Recurrent Severe Infections Caused by a Novel Leukocyte Adhesion Deficiency

Abstract

THE recruitment of neutrophils to sites of inflammation is initiated by the local production of bacteria-derived attractants, inflammatory cytokines, and other host-derived factors. These factors induce the rolling of neutrophils on the blood-vessel wall,^{1 2 3 4} followed by firm adhesion and extravasation into the surrounding infected or inflamed tissue.^{2 3 4} In recent years, there have been rapid advances in identifying the specific adhesion molecules that mediate the process of neutrophil recruitment.^{1 , 5 , 6} The initial rolling of neutrophils is mediated by members of the selectin family.^{2 , 4 , 7 , 8} These include E-selectin and P-selectin, which are expressed on the surface of activated endothelial cells, and L-selectin, which is constitutively expressed on neutrophils.^{5 , 6} The carbohydrate ligands for E-selectin and P-selectin have recently been characterized as the carbohydrate structure Sialyl-Lewis X (NeuAcα2,3Galβ1,4(Fucα1,3)GlcNAc) on the cell-surface glycoproteins and glycolipids of the neutrophil.^{5 , 6 , 9 10 11 12} Subsequent activation of the rolling neutrophil results in up-regulated expression of the adhesion molecules LFA-1 and Mac-1, two members of the integrin family that bind to the glycoprotein ICAM-1 (intracellular adhesion molecule 1), on the endothelial cells. It is well established that this interaction is essential to both firm adhesion to the blood-vessel wall and extravasation into the surrounding tissue. ^{1 , 2 , 7 , 13 , 14}