Cellular and Molecular Mechanisms Underlying Autoimmune Manifestations in Wiskott Aldrich Syndrome

The Wiskott-Aldrich Syndrome (WAS) is a monogenic X-linked immunodeficiency also characterized by thrombocytopenia, eczema, and a high susceptibility to develop tumors and multiple autoimmune manifestations. WAS is caused by mutations impairing the expression or function of the hematopoietic-specific WAS protein (WASp), a key regulator of actin cytoskeleton remodelling upon cell stimulation. WAS-associated immunodeficiency is due to dysfunction of many immune cell types, including T, B, NK cells, and dendritic cells (DCs). The life expectancy of patients affected by WAS is severely reduced, unless they are successfully cured by hematopoietic stem cells (HSC) transplantation. The comprehension of cellular and molecular aspects in the pathogenesis of autoimmune diseases in WAS is crucial, since autoimmunity is associated with a higher risk of a later development of tumors and with an increased mortality. Moreover platelet defect represents a still unsolved aspect of the disease. In the present project, we plan to investigate cellular and molecular mechanisms underlying autoimmune manifestations observed in this disease. We will perform these studies both in patients-cells and in the murine Was-/- counterpart. The comprehension of new pathological mechanisms will be instrumental to redirect and adapt therapeutic approaches in order to improve the clinical care for these specific patients as well as the management of more common forms of autoimmunity.