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...

Macrophages and dendritic cells have been recognized as key players in the defense against mycobacterial infection. However, more recently, other cells in the lungs such as alveolar epithelial cells (AEC) have been found to play important roles in the defense and pathogenesis of infection. In the present study we first compared AEC with pulmonary macrophages (PuM) isolated from mice in their ability to internalize and control Bacillus Calmette-Guérin (BCG) growth and their capacity as APCs. AEC were able to internalize and control bacterial growth as well as present antigen to primed T cells. Secondly, we compared both cell types in their capacity to secrete cytokines and chemokines upon stimulation with various molecules including mycobacterial products. Activated PuM and AEC displayed different patterns of secretion. Finally, we analyzed the profile of response of AEC to diverse stimuli. AEC responded to both microbial and internal stimuli exemplified by TLR ligands and IFNs, respectively. The response included synthesis by AEC of several factors, known to have various effects in other cells. Interestingly, TNF could stimulate the production of CCL2/MCP-1. Since MCP-1 plays a role in the recruitment of monocytes and macrophages to sites of infection and macrophages are the main producers of TNF, we speculate that both cell types can stimulate each other. Also, another cell-cell interaction was suggested when IFNs (produced mainly by lymphocytes) were able to induce expression of chemokines (IP-10 and RANTES) by AEC involved in the recruitment of circulating lymphocytes to areas of injury, inflammation, or viral infection. In the current paper we confirm previous data on the capacity of AEC regarding internalization of mycobacteria and their role as APC, and extend the knowledge of AEC as a multifunctional cell type by assessing the secretion of a broad array of factors in response to several different types of stimuli.