The immune response combines extraordinary specificity of recognition with extremely complex control mechanisms that govern its effector mechanisms. Childhood primary immunodeficiency disorders can be viewed as """"""""experiments of nature"""""""" in which a discrete genetic defect affects the expression and/or the structure/function of essential lymphocyte proteins and results in immune dysfunctions. A molecular or genetic definition of primary immunodeficiencies is essential for accurate diagnosis and therapy of the disorders and for better understanding of normal immune functions. In this program project, we propose to study a limited set of immunological diseases because of our success in analyzing both patient materials as well as transgenic mice models. We will use recently acquired knowledge of the causes of the X-Linked hyper IgM syndrome, the X-linked agammaglobunemia, severe combined immunodeficiencies, and T cell receptor deficiencies. We anticipate extensive usage of molecular biology and cell biology techniques to further define these diseases. Novel transgenic animal models, which we generated or which we are developing will also become powerful tools for a systematic dissection of the biochemical processes, which govern ontogeny of the immune system. The four scientific components of the Program are: Project 1: Transgenic Models of T Cell Receptor Immunodeficiencies. Cox Terhorst, Beth Israel Hospital. Project 2: HIGMX-1: Transgenic Models of CD40 and CD40L deficiency. Raif Geha and Fred Rosen, Children's Hospital. Project 3: Murine XLA and SCID Models. Frederick ALT and Fred Rosen, The Center for blood Research. Immunodeficiency Patient Core Facility Raif Geha and Fred Rosen, Children's Hospital.
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