Cpdm: Cloning a Gene That Regulates Eosinophil Function

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DESCRIPTION (provided by applicant): Eosinophils play a major role in the pathogenesis of a variety of human diseases. Dysregulation of cytokines produced by lymphocytes that result in eosinophilia affecting multiple organs by a single gene mutation provides a unique and valuable model to define eosinophils in health and disease. The spontaneous, autosomal, recessive, chronic proliferative dermatitis mouse mutation (gene symbol: cpdm) is such a model. The cpdm locus maps to the middle of mouse Chromosome 15. Homozygotes (cpdm/cpdm) show marked, progressive, epidermal proliferation associated with infiltration of eosinophils, mast cells, and MHC II+ cells. Eosinophilia in the skin and other organs is accompanied by a defect in the secretion of ILl2 and abnormalities in the development of lymphoid organs. Candidate genes have been identified and these will be sequenced for nucleotide changes. Sequencing priority will be based upon changes in expression levels using quantitative RT PCR methods. Based on the complex phenotype, functional assays, and resolution of the cpdm skin disease following exogenous recombinant ILl2 treatment, we postulate that the function of cpdm includes but is not limited to the regulation of ILl2 production. We hypothesize that dysregulation of cytokines resulting from this defect augments Th2 cytokine production (IL4, IL5, ILl3, and GMCSF) causing blood and tissue eosinophilia and eosinophil-induced tissue damage. Studies on the mechanism of eosinophilic dermatitis will initially focus on this potential pathway by generating crosses of cpdm/cpdm mice with mice lacking IL12b, llAra, or IL5. Since many organs in addition to the skin are affected in cpdm/cpdm mice, we believe that defining the genetics and mechanisms of eosinophilic skin disease will enable us to better understand eosinophilic diseases in the lung and other tissues.