CLINICAL STUDIES OF ABNORMAL HOST DEFENSE

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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 Chediak-Higashi syndrome, neutrophil specific granule deficiency, chronic granulomatous disease of childhood (CGD), leukocyte adhesion deficiency and the syndrome of hyperimmunoglobulin-E and recurrent infections. Cohorts of patients have been collected over the years which we continue to follow at NIH. Currently we follow over 100 patients with CGD, about 30 patients with the hyperimmunoglobulin-E recurrent infection syndrome, and 18 patients with other phagocyte dysfunction syndromes, including leukocyte adhesion deficiency, cyclic neutropenia, neutrophil specific granule deficiency and Chediak-Higashi syndrome. 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. 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. For example, we demonstrated a patient with life-threatening infections whose phagocytes fail to respond to endotoxin. We are dissecting the molecular basis for failed endotoxin responsiveness in this patient and this year demonstrated her neutrophils fail to activate P38 kinase in response to endotoxin. In addition we demonstrated that the mutation in a patient with neutrophil specific granule deficiency resulted from a novel mutation with loss of function of the transcription factor CCAAT/enhancer binding protein epsilon. In other studies we showed that the hyper IgE syndrome with recurrent infections is an autosomal dominant multisystem disorder with a genetic mutation that maps to chromosome 4.