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.

Abstract

Leukocyte Adhesion Deficiency Type II (LAD II) 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 II to the de novo pathway of GDPfucose 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. ( J. Clin. Invest.

Kindlins in FERM adhesion

“…42 As shown in Figure 4, LAD type I is characterized by defects in leukocyte adhesion caused by deficiencies of integrin ␤ 2 subunit 46 and LAD type II by mutation inactivating a fucose transporter resulting in abnormal expression and function of selectin family members. 47 By 2005, there were several reports describing LAD-III-like patients from different families, [41][42][43][44] and it became evident that, in contrast to LAD-I and -II, none of those patients has mutations in integrins or selectins themselves, but rather an essential common activator of integrins was missing.…”

Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene

“…16 In search for the defective pathway in the fucose metabolism, it was found that when fibroblasts and lymphoblastoid cells derived from a LADII patient were grown in the presence of millimolar concentrations of fucose, cell surface fucosylation could be restored. 17 Following this observation, Marquardt et al 18 orally administered L-fucose to the Turkish LADII patient and observed a remarkable clinical response. Within days of fucose intake, neutrophil counts normalized and functional E-and P-selectin ligands were expressed on myeloid cells.…”

Mice lacking the signaling molecule CalDAG-GEFI represent a model for leukocyte adhesion deficiency type III

“…Affected patients exhibit clinical symptoms such as severe recurrent infections, a heightened tendency to bleed, and marked leukocytosis. It has been proposed that this group of integrin activation disorders be designated LAD-III (9) based on the nomenclature for LAD-I and LAD-II, which describes patients with impaired expression of β 2 integrins (5) and defective fucosylation of selectin ligands (14), respectively. Because the expression of β 1 , β 2 , and β 3 integrins appears to be normal in LAD-III patients, it seems likely that a genetic defect in 1 or more intracellular signaling molecules involved specifically in the activation of leukocyte and platelet integrins is the basis of the LAD-III syndrome.…”