Characterization of the pathophysiology of Wiskott-Aldrich transgenic mice

Wiskott-Aldrich syndrome (WAS) is an X-Iinked recessive disease in which affected patients have any combination of the triad of classical symptoms of thrombocytopenia, eczema and immunodeficiencies. The gene has been cloned and sequenced, but its function is unknown. In order to determine the pathophysiology of the disease, transgenic animals have been generated which overexpress the normal Wiskott-Aldrich syndrome protein (WASP) in T lymphocytes. By characterizing the pathobiology and immunology of these mice, we will better understand the normal function of Wiskott Aldrich syndrome protein (WASP).

The WASP transgenic mice have a profound phenotype that is characterized most prominently by splenomegaly and lymphadenopathy. Peripheral blood leukocytes are mildly, but significantly reduced, with all lineages being affected. WASP transgenic mice also have a mild thrombocytosis and megakaryocytosis. Histologically, the animals have enlarged germinal centers and increased numbers of germinal centers and lymphoproliferation in lymph nodes and spleens. This is reflected by elevated in vitro proliferative responses by both B and T cells. Signal transduction experiments show increased phosphorylation of several proteins in WASP transgenic cells versus cells from non-transgenic littermates. Based on these findings, it is believed that overexpression of WASP protein either in an antigen dependent or independent manner upregulates the immune response of B and T cells to various mitogens and pathogens. As a result, WASP transgenic mice develop chronic splenomegaly and lymphadenopathy due to the "activated" status of their immune cells. The differential phosphorylation of several proteins involved in signal transduction, even in the resting state, suggests that the immune systems of the WASP transgenic animals may be non-specifically activated. These same signal transduction proteins, which are affected by overexpression of the WASP protein are likely involved in the pathophysiology of WAS. Further efforts will be taken to identify these proteins and elucidate their role in both the pathophysiology of these transgenic mice as well as Wiskott-Aldrich syndrome. In the future, further experiments will be done to determine if this is an antigen dependent or independent response.