The major objective of this project has been to study neutrophil function in health and disease. Determination of the biochemical and genetic basis of inherited diseases affecting phagocytes and associated with recurrent infections, and the diagnosis and treatment of these diseases is a major component of this project. Also within the scope of this project is the study of in vitro model systems of these inherited diseases using preparations of phagocytic cells derived from normal volunteers and patients. We have shown that Chronic Granulomatous Diseases (CGD) are a heterogeneous group of diseases resulting from absent H202 production by phagocytes, associated with recurrent infections. The X-lined form results from a defect in the gene coding for the 91 kDa subunit of cytochrome b. We show that different kindreds have different lesions of this gene, in that some patients make no mRNA coding for this protein, others make mRNA but no protein, while some make a functionally defective protein. These observations suggest that the gene defect may be a new mutation in may kindreds and that mutations occur at different sites. We have recently shown that there are two forms of cytochrome b-positive, autosomal recessive CGD. The most common form is missing a 47 kDa cytosol protein, whose phosphorylation plays a role in activation of neutrophils oxidative metabolism. We have demonstrated that the lesion responsible for neutrophil specific granule deficiency is a differentiation stage specific lesion in myeloid cell gene regulation. In particular, there is a failure of lactoferrin mRNA production in myeloid cells, but lactoferrin is synthesized normally in nasal secretions of specific granule deficient patients.
Showing the most recent 10 out of 30 publications
