Primary Immunodeficiencies (PID) commonly result from either an inherited block in cellular development of the immune system or in the inability of the immune system to properly regulate immune responses. In some specific diseases, developmental blocks are associated with both a precise immune defect and an altered inflammatory response (e.g. Omenn's syndrome). Patients with PID have been the source for numerous studies that resulted in significant insights into basic mechanisms of the immune system, and continue to offer unique investigative opportunities. The Hyper-IgE syndrome (HIES) is a primary immunodeficiency disorder generally characterized by chronic eczema, recurrent staphylococcal infections, and increased serum IgE levels. The autosomal dominant (AD) form (Job's syndrome) is additionally distinguished by multi-system manifestations including abnormal dentition, joint hyperextensibility, and a distinct facial structure. Most cases of Job's syndrome are sporadic in nature, however familial cases have also been reported. Recently, hypomorphic mutations in the Stat3 gene have been found to be a causative factor in Job's syndrome. Specifically, heterozygous, dominant-negative point mutations were found in distinct domains of the Stat3 gene including: the highly conserved DNA binding domain, the Src homology domain, and in the transactivation domain. While patients with Job's syndrome harbor mutations in Stat3, there still is no clear relationship between the exact genetic lesion and the phenotype of patients with HIES. In this proposal, we seek to generate murine models of Job's syndrome that accurately recapitulate the human disease in order to understand the basic mechanisms that lead to varied clinical manifestations
Job's syndrome is a Primary Immunodeficiency affecting multiple organ systems with defects in the immune response, bone growth, and skin. Mutations in Stat3 have recently been reported in patients with Job's syndrome, yet the exact mechanism of action leading to the diverse clinical manifestations remains unknown. The studies in this proposal seek to understand the basic mechanisms and consequences of Stat3 mutations by establishing a mouse model for the disease, which may lead to the development of novel and rational therapeutic targets for patients with Hyper-IgE syndrome.