The purpose of this project is to determine the genetic basis of inherited diseases affecting neutrophil function and associated with recurrent infections, and diagnosis and treatment of such disorders. Chronic Granulomatous Diseases of Childhood (CGD) are a group of diseases with common phenotype including absent H202 production by phagocytes, recurrent infections, and granuloma formation. We have documented the prevalence of the four distinct genetic forms of CGD (60% X-linked defect in cytochrome b558 gp9l-phox subunit; 5% autosomal recessive (AR) defect in cytochrome p22-phox subunit; 30% AR affecting p47-phox cytosolic oxidase factor; 5% AR affecting p67phox cytosolic factor). Studies of p67-phox gene structure reveals two normal allelic HinDIII restriction enzyme patterns which will be useful in prenatal diagnosis and mapping chromosome 1q25 region. In other studies expression of p47-phox by retroviral vector provides an important tool for eventual genetic reconstitution of this form of CGD. We have documented the effectiveness of low dose steroids in management of obstructive granulomas of gastrointestinal and urinary system. We have documented the importance of early surgical extirpation of pulmonary aspergillus infections and drainage of liver abscesses. Review of our CGD patients' histories indicated that prophylactic trimethaprim-sulfa reduces bacterial infections without causing an increase in fungal infection. Using an in vitro assay of fungal killing by neutrophils, we have documented that a small number of normal neutrophils act synergistically with a larger number of CGD neutrophils to kill aspergillus hyphae providing a rationale for use of granulocyte transfusions in infected CGD patients.
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