CLINICAL STUDIES OF ABNORMAL HOST DEFENSE

本项目的目的是研究宿主异常的患者 防御 在1996财政年度，我们继续进行自然历史的长期研究 以及吞噬细胞功能异常患者的发病机制。 这些患者包括儿童慢性肉芽肿性疾病， 高免疫球蛋白E-复发性感染综合征（Job's），白细胞 粘连缺陷和其他复发性感染的患者， 不属于特定的疾病类别。我们尤其 将注意力集中在一名14岁的女孩身上， 对内毒素的作用难治的细菌感染 脂多糖（LPS）在体内和体外。静脉内激发 体内LPS感染者发热低于正常，变化不大 在循环中性粒细胞的数量和低于正常的升高， TNF-α、IL-6、IL-8、G-CSF和乳铁蛋白的血浆水平，但正常 抗炎介质IL-1ra和可溶性TNF水平 受体的 虽然患者单核细胞表达CD14，LPS受体， 并且似乎以特定的方式结合LPS，患者外周血 单个核细胞在刺激后不能产生TNF-α和G-CSF LPS体外刺激，对IL-1无反应，热灭活S.金黄色 或可溶性葡聚糖。 外周血中性粒细胞也显示正常 CD14表达，但对LPS（100 - 1000ng/ml）无反应， 治疗引起C10、CD 18、CD 11b、CD 67 正常中性粒细胞中L-选择素表达降低。 用化学引诱物处理正常和患者中性粒细胞 fmet-leu-phe（0.1 μ M）导致这些蛋白质的表达的等效改变。 表面标记。 患者中性粒细胞不能被LPS预充 或IL-1B用于增强fmet-leu-phe诱导的超氧化物生成，但 正常情况下对TNF-α和血小板活化因子有反应。 这 患者，对LPS和IL-1低反应，受体后缺陷，但 早期的信号级联，提供了一个重要的模型， LPS信号传导。

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.