Leukocyte adhesion deficiency syndromes: adhesion and tethering defects involving beta 2 integrins and selectin ligands.

Leukocyte adhesion deficiency (LAD) syndromes are failures of innate host defenses against bacteria, fungi, and other microorganisms resulting from defective tethering, adhesion, and targeting of myeloid leukocytes to sites of microbial invasion. LAD I and variant LAD I syndromes are caused by mutations that impair expression or function of integrins of the beta 2 class (CD11/CD18 integrins, or "leukocyte" integrins). In contrast, subjects with LAD II have similar clinical features but intact leukocyte integrin expression and function. The molecular basis for LAD II is defective glycosylation of ligands on leukocytes recognized by the selectin family of adhesion molecules as well as defective glycosylation of other glycoconjugates. The defect has recently been attributed to mutations in a novel fucose transporter localized to the Golgi apparatus. Establishing the molecular basis for LAD syndromes has generated insights into mechanisms of leukocyte accumulation relevant to a broad variety of immunodeficiency syndromes as well as to diseases and disorders of unregulated inflammation that result in tissue damage.