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 genetic animal models. We will use recently acquired insights into the causes of the X-linked Lympho Proliferative disease (XLP), Wiskott-Aldrich Syndrome (WAS), severe combined immunodeficiencies (SCID), Omenn syndrome, Hyper IgM syndrome, and Common Variable Immunodeficiencies. Our genetic animal models will become powerful tools for a systematic dissection of the biochemical processes involved in the pathogenesis of these diseases, but they will also shed light on basic mechanisms that govern ontogeny of the immune system. We propose to continue to integrate our expertise into the Program Project Grant entitled Models of Immunodeficiencies. Cox Terhorst - The Role of the XLP Gene, SAP, in T and B Cell Functions. Raif Geha - Mechanism of WASP Function in T cell Responses Fred AIt - Murine models of Severe Combined Immunodeficiencies.
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