HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Delisi, C. Articles by Siraganian, R. P. Search for Related Content PubMed Articles by Delisi, C. Articles by Siraganian, R. P.

Receptor Cross-Linking and Histamine Release

II. Interpretation and Analysis of Anomalous Dose Response Patterns

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

Abstract

We report the results and analysis of dose-response and desensitization studies of rabbit basophils by a variety of antigens. Unlike the response of human basophils, the histamine release curves rarely rise and fall in a symmetric fashion, but more often either rise to a plateau, peak, and then fall to a non-zero plateau, or exhibit bimodality. In those cases in which the curves peak, preincubation with antigen in the absence of Ca⁺⁺ has a smaller effect at the high and low concentration portions of the curve than it does toward the center, where the inhibitory effect is maximum.

We show that the results can be explained by a simple model in which: 1) The signals for release and desensitization both increase as the concentration of receptor cross-links increases and 2) the signals reach a plateau (i.e., they have a maximum value) when the number of receptor cross-links becomes sufficiently large. By changing the parameters of the model, the balance between desensitization and release changes, and all the observed patterns can be reproduced. In particular, if both signals saturate (reach their maximum value) at a ligand concentration below that of maximum cross-linking, the histamine release curve will plateau. If the release signal saturates but the inhibitory signal continues to increase as ligand concentration increases toward its optimum value, the histamine release curve will be bimodal.

Many of the parameters can be identified with those that affect receptor clustering. These include the affinity of IgE for the antigen, the number of IgE molecules per basophil, IgE hinge flexibility, membrane fluidity, and antigen concentration and valence. This identification permits a variety of additional predictions. One such prediction is that the difference between a dose-response curve that plateaus and one that is biphasic and unimodal reflects easier desensitization of cells responsible for the latter curve and/or that have a smaller number of cross-links. Both predictions are readily testable experimentally.