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The occurrence of recurrent bacterial infections, neutrophil motility dysfunction and normal expression of beta 2 integrins (CD18) in two unrelated children suggested an as yet undescribed adhesion deficiency. The fact that both children exhibited the rare Bombay blood group and were Lewis negative, each involving carbohydrates with different fucose linkages, suggested a possible defect in the fucose-containing ligand for E- and P-selectin, sialyl Lewis X (SLe(x)). Using a monoclonal anti-SLe(x) antibody, we did not detect expression of SLe(x) on the neutrophils of the patients. Adhesion of neutrophils to endothelial cells activated with interleukin-1 beta or histamine was markedly decreased (5% of control). The observation that the neutrophils did not bind to recombinant E-selectin and purified P-selectin confirmed the SLe(x) deficiency as the basis for adhesion deficiency. Using several in vivo techniques, we were able to show that neutrophil rolling, the first step in their adhesion, is markedly decreased, and therefore neutrophil emigration through the endothelium and arrival at site of inflammation is significantly diminished (1-2% of normal). Low binding of fucose-specific lectins to the patients' B lymphocytes transformed with Epstein-Barr virus was observed, while the binding of mannose-specific lectins was normal, providing further evidence for a general fucose deficiency as the primary defect. The existence of the patients and their deficiency emphasizes the essential role of the endothelial cell selectins and their ligand, SLe(x), in recruitment of neutrophils to sites of infection. |
