The purpose of this project is to study patients with abnormal host defense; to determine the cause of their abnormality; and to devise effective therapies for their underlying disorder and the life-threatening infections associated with their disease processes. The LHD has a long tradition of investigating patients with abnormalities of phagocytic cell function. These studies include early delineation of the clinical, functional, and in some cases, the molecular defects of patients with neutrophil specific granule deficiency, chronic granulomatous disease of childhood (CGD), leukocyte adhesion deficiency and the syndrome of hyperimmunoglobulin-E and recurrent infections and IRAK-4 deficiency. Cohorts of patients have been collected over the years which we continue to follow at NIH. Currently we follow over 150 patients with CGD, about 40 patients with the hyperimmunoglobulin-E recurrent infection syndrome, and 30 patients with other phagocyte dysfunction syndromes, including leukocyte adhesion deficiency, cyclic neutropenia, neutrophil specific granule deficiency and Chediak-Higashi syndrome and IRAK-4 deficiency. All these patients serve as a national resource for investigators desiring samples from patients and are available for clinical research protocols involving intramural or extramural scientists. We now have EB virus transformed B cells from most of our patients and we have been pleased to share these B cell lines with other intramural or extramural colleagues. We continue to monitor and expand these cohorts of patients who serve as models for long term studies of the immunological manipulation of the abnormal host defenses. For example, this year we showed that a patient who fails to respond to bacterial lipopolysaccharide (LPS) and IL-1 has a defect of the IRAK-4 gene. In addition, we continue to make important clinical observations on these patients which are of use to others providing patient care for these patients and patients with related problems. In 2003 we completed a ten year double blind clinical trial in patients with CGD and demonstrated that itraconazole prophylaxis prevents serious and superficial fungal infections in these patients without significant toxicity. Based on these studies we recommended that itraconazole be added to the regimen of routine medicines used in the management of CGD. In other studies we investigated the basis for excessive granuloma formation in CGD. We showed that CGD neutrophils make 100 fold more IL-8 chemoattractant and increased IL-8 mRNA than normal neutrophils when stimulated with the chemoattractant fmet-leu-phe and this increase is reversed by addition of physiological concentrations of hydrogen peroxide, which is absent in CGD. This abnormal regulation of IL-8 may contribute to the excess granuloma formation in CGD.
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