Leukocyte Adhesion Deficiencies

The leukocyte adhesion deficiencies are a group of autosomal recessive disorders caused by defects in leukocyte and endothelial adhesion molecules. These diseases are characterized by a failure of leukocyte, particularly neu-trophil, recruitment to sites of infection, resulting in severe periodontitis and other recurrent infections starting early in life, and the inability to make pus. Different types of leukocyte adhesion deficiencies are caused by mutations in different genes.

• Leukocyte adhesion deficiency type 1 (LAD-1) is a rare autosomal recessive disorder characterized by recurrent bacterial and fungal infections and impaired wound healing. In these patients, most adhesion-dependent functions of leukocytes are abnormal. These functions include adherence to endothelium, neutrophil aggregation and chemotaxis, phagocytosis, and cytotoxicity mediated by neutrophils, natural killer (NK) cells, and T lymphocytes. The molecular basis of the defect is absent or deficient expression of the p2 integrins (heterodimers of CD18 and the CD11 family of glycoproteins) due to various mutations in the CD18 gene. The p2 integrins include leukocyte function-associated antigen 1 (LFA-1 or CD11aCD18), Mac-1 (CD11bCD18), and p150,95 (CD11cCD18). These proteins participate in the adhesion of leukocytes to other cells, notably endothelial cells, and the binding of T lymphocytes to antigen-presenting cells (APCs) (see Chapter 3).

• Leukocyte adhesion deficiency type 2 (LAD-2) is another rare disorder that is clinically similar to LAD-1 but is not due to integrin defects. In contrast, LAD-2 results from an absence of sialyl Lewis X, the tetrasac-charide carbohydrate ligand on neutrophils and other leukocytes that is required for binding to E-selectin and P-selectin on cytokine-activated endothelium (see Chapter 3). This defect is caused by a mutation in a GDP-fucose transporter responsible for the transport of fucose into the Golgi, resulting in an inability to synthesize sialyl Lewis X. The absence of sialyl Lewis X results in defective binding of leukocytes to endo-thelium, the absence of leukocyte "rolling," and therefore the defective recruitment of leukocytes to sites of infection. This abnormality in fucosylation seen in LAD-2 also contributes to a Bombay blood group phe-notype caused by the absence of all ABO blood group antigens as well as to mental retardation and other developmental defects. Fucose is an essential component of the H glycolipid that forms the core antigen in the ABO system.

• Leukocyte adhesion deficiency type 3 (LAD-3) involves a defect in inside-out signaling and thus a defect in chemokine-induced integrin activation that is required for leukocytes to bind firmly to endothelium (see Chapter 3). In a subset of patients it is caused by mutations in the gene encoding KINDLIN-3. KINDLIN-3 is a protein that binds to the cytoplasmic tail of some integrins and is involved in signaling. Increased bleeding is also observed in subjects with KINDLIN-3 mutations because of integrin dysfunction in platelets.

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