A novel syndrome of variant leukocyte adhesion deficiency involving defects in adhesion mediated by b1 and b2 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 significant morbidity that is caused by absent or greatly diminished surface expression of integrins of the b2 class. We report clinical features and analysis 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 b2 integrins. Analysis of adhesion of these cells to immobilized ligands and to endothelial cells and assays of cell-cell aggregation and chemotaxis demonstrated a profound defect in adhesion mediated by b2 integrins indicative of a variant form of LAD-1. A novel cell line established from Epstein-Barr virus–transformed lymphoblasts from the subject demonstrated deficient b2 integrin–dependent adhesive function similar to that of the primary leukocytes. In addition, these cells had markedly impaired b1 integrin–dependent adhesion. Sequence analysis and electrophoretic mobility of b1 and b2 proteins from the cell line demonstrated that the defects were 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 insideout signaling mechanisms that regulate the activity of integrins of these classes. These features define a unique LAD-1 variant syndrome that may reveal important insights that are generally relevant to inside-out signaling of integrins, a molecular process that is as yet incompletely understood. (Blood. 2001;97: 767-776)