In a steady state, WASp exists in an autoinhibited form, and its activation is dependent on the activity of WIP (WASp interacting protein), Cdc42 (Cell division
control protein 42) and PIP2 (phosphatidylinositol biphosphate), upon which the C-terminus of WASp binds to and activates the Arp2/3 (actin-related proteins) complex [2]. The Arp2/3 complex stimulates actin polymerization by creating a new nucleation find more core, which is an initial step in the formation of actin filaments [3] and important for processes, such as cell motility, phagocytosis, and the formation of the immunological synapse (IS). As WASp is expressed in CD34+ stem cells and their progeny [4], patients with WAS display functional abnormalities in all hematopoietic stem cell-derived lineages, including neutrophils, monocytes, DCs, Langerhans cells, platelets, and lymphocytes. All lymphocytes, namely, B, T, as well as NK cells in patients with WAS exhibit HSP assay anomalies in signaling as well as in the formation of the cytoskeleton [5, 6]. Regarding clinical symptoms, WAS is characterized by abnormal immune system functions, recurrent infections and inflammatory skin disorders such as eczema, and microthrombocytopenia. In
addition, WAS patients are at greater risk of developing autoimmune disorders. Similarly, Was−/− mice generated on 129, but not on C57BL/6, background have been reported to develop spontaneous colitis [7, 8]. Although the mechanisms of WAS-associated autoimmunity are not yet clarified, it has been proposed that this can be due to the bystander tissue damage during chronic inflammation or incomplete pathogen
clearance triggered Sorafenib by the defective immune system, as well as due to loss of tolerance to self-antigens caused by defective localization and function of Was-deficient natural regulatory T cells [5]. Importantly, WAS patients also show a higher risk of developing hematopoietic malignancies already in childhood [9]. The higher incidence of tumors in WAS patients might depend on defective cancer immunosurveillance due to the WASp deficiency in the immune system; yet WASp mutations can also lead to cell genomic instability and tumorigenesis [10] so the situation is still unclear. This link between WAS and increased cancer incidence has been explored by Catucci et al. [11] in the present issue of the European Journal of Immunology. In order to test the hypothesis that Was deficiency affects tumor immunosurveillance in vivo, the authors crossed Was−/− mice to Cdkn2a−/− mice. The Cdkn2a (cyclin dependent kinase inhibitor 2A) gene codes for an important tumor suppressor [12] and Cdkn2a−/− mice are more prone to developing tumors [13]. Cdkn2a−/− Was−/− double knock-out (DKO) mice showed impaired survival, when compared to Cdkn2a−/− mice.