CLINICAL STUDIES OF ABNORMAL HOST DEFENSE

这个项目的目的是研究宿主防御异常的患者；确定他们异常的原因；并为他们潜在的疾病和与他们的疾病过程相关的危及生命的感染设计有效的治疗方法。LHD调查吞噬细胞功能异常患者的传统由来已久。这些研究包括早期描述Chediak-Higashi综合征、中性粒细胞特殊颗粒缺陷、儿童慢性肉芽肿性疾病(CGD)、白细胞黏附缺陷以及高免疫球蛋白-E综合征和反复感染患者的临床、功能和某些情况下的分子缺陷。多年来已经收集了患者队列，我们在NIH继续跟踪调查。目前，我们跟踪观察了100多名CGD患者，约30名高免疫球蛋白-E反复感染综合征患者，以及18名其他吞噬细胞功能障碍综合征患者，包括白细胞黏附缺陷、循环中性粒细胞减少、中性粒细胞特异性颗粒缺陷和Chediak-Higashi综合征。所有这些患者都是希望从患者身上获取样本的研究人员的全国性资源，并可用于涉及院内或院外科学家的临床研究方案。我们现在有来自我们大多数患者的EB病毒转化的B细胞，我们很高兴与其他壁内外同事分享这些B细胞系。我们继续监测和扩大这些患者队列，这些患者作为长期研究异常宿主防御的免疫操纵的模型。此外，我们继续对这些患者进行重要的临床观察，以帮助其他人为这些患者和有相关问题的患者提供患者护理。例如，我们展示了一位患有危及生命的感染的患者，其吞噬细胞对内毒素没有反应。我们正在剖析这位患者内毒素反应失败的分子基础，今年证明她的中性粒细胞未能激活P38激酶对内毒素的反应。此外，我们还证明，中性粒细胞特异性颗粒缺陷患者的突变是由于一种新的突变导致的，该突变带有转录因子CCAAT/增强子结合蛋白epsilon的功能丧失。在其他研究中，我们发现伴有反复感染的高IgE综合征是一种常染色体显性多系统疾病，其基因突变映射到4号染色体。

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.