Lymphoproliferative Disorders in Primary Immunodeficiencies

原发性免疫缺陷中的淋巴增殖性疾病

• 批准号: 8011454
• 负责人: John Michael Routes
• 金额: $ 28.29万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 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/8011454
• 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; Genes; Genetic Polymorphism; Granulomatous; HIV-1; Herpesviridae; Household; Human; Human Genome; Immune system; Immunologic Deficiency Syndromes; Immunosuppression; Infection; Inflammatory; Interleukin-10; 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

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.

描述（由申请人提供）：我们证明了具有常见可变免疫缺陷（CVID）以及肉芽肿和淋巴细胞间质肺疾病（GLILD）的患者对B细胞淋巴瘤和早期死亡率的发展有高风险。我们还发现，大多数CVID和GLILD（CVID-GLILD）的大多数患者被人类疱疹病毒8型（HHV8）感染。在AIM 1中，我们将确定较大的CVID患者和大量原发性免疫缺陷患者的HHV8感染患病率。为了确定HHV8的来源，我们将确定受感染和未感染的CVID患者的HHV8感染的患病率，并通过通过PCR和DNA Squeencn secenct of K1 Amplicon的DNA Squeencn的高度多型HHV8 K1 ORF来确定感染队列中HHV8的分子系统发育。在AIM 2中，我们将通过检查CVID患者的HHV8感染在淋巴增生性疾病，肺和肝病中的作用，通过检查肺，肝脏或淋巴结组织活检以获取HHV8感染的证据。在AIM 3中，我们将确定细胞免疫的异常是否识别患有HHV8感染风险的CVID患者，并确定IL-6，TNF-1或IL-10基因或Taci基因中CVID患有HHV8感染的TACI基因中的特定启动子多态性。 AIM 1：确定感染HHV8的CVID患者中HHV8的分子系统发育，并确定HHV8是否是较大的CVID患者和其他原发性免疫缺陷患者的机会性病原体。 目标2：确定HHV8感染在CVID患者中肺部疾病，肝病，淋巴增生性疾病的病因中的作用。 AIM 3：确定细胞因子基因的启动子多态性，失调的炎性细胞因子的产生失调以及TACI基因易于感染HHV8的TACI基因的细胞免疫或突变缺陷。