Leukocyte Adhesion Deficiencies

ABSTRACT

• A cascade of adhesive events is needed for efficient localization of leukocytes at foci of inflammation. Members of the selectin family of glycoproteins are required for primary adhesion of flowing leukocytes interacting with endothelial cells at venular shear rates. L-selectin (CD62L) is expressed constitutively on neutrophils, monocytes, eosinophils, and subsets of lymphocytes and binds to carbohydrate ligands on endothelial cells and other leukocytes. E-selectin (CD62E) is not constitutively expressed by endothelial cells but is up-regulated following stimulation with inflammatory cytokines such as IL-1. P-selectin (CD62P) is found in α granules of platelets and Wiebel-Palade bodies of venular endothelial cells, and is rapidly up-regulated to the luminal surface following stimulation (e.g., with histamine). The selectins bind to sialylated and fucosylated carbohydrate ligands on cell surface glycoproteins. This interaction at venular shear rates results in rolling of leukocytes along the endothelium. Stationary adhesion and transendothelial migration of leukocytes depends on the interaction of integrins on the leukocyte surface with ligands on the endothelial cells. The integrins of greatest importance to neutrophils are Mac-1 (CD11b/CD18) and LFA-1 (CD11a/CD18), members of the β₂ integrin family. Cell activation is required for effective transition from selectin-dependent rolling to stable integrin-dependent adhesion. Chemotactic substances on the surface of endothelial cells (e.g., IL-8 and platelet-activating factor) stimulate this activation. Intercellular adhesion molecule-1 (CD54) is the principal ligand on endothelial cells for these integrins. It is constitutively expressed on venular endothelium and is markedly up-regulated by stimulation of these cells with inflammatory cytokines. Blockade or absence of individual components can interrupt this cascade of events. Failure of the selectin-dependent step results in failure of leukocytes to effectively bind to endothelial cells, with consequent failure of effective emigration. Failure of the integrin-dependent step allows rolling of leukocytes, but emigration is again prevented.

• Aberrations in adhesive mechanisms account for several clinical syndromes that involve an increase in susceptibility to bacterial infection. Leukocyte adhesion deficiency I (LAD I) (MIM 116920) was the first to be defined at a molecular level; it results from mutations in CD18, the β subunit of β₂ integrins, leading to partial or complete absence of expression, or dysfunction of these integrins. In addition to their role in neutrophil emigration, these integrins serve additional functions in host defense against infection. LFA-1 is involved in costimulation of lymphocytes during antigen presentation. Mac-1 functions as a receptor for complement opsonized bacteria, enhancing phagocytosis and bactericidal mechanisms (e.g., enhanced reactive oxygen production). Patients with LAD I appear to fall into two phenotypes. The severe phenotype occurs when CD18 expression is absent or extremely low. These patients are subject to overwhelming, life-threatening bacterial infections. The moderate phenotype occurs when either CD18 expression is very low or CD18 integrins are dysfunctional. These patients exhibit increased susceptibility to bacterial infections, but most have survived to adulthood. Numerous CD18 mutations have been defined, and patients are often compound heterozygotes, with differing mutations from the maternal and paternal alleles.

• A second type of leukocyte adhesion deficiency, ...