The purpose of this project is to study patients with abnormal host defense. In FY'96 we continued our long term studies on natural history and disease pathogenesis on patients with abnormal phagocyte function. These included patients with chronic granulomatous disease of childhood, HyperimmunoglobulinE-recurrent infection syndrome (Job's), leukocyte adhesion deficiency and other patients with recurrent infections who do not fall into a specifically defined disease category. In particular, we have focused attention on a 14 yo girl with recurrent life threatening bacterial infections who is refractory to the effects of endotoxin lipopolysaccharide (LPS) in vivo and in vitro. Intravenous challenge of the patient with LPS in vivo caused a subnormal fever, little alteration in the number of circulating neutrophils and subnormal elevations in plasma levels of TNF-alpha, IL-6, IL-8, G-CSF, and lactoferrin but normal levels of the anti-inflammatory mediators IL-1ra and soluble TNF receptor. Although patient monocytes expressed CD14, the LPS receptor, and appeared to bind LPS in a specific manner, patient peripheral blood mononuclear cells failed to produce TNF-alpha and G-CSF after stimulation with LPS in vitro and failed to respond to IL-1, heat-killed S. aureus or soluble glucan. Peripheral blood neutrophils also exhibited normal expression of CD14 but failed to respond to LPS (100-1000ng/ml), a treatment which caused increased expression of C10, CD18, CD11b, CD67, and CD45 and decreased expression of L-selectin in normal neutrophils. Treatment of normal and patient neutrophils with the chemoattractant fmet-leu-phe (0.1 uM) resulted in equivalent altered expression of these surface markers. Patient neutrophils could not be primed by either LPS or IL-1B for enhanced fmet-leu-phe induced superoxide generation, but primed normally to TNF-alpha and platelet-activating factor. This patient, hyporesponsive to LPS and IL-1 with a defect post receptor but early in the signaling cascade, provides an important model for study of LPS signalling.
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