PHAGOCYTIC CELL FUNCTION

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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-linked form is usually associated with absence of cytochrome b from phagocytes, while the autosomal form does not lack cytochrome b. We have documented exceptions to this, and even an autosomal dominant form. We have found that Interferon gamma treatment of monocytes from some CGD patients (usually autosomal form) results in normalization of H202 production, suggesting that this may be a treatment modality. Granuloma formation in CGD may cause obstructions, but our studies indicate good outcome with steroid therapy. An in vitro model of granuloma formation using monocytes suggests that CGD patients may not effectively destroy inflammatory mediators such as LTB4, leading to exuberant cellular reaction and granuloma. We have been studying a patient with deficiency of specific granules. Further study indicated the absence of defensins, bactericidal proteins present in azurophil granules. Although this patient also fails to make lactoferrin, Southern blots indicate that he has the gene for this protein. This disease may be a defect in gene regulation.