This proposal represents a continuation of our efforts to characterize the mechanisms regulating mast cell (MC) phenotypic heterogeneity and to analyze the roles of MCs of differing phenotype in immunobiology and physiology. MCs are of great clinical interest because they are regarded as critical participants both in acute IgE-dependent processes, such as fatal anaphylaxis, and in the late effects of interactions between IgE and specific antigen, such as the late phase responses which are thought to contribute importantly to the pathogenesis of certain forms of asthma. However, recent findings have questioned the importance of the MC in such responses. For example, mutant mice virtually devoid of MCs, like normal mice, can be primed to exhibit fatal IgE-dependent anaphylaxis upon challenge with specific antigen. On the other hand, we recently found that i.v. injection of anti-igE antibodies produces extensive MC degranulation, striking changes in pulmonary and cardiovascular function, and death in normal mice, but has none of these effects in MC-deficient mice. We purpose that these apparently discordant findings can be encompassed in a single testable hypothesis: At low levels of IgE (such as in naive mice), the pulmonary and cardiovascular effects associated with anaphylaxis are largely MC-dependent, while at higher circulating levels of IgE (such as in mice primed to express active anaphylaxis), MC- independent mechanisms are recruited which permit expression of anaphylaxis in the absence of MCs. Moreover, we propose that in those acute or late phase IgE-dependent reactions which demonstrably require MCs, the precise contribution of MCs, and, as a result, the biological expression of the reactions themselves, can be regulated by factors influencing the numbers, anatomical distribution, and phenotype of the MC populations participating in the responses. The objective of the studies proposed herein is to test these hypotheses by eliciting and characterizing various representative forms of acute and late phase IgE-dependent reactions under circumstances where both levels of IgE, and the numbers and phenotype of the participating MCs can be controlled experimentally.
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