Recruitment of leukocytes from the vasculature to sites of inflammation involves a highly regulated interplay between adhesion molecules and their ligands. During the recruitment process, circulating leukocytes are locally captured and begin to roll along the inflamed vessel wall, a process that requires the selectin family of adhesion molecules and their respective ligands. During rolling, leukocytes receive signals from the inflamed vessel wall, which induce a further slowing down and eventual firm arrest (adhesion) of the leukocyte to the vessel wall. Firm leukocyte adhesion depends on leukocyte integrins, a family of transmembrane receptors, specialized for anchoring cells to the surrounding matrix or to other cells. After firm adhesion, leukocytes start to spread and begin to slowly crawl along the vessel wall until they find their optimal location for extravasation into tissue.
Several disorders have been described in which distinct steps along the recruitment cascade are defective. These disorders have been termed leukocyte adhesion deficiencies (LAD) and are generally characterized by recurrent infections and marked leukocytosis. So far, three different LADs (LAD I–III) have been reported. Although the genetic defects underlying LAD-I and -II have been known for several years, the precise molecular basis of LAD-III has only recently been identified. In children with LAD-I, mutations in the β2 integrin gene, which is specifically expressed in leukocytes, results in a profound defect in leukocyte adhesion giving rise to serious infections in early life and high infant lethality. LAD-II, also known as congenital disorder of glycosylation IIc (CDG IIc), primarily affects leukocyte capture and rolling and is caused by a defective sugar transporter leading to disturbed glycosylation of selectin ligands. Infections in LAD-II are often milder and patients usually survive into adulthood. LAD-III resembles in many aspects the clinical presentation of LAD-I and was initially described as LAD-I/variant, though this name is delusive as the molecular defect underlying LAD-III is distinct from LAD-I. Analogous to LAD-I, children with LAD-III may show delayed separation of the umbilical cord and suffer from frequent serious infections mainly localized to the skin and soft tissues. In contrast to LAD-I, patients with LAD-III demonstrate a life-threatening Glanzmann-like bleeding tendency caused by defective platelet aggregation. Molecular characterization of leukocytes isolated from LAD-III patients revealed that β1, β2, and β3 integrins are normally expressed. However, they remain inactive even under situations that usually activate them. This observation suggested that a mutation in an integrin regulatory protein, specifically expressed in hematopoietic cells, is responsible for the leukocyte and platelet defects.
