Germline but macrophage-tropic CYBB mutations in kindreds with X-linked predisposition to tuberculous mycobacterial diseases

Germline mutations in the human CYBB gene, encoding the gp91phox subunit of the phagocyte NADPH oxidase, impair the respiratory burst of phagocytes and result in X-linked chronic granulomatous disease. We report two kindreds in which otherwise healthy male adults show X-linked recessive Mendelian susceptibility to mycobacterial diseases. These patients harbor mutations in CYBB that profoundly reduce the respiratory burst in monocyte-derived macrophages, but not in monocytes or granulocytes. The macrophage-specific functional consequences of the germline mutation result from the cell-specific impairment of NADPH oxidase assembly. This "experiment of nature" indicates that the respiratory burst in human macrophages is a crucial mechanism for protective immunity to mycobacteria.