MONOCYTES FROM WISKOTT-ALDRICH PATIENTS DISPLAY REDUCED CHEMOTAXIS AND LACK OF CELL POLARIZATION IN RESPONSE TO MONOCYTE CHEMOATTRACTANT PROTEIN-1 AND FORMYL-METHIONYL-LEUCYL-PHENYLALANINE

Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized b y trombocytopenia, eczema, and progressive decline of the immune funct ion. In addition, lymphocytes and platelets from WAS patients have mor phologic abnormalities. Since chemokines may induce morphologic change s and migration of leukocytes, we investigated the monocyte response t o chemoattractants in cells from WAS patients with an identified mutat ion in the WAS protein gene. Here, we report that monocytes derived fr om four patients with molecularly defined typical WAS have a severely impaired migration in response to FMLP and to the chemokines monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein- 1 alpha compared with normal donors, Conversely, neither MCP-1 binding to monocytes nor induction of the respiratory burst by MCP-1 and FMLP is significantly different between WAS patients and normal donors. Wi thin a few minutes of stimulation, monocytes respond to chemokines wit h increased expression of adhesion molecules and with morphologic chan ges such as cell polarization. Although up-regulation of CD11b/CD18 ex pression following stimulation with FMLP or MCP-1 preserved in WAS pat ients, cell polarization is dramatically decreased, Staining of F-acti n by FITC-phalloidin in monocytes stimulated with chemoattractants sho ws F-actin to have a rounded shape in WAS patients, as opposed to the polymorphic distribution of F-actin in the polarized monocytes from he althy donors. These results suggest that WAS protein is involved in th e monocyte response to the chemokines MCP-1 and macrophage inflammator y protein-1 alpha.