Immune-complexes (ICs) are produced and deposit in the vasculature in many diseases in human patients, including systemic lupus erythematosis, and are responsible for many manifestations of the disease, e.g. glomerulonephritis. Leukocytes, particularly neutrophils, are attracted to sites of IC deposition and play essential roles in the pathogenesis of IC-mediated injury. In vitro studies have shown that neutrophils can attach (tether) to ICs via Fc-gamma-RIII on their microvilli. There is a further requirement for the leukocyte integrin, CD11b/CD18 (Mac-1), for firm adhesion of neutrophils to ICs. This is a novel mechanism whereby leukocytes may be attracted to sites of IC deposition in the vasculature.
The aims of these studies are to determine the domains of Mac-1 that are required for Fc-gamma-R-mediated sustained adhesion of leukocytes to ICs and to examine the roles of Fc- gamma-R and Mac-1 in neutrophil recruitment to ICs in vivo.
These aims will be accomplished by creating mutants of Mac-1, which will be evaluated for adhesion to ICs, using in vitro static and flow-based assay systems, and by establishing in vivo murine models of IC deposition that can be assessed using intravital microscopy. These models of IC deposition will be applied to Mac- 1-, Fc-gamma-R-, complement-, ICAM- and selectin-knock-out mice to evaluate the roles of these receptors and mediators in neutrophil adhesion to ICs in vivo. Further understanding of the interaction between neutrophils and ICs will provide crucial information for the potential prevention and treatment of IC- mediated disease.
| Stokol, Tracy; O'Donnell, Peter; Xiao, Ling et al. (2004) C1q governs deposition of circulating immune complexes and leukocyte Fcgamma receptors mediate subsequent neutrophil recruitment. J Exp Med 200:835-46 |
