The Wiskott-Aldrich syndrome protein (WASp) is mutated in the severe immunodeficiency disease Wiskott-Aldrich syndrome (WAS). The function of B cells and the physiologic alterations in WAS remain unclear. We show that B cells from WAS patients exhibited decreased motility and had reduced capacity to migrate, adhere homotypically, and form long protrusions after in vitro culture. WASpdeficient murine B cells also migrated less well to chemokines. Upon antigen challenge, WASp-deficient mice mounted a reduced and delayed humoral immune response to both T-cell-dependent and -independent antigens. This was at least in part due to deficient migration and homing of B cells. In addition, the germi- The Wiskott-Aldrich syndrome (WAS) is caused by mutations in the Wiskott-Aldrich syndrome protein (WASp). 2 WAS patients display increased susceptibility to pyogenic, viral, and opportunistic infections and are predisposed to develop eczema, autoimmune, or lymphoproliferative disease. 3,4 Exclusively expressed in hematopoietic cells, WASp normally exists in an inactive state caused by intramolecular protein folding that prevents its activation. 5 Upon association with guanosine triphosphate (GTP)-bound Cdc42 and phosphatidylinositol-4,5-bisphosphate (PIP2), the C-terminus of WASp interacts with the Arp2/3 complex and with actin monomers, resulting in actin polymerization and consequent changes of cell shape and structure. 5 Many different mutations in WASp have been characterized, leading to expression of truncated fragments or to lack of expression. A novel type of mutation (L270P) has been identified in patients suffering from severe congenital neutropenia. 6 This mutation disrupts the critical autoinhibiting conformation of WASp and renders WASp constitutively active.Early evidence for a cytoskeletal role of WASp in immune cells came from thorough analysis of patient blood lymphocytes, revealing abnormal cell surface architecture. [7][8][9] However, a recent report suggests that fresh peripheral blood lymphocytes from WAS patients have normal numbers of microvillli. 10 Results from WASpnull mice have shown significant impairment in T-cell activation and formation of the immunologic synapse. 11-14 Natural killer cells, dendritic cells, macrophages, and hematopoietic stem cells have altered cytoskeletal responses. [15][16][17][18][19][20][21][22] The evidence for malfunction of WASp-deficient B cells is contradictory. WAS patients respond poorly to T-cell-independent antigens, suggesting a role for B cells in disease development. 3,4 One report shows impaired B-cell receptor triggering, 23 whereas 3 others indicate normal activation. 11,12,24 B-cell lines derived from WAS patients have reduced levels of F-actin, 25 and B cells from WASp-null mice exhibit a lower cell polarization and spreading response. 26 The B-cell contribution to development of WAS remains elusive. Furthermore, it is unclear how the absence of WASp in hematopoietic cells leads to immunodeficiency. In this paper, we have investigated the function of WASp-d...

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