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

描述(由申请人提供)：评估临床疾病的遗传易感性是个性化医疗保健愿景的核心主题。罕见的有害生殖系突变已被发现导致多达150种不同的初级免疫缺陷。在大多数情况下，易患多种传染病。然而，现在变得明显的是，某些基因的罕见突变可以导致更微妙/更狭窄的临床表型。这项研究的目的是建立一种体外全基因组转录组分析，以测量此类患者的白细胞对宿主和病原体来源的免疫激活剂的反应。具体地说，我们首次提出对对照受试者的血液白细胞反应性进行表征。这一目标将使用全基因组表达微阵列来评估暴露于Toll样受体和白介素1受体家族配体的12名健康受试者的全血反应性。其次，我们将确定已知先天TLR免疫缺陷患者血液中血白细胞反应性模式的具体变化。这一目标将评估18名因两个关键信号分子IRAK4和MYD88功能缺陷而对侵袭性肺炎球菌疾病易感性增加的受试者的反应性。总而言之，该项目将作为开发新工具的基础，以筛选和表征初级免疫缺陷。 与公共卫生的相关性：构成了开发新的全基因组转录组分析战略的基础，用于检测和识别初级免疫缺陷。这项检测可用于确定对反复发生的危及生命的感染的敏感性。

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.