An immunogenetic model of allergic asthma.

摘要

Allergic asthma is a multifactorial disease which has a significant genetic component. It is characterized by airway hyperreactivity (AHR), eosinophilia, and excessive IgE production. Substantial evidence indicates that allergic asthma results from immune dysregulation which results in excessive antigen-driven T-helper lymphocyte Th2 differentiation and consequently, IL-4 production. Important factors in Th2 differentiation include the actions of IL-4 and IL-12 which upregulate and downregulate Th2 immune responses, respectively. However, the mechanisms by which these cytokines are produced and the mechanisms by which they influence AHR are unknown. To address this question, we established a model of genetic susceptibility to allergic asthma symptoms by challenging inbred strains of mice with an antigen exposure designed to evoke Ag-induced AHR, eosinophilia, and IgE production. Using this model, we investigated possible pathophysiologic immune mechanisms as well as determined the genetic control of asthma symptoms. We confirmed that Ag-induced ABR is a consequence of Th2 cell IL-4 production by preventing Ag-induced Th2 differentiation, IL-4 production, and AHR in signal transduction and activator of transcription factor 6 (STAT6) deficient mice. In addition, we were able to prevent Ag-induced AHR by upregulating Th1 differentiation in response to a natural mycobacterial infection. As a consequence of our experiments, we gained insight into the mechanisms of ABR by demonstrating that Ag-induced eosinophilia, and IgE production are genetically controlled in mice but occur as parallel processes which. are not mechanistically related to AHK In addition, we found that susceptibility to ABR was controlled by at most two genes and we provide evidence that one of those genes is located on murine chromosome five. Interestingly, a candidate gene in this area, platelet derived growth factor receptor beta subunit, could contribute toward the development of AHR by increased STAT6 activity. In conclusion, studies in this thesis significantly advanced our understanding of the pathogenesis of allergic asthma and may support the development of new therapeutic modalities.