Review article Recent advances in understanding the pathophysiology of Wiskott-Aldrich

Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency caused by mutations in the gene encod-ing for WASP, a key regulator of signal-ing and cytoskeletal reorganization in hematopoietic cells. Mutations in WASP result in a wide spectrum of clinical manifestations ranging from the rela-tively mild X-linked thrombocytopenia to the classic full-blown WAS pheno-type characterized by thrombocytope-nia, immunodeficiency, eczema, and high susceptibility to developing tu-mors and autoimmune manifestations. The life expectancy of patients affected by severe WAS is reduced, unless they are successfully cured by bone marrow transplantation from related identical or matched unrelated donors. Because many patients lack a compatible bone marrow donor, the administration of WAS gene–corrected autologous hema-topoietic stem cells could represent an alternative therapeutic approach. In the present review, we focus on recent progress in understanding the molecu-lar and cellular mechanisms contribut-ing to the pathophysiology of WAS. Although molecular and cellular studies have extensively analyzed the mecha-nisms leading to defects in T, B, and dendritic cells, the basis of autoimmu-nity and thrombocytopenia still remains poorly understood. A full understanding of these mechanisms is still needed to further implement new therapeutic strat-egies for this peculiar immunodefi-ciency. (Blood. 2009;113:6288-6295