Genome-wide profiling of immune responsiveness in patients with primary immunodef

描述（由申请人提供）：评估遗传决定的临床疾病易感性是个性化医疗保健愿景的核心主题。已经发现罕见的有害生殖系突变导致多达150种不同的原发性免疫缺陷。在大多数情况下，易患多种传染病。然而，现在越来越明显的是，一些基因中的罕见突变可能导致更微妙/狭窄的临床表型。本研究旨在建立一种离体全基因组转录组测定法，以测量此类患者中白细胞对宿主和病原体源性免疫激活剂的反应。具体来说，我们首先提出在对照组受试者的血液白细胞反应的特点。该目标将使用全基因组表达微阵列来评估暴露于Toll样和白细胞介素1受体家族配体的12名健康受试者的全血中的反应性。其次，我们将确定特定的改变模式的血液白细胞反应性的患者的血液中已知的先天性缺陷的TLR免疫。该目标将评估18名受试者的反应性，这些受试者对侵袭性肺炎球菌疾病的易感性增加归因于两种关键信号分子IRAK 4和MYD 88的功能缺陷。总之，该项目将作为开发新工具的基础，以筛选和表征原发性免疫缺陷。 公共卫生相关性：为开发新的全基因组转录组谱分析策略以检测和鉴定原发性免疫缺陷奠定了基础。该测定可用于确定对复发性、危及生命的感染的易感性。

DESCRIPTION (provided by applicant): The assessment of genetically determined predispositions to clinical diseases is a theme central to the vision of a personalized health care. Rare deleterious germline mutations have been found to cause up to 150 different primary immunodeficiencies. In most instances, there is predisposition to multiple infectious diseases. However, it is now becoming apparent that rare mutations in some genes can result in more subtle/narrow clinical phenotypes. This study aims at establishing an ex-vivo genome-wide transcriptome assay to measure leukocyte responses to host- and pathogen-derived immune activators in such patients. Specifically, we are first proposing to characterize blood leukocyte responsiveness in control subjects. This aim will use whole genome expression microarrays to assess responsiveness in whole blood of 12 healthy subjects exposed to Toll-like and Interleukin 1 receptor family ligands. Secondly, we will identify specific alterations in patterns of blood leukocyte responsiveness in the blood of patients with known inborn errors of TLR immunity. This aim will assess responsiveness of 18 subjects with increased susceptibility to invasive pneumococcal disease attributed to a defect in function of two key signaling molecules: IRAK4 and MYD88. Altogether this project will serve as a foundation for the development of novel tools to screen for and characterize primary immune deficiencies. PUBLIC HEALTH RELEVANCE: Constitutes a basis for the development of novel genome-wide transcriptome profiling strategy for the detection and identification of primary immunodeficiencies. This assay may be used for determining susceptibility to recurrent, life threatening infections.