- Badolato R,
- Sozzani S,
- Malacarne F,
- et al.
Purpose of the Study
Several previous studies have documented a subtle abnormality of neutrophil and macrophage function in patients with Wiskott-Aldrich syndrome. This study was designed to investigate the cause of phagocyte dysfunction in Wiskott-Aldrich syndrome. Monocyte/macrophage dysfunction could contribute to the recurrent infections seen in this syndrome.
Four patients with Wiskott-Aldrich syndrome were studied.
Morphologic changes after stimulation were defined by light microscopy and immunofluorescence for actin. Chemotaxis was measured in a microchamber and superoxide production was defined using a cytochrome c reduction technique.
Monocyte chemotaxis responses to macrophage inflammatory protein 1α (MIP1α), monocyte chemoattractant protein-1 (MCP-1), and formyl-methionyl-leucyl-phenylalanine (FMLP) were abnormal. Similarly, actin polarization and morphologic polarization were defective in the stimulated monocytes from patients with Wiskott-Aldrich syndrome. Conversely, respiratory burst and upregulation of adhesion molecules was intact after stimulation.
Monocyte activities requiring chemotaxis or polarization are defective in patients with Wiskott-Aldrich syndrome. Aberrant leukocyte recruitment to areas of inflammation could contribute to the recurrent infections in this syndrome.
A previous report demonstrated that actin polarization after stimulation of T cells is aberrant in this disorder; therefore, this report is consistent with a global abnormality affecting transduction of cell surface signals to the cytoskeleton. This was also expected based on the molecular characterization of the WASp protein, which is defective in Wiskott-Aldrich syndrome. The WASp protein acts as a docking site for signaling molecules and GTPases implicated in actin polymerization. The implications of these findings is that treatment of patients with biological agents such as cytokines may be beneficial as modulators in particular clinical settings but is unlikely to overcome the defect in this syndrome because it is cell-intrinsic.