Chapter 188

## Abstract

Abstract

1. 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.

2. 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.

3. A second type of leukocyte adhesion deficiency, called LAD II (MIM 266265), results from dysfunction of the selectin pathway of adhesion. This syndrome results from a general defect in fucose metabolism, causing an absence of key carbohydrate ligands for the selectins [e.g., sialylated Lewis X (sLeX)]. Abnormalities in the inflammatory process are consistent with failure of normal selectin functions. Neutrophils fail to exhibit the typical rolling behavior required for effective localization at sites of inflammation, and skin infections without pus have been observed. While these patients have increased susceptibility to infections, particularly early in life, infections have not been life-threatening as is the case with the LAD I severe phenotype. The exact defect in the de novo pathway of fucose production from GDP-mannose to GDP-fucose is not known with certainty, but recent evidence indicates that in cell lysates from a LAD II patient, GDP-D-mannose-4,6-dehydratase (GMD), the first of the two enzymes of the pathway, has defective activity when compared to control subjects.

5. Animal models with leukocyte adhesion deficiencies have been developed. Targeted deletions of each of the selectins and CD18 integrins in mice reveal inflammatory deficits when animals are specifically challenged. All animals deficient in these specific adhesion molecules are viable and fertile, and only two of the mutations to date have resulted in phenotypes with spontaneous infections of animals maintained in barrier facilities. The CD18-deficient mice mimic most of the features of LAD I, but selective deficiencies of LFA-1 and Mac-1 do not. Mice with combined deficiency of E-selectin and P-selectin develop a syndrome sharing aspects of the inflammatory deficits of patients with LAD II.

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