A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by beta(1) and beta(2) integrins

Leukocyte adhesion deficiency type I (LAD-1) is a disorder associated with severe and recurrent bacterial infections, impaired extravascular targeting and accumulation of myeloid leukocytes, altered wound healing, and signifi cant morbidity that is caused by absent or greatly diminished surface expre ssion of integrins of the pp class. We report clinical features and analysi s of functions of cells from a patient with a myelodysplastic syndrome and infectious complications similar to those in the severe form of LAD-1, but whose circulating neutrophils displayed normal levels of beta (2) integrins . Analysis of adhesion of these cells to immobilized ligands and to endothe lial cells and assays of cell-cell aggregation and chemotaxis demonstrated a profound defect in adhesion mediated by beta (2) integrins indicative of a variant form of LAD-1. A novel cell line established from Epstein-Barr vi rus-transformed lymphoblasts from the subject demonstrated deficient beta ( 2) integrin-dependent adhesive function similar to that of the primary leuk ocytes. In addition, these cells had markedly impaired beta (1) integrin-de pendent adhesion. Sequence analysis and electrophoretic mobility of beta (1 ) and beta (2) proteins from the cell line demonstrated that the defects we re not a result of structural abnormalities in the integrin subunit chains themselves and suggest that the adhesive phenotype of these cells is due to one or more abnormalities of inside-out signaling mechanisms that regulate the activity of integrins of these classes. These features define a unique LAD-I variant syndrome that may reveal important insights that are general ly relevant to inside-out signaling of integrins, a molecular process that is as yet incompletely understood. (C) 2001 by The American Society of Hema tology.