on the basophil plasma membrane to the amount of histamine released. The method is valid at low doses of antigen where, it is shown, the number of bound antigens and the number of IgE clusters are linearly proportional to the total concentration of antigen. Cross-linking of receptors on some portion of the surface is considered to be a necessary condition for transmission of a signal that leads to degranulation. No assumption is made about whether the degranulation thus stimulated is local or global. Analysis of the low-dose portion of the dose-response curve, however, indicates the following: 1) Degranulation is local, and the maximum number of local centers per cell ("compartments") is small ( 10). 2) The number of IgE clusters required to initiate such local release is small but variable and depends upon the cell source and antigen valence. The results varied between three and eight for Con A, AgE, and anti-IgE. 3) These numbers represent thresholds for release; i.e., to a good approximation some minimum number of antigens in excess of one must be multiply bound before any histamine can be released. This suggests a high degree of cooperativity in the biochemical sequelae to clustering. 4) Only a small fraction of clusters are transmitting a release signal. This suggests, and is consistent with the idea, that clusters are interacting with some other membrane molecule and that only those that are bound to the other molecule are biologically active. 5) With respect to transmitting a signal for histamine release the number of independent clusters appears to be a more fundamental quantity than the total number of cross-linked receptors; i.e., there is little difference in activity as the size of a cluster increases due to increase in ligand valence.

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