Lymphoproliferative Disorders in Primary Immunodeficiencies

原发性免疫缺陷中的淋巴增殖性疾病

基本信息

批准号：
7546580
负责人：
John Michael Routes
金额：
$ 31.44万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7546580
关键词：
B-Cell Lymphomas B-Cell NonHodgkins Lymphoma Biopsy Bone Marrow Cancer Etiology Cellular Immunity Chronic Active Hepatitis Common Variable Immunodeficiency Cytokine Gene DNA Sequence Defect Development Etiology Family member Genetic Polymorphism Granulomatous HIV-1 Herpesviridae Household Human Human Genome IL10 gene Immune system Immunologic Deficiency Syndromes Immunosuppression Infection Inflammatory Interleukin-6 Interstitial Lung Diseases Link Liver Liver diseases Lung Lung diseases Lymph Node Tissue Lymphocyte Lymphoproliferative Disorders Malignant - descriptor Malignant Neoplasms Molecular Morbidity - disease rate Mutation Open Reading Frames Patients Phylogeny Prevalence Production Risk Role Source Staging Susceptibility Gene TNF gene Virus cohort cytokine high risk latent nuclear antigen liver biopsy lymph nodes mortality pathogen promoter

项目摘要

DESCRIPTION (provided by applicant): We demonstrated that patients with common variable immunodeficiency (CVID) and granulomatous and lymphocytic interstitial lung disease (GLILD) are at high risk for the development of B cell lymphomas and early mortality. We also found that a majority of patients with CVID and GLILD (CVID-GLILD) were infected with human herpes virus type 8 (HHV8). In Aim 1, we will determine the prevalence of HHV8 infection in patients with a larger cohort of patients with CVID and broad spectrum of primary immunodeficiencies. To identify the source of HHV8, we will determine the prevalence of HHV8 infection in family members and household contacts of infected and uninfected patients with CVID and determine the molecular phylogeny of HHV8 in infected cohorts by amplifying the highly polymorphic HHV8 K1 ORF by PCR and performing DNA sequencing of the K1 amplicon. In Aim 2, we will expand our observations on the role of HHV8 infection in lymphoproliferative disorders, lung and liver disease in patients with CVID by examining lung, liver or lymph node tissue biopsies for evidence of HHV8 infection. In Aim 3, we will determine if abnormalities in cellular immunity identify patients with CVID at risk for infection with HHV8 and determine if specific promoter polymorphisms in the IL- 6, TNF-1 or IL-10 genes or mutations in the TACI gene predispose patients with CVID to infection with HHV8. Aim 1: Ascertain the molecular phylogeny of HHV8 in CVID patients infected with HHV8 and determine if HHV8 is an opportunistic pathogen in a larger cohort of patients with CVID and other primary immunodeficiencies. Aim 2: Ascertain the role of HHV8 infection in the etiology of lung disease, liver disease, lymphoproliferative disorders in patients with CVID. Aim 3: Determine if promoter polymorphisms of cytokine genes, dysregulated inflammatory cytokine production, and defects in cellular immunity or mutations in the TACI gene predispose patients with CVID to infection with HHV8.Project Narrative People with impaired immune systems (primary immunodeficiency) have an increased risk of developing and dying from cancer. In this application, we will try to determine the cause of the cancer that occurs in patients with primary immunodeficiency.

描述（由申请人提供）：我们证明患有常见变异型免疫缺陷（CVID）和肉芽肿性和淋巴细胞性间质性肺病（GLILD）的患者发生 B 细胞淋巴瘤和早期死亡的风险很高。我们还发现，大多数 CVID 和 GLILD 患者 (CVID-GLILD) 感染了人类疱疹病毒 8 型 (HHV8)。在目标 1 中，我们将确定更大范围的 CVID 和广泛原发性免疫缺陷患者中 HHV8 感染的患病率。为了确定 HHV8 的来源，我们将确定感染和未感染 CVID 患者的家庭成员和家庭接触者中 HHV8 感染的患病率，并通过 PCR 扩增高度多态性的 HHV8 K1 ORF 并执行K1 扩增子的 DNA 测序。在目标 2 中，我们将通过检查肺、肝或淋巴结组织活检是否有 HHV8 感染的证据，扩大对 HHV8 感染在 CVID 患者淋巴增殖性疾病、肺和肝疾病中的作用的观察。在目标 3 中，我们将确定细胞免疫异常是否可识别有 HHV8 感染风险的 CVID 患者，并确定 IL-6、TNF-1 或 IL-10 基因中的特定启动子多态性或 TACI 基因中的突变是否会使患者易感CVID 感染 HHV8。目标 1：确定感染 HHV8 的 CVID 患者中 HHV8 的分子系统发育，并确定 HHV8 是否是更大的 CVID 和其他原发性免疫缺陷患者群体中的机会性病原体。目标 2：确定 HHV8 感染在 CVID 患者肺病、肝病、淋巴增殖性疾病病因中的作用。目标 3：确定细胞因子基因的启动子多态性、炎症细胞因子产生失调以及细胞免疫缺陷或 TACI 基因突变是否会使 CVID 患者容易感染 HHV8。项目叙述免疫系统受损（原发性免疫缺陷）的人患癌症和死于癌症的风险增加。在此应用中，我们将尝试确定原发性免疫缺陷患者发生癌症的原因。