Primary immunodeficiency disorders result from genetic defects that leave their human hosts immunocompromised and susceptible to devastating illnesses. Our long term goal is to elucidate the molecular basis of inherited immunodeficiency disorders. The focus of this proposal is to define the role of IL-4 receptor alpha chain (IL-4Ra) mutations in the pathogenesis of the hyper IgE syndrome (HIE), a primary immunodeficiency disorder characterized by serious recurrent infections and high IgE levels. We have identified a gain of function mutation (Q576R) in the cytoplasmic domain of the IL-4Ra chain which is prevalent in patients with HIE syndrome and allergic inflammatory disorders. We hypothesize that this mutation contributes to the pathogenesis of hyper IgE syndrome and related allergic disorders. We propose to establish the mechanism by which the mutant IL-4Ra allele contributes to the pathogenesis of HIE and other allergic inflammatory disorders by studying the interaction of mutant IL-4Ra chain with signaling intermediates both in vitro and using cellular models. We also propose to develop a transgenic mouse model to study the impact of the mutant IL-4Ra allele on the development of allergic inflammation in murine models of atopy. These studies will provide better understanding of the pathogenesis of HIE and its allied disorders and will facilitate the design of rational therapeutic approaches.
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