Molecular defects in LAD syndromes. In each syndrome, leukocytes have defects in adhesion and targeting to sites of microbial invasion and tissue injury.^1–3,8  Molecular defects in LAD syndromes result in recurrent infections with bacteria and fungal pathogens, inability to form pus at extravascular sites, and other clinical features. LAD-I is caused by mutations in the gene for the β2 subunit of the β2 family of integrins (also termed leukocyte integrins and CD11/CD18 integrins), resulting in decreased or absent levels of these heterodimers on circulating leukocytes. This impairs their ability to rapidly adhere tightly to activated, “inflamed” endothelial cells in response to signaling molecules (PAF, chemokines) displayed on the endothelial surface and to emigrate from vessels at sites of infection or injury. Leukocytes from subjects with LAD-II have intact β2 integrin expression and function but impaired adhesive functions of selectin ligands, chiefly P-selectin glycoprotein ligand 1 (PSGL-1). This defect is caused by mutations in a fucose transporter and consequent defective fucosylation of PSGL-1 and other glycoproteins, and results in impaired tethering and rolling of leukocytes on activated endothelial cells. These are initial events in the multistep process of leukocyte adhesion and emigration.¹  In LAD-Iv/III, expression of integrin heterodimers and selectin ligands is normal, but there is defective activation-dependent signaling (inside-out signaling; starbursts in the figure) of β2 integrins resulting in adhesion defects similar to those in LAD-1. There is also defective signaling of α_IIbβ₃ integrin on platelets, resulting in impaired aggregation and a Glanzmann-like bleeding disorder. In addition, there is evidence for impaired β1 integrin activation on hematopoietic cells in LAD-lv/III. Adapted from Bunting et al.¹