TARGETED DISRUPTION OF MOUSE IGE AND IGE-RECEPTOR GENES

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Mast cell activation by IgE is a central event in the pathogenesis of allergic disorders and may be important in host defense against parasites. IgE is produced by mucosal B cells. Upon appropriate stimulation, including exposure to IL-4, transcription of the "germline" form of the Cepsilon gene occurs in B cells and is followed by a recombination event which results in the juxtaposition of variable and constant region gene sequences with synthesis of complete epsilon heavy chain. IgE is bound by the alpha chain of the high-affinity receptor on mast cells and basophhils, FcepsilonRI. Crosslinking of FcepsilonRI results in their activation leading to allergic pathology. The goal of the research presented in this application is to generate mice with null mutations at the Cepsilon and FcepsilonRI-alpha genes by gene targeting in embryonic stem (ES) cells. These will be used in several studies. 1. The requirement for complete germline Cepsilon transcripts in switch recombination will be examined. Cepsilon mutants will lack exons Cepsilon1-4 but have intact Sepsilon switch and I exon sequences. The occurrence of transcription and Smu-Sepsilon isotype switching will be assessed in wild-type and mutant B cells. 2. Mouse models of airways inflammation will be used to examine the role of IgE/FcepsilonRI in inducing bronchial hyperreactivity as well as pulmonary inflammatory infiltrates after challenge with airborne antigens. 3. The roles of IgE and FcepsilonRI in the development of intestinal mastocytosis, blood eosinophilia and parasite clearance will be investigated using the murine nematode parasite, Nippostrongylus brasiliensis. 4. IgE/FcepsilonRI function in the generation of the ocular inflammation of IL-4 transgenic mice and in the eosinophilic infiltration and rejection of IL-4-expressing tumors will be studied.