Leukocyte Adhesion Deficiency Type II is a generalized defect of de novo GDP-fucose biosynthesis - Endothelial cell fucosylation is not required for neutrophil rolling on human nonlymphoid endothelium

Leukocyte Adhesion Deficiency Type II (LAD IT) is a recently described syndrome and the two patients with this defect lack fucosylated glycoconjugates, These glycoconjugates include the selectin ligand, sialyl Lewis(x), and various fucosylated blood group antigens. To date, the molecular anomaly in these patients has not been identified. We Localized the defect in LAD IT to the de novo pathway of GDP-fucose biosynthesis, by inducing cell-surface expression of fucosylated glycoconjugates after exposure of lymphoblastoid cell lines from the LAD II patients to exogenous fucose. This defect is not restricted to hematopoietic cells, since similar findings were elicited in both human umbilical vein endothelial cells (HUVEC) and fibroblasts derived from an affected abortus. We have used these LAD II endothelial cells to examine the consequence of fucosylation of endothelial cells on the rolling of normal neutrophils in an in vitro assay. Neutrophil rolling on LPS-treated normal and LAD II HUVEC was inhibited by an E-selectin monoclonal antibody at both high and low shear rates. LAD II HUVEC lacking fucosylated glycoproteins supported leukocyte rolling to a similar degree as normal HUVEC or LAD II cells that were fucose-fed. At low shear rates, an L-selectin antibody inhibited neutrophil rolling to a similar degree whether the LAD II cells had been fucose-fed or not. These findings suggest that fucosylation of nonlymphoid endothelial cells does not play a major role in neutrophil rolling and that fucose is not a critical moiety on the L-selectin ligand(s) on endothelial cells of the systemic vasculature.