Functional defect in neutrophil cytosols from two patients with autosomal recessive cytochrome-positive chronic granulomatous disease.

The kinetics of activation of the respiratory burst oxidase in the cell-free oxidase-activating system have been explained by a three-stage mechanism in which the membrane-associated oxidase components M: (a) take up a cytosolic factor S to form a complex M.S that is (b) slowly converted in the second stage to a precatalytic species [M.S]*, which finally (c) takes up two more (possibly identical) cytosolic components, C alpha and C beta, to successively generate [M.S]*C alpha, a low-activity (i.e., high Km) oxidase, and finally [M.S]*C alpha C beta, the ordinary (i.e., low Km) oxidase (Babior, B.M., R. Kuver, and J.T. Curnutte. 1988. J. Biol. Chem. 263:1713-1718). Studies with the cell-free oxidase-activating system from normal neutrophils and from neutrophils obtained from two patients with type II (autosomal recessive cytochrome-positive) chronic granulomatous disease (CGD) have suggested that (a) the defective element in the cytosol from patient neutrophils is S; (b) in normal neutrophil cytosol, S is limiting with respect to M; and (c) C alpha and C beta interact cooperatively with the activated precursor complex [M.S]*. It was further speculated that S might be identical to the nonphosphorylated progenitor of the phosphorylated 48-kD proteins that are missing in certain forms of CGD, and that other forms of type II CGD besides the one described in this report remain to be discovered.