Lymphoproliferative Disorders in Primary Immunodeficiencies

描述(由申请人提供)：我们证实，患有共同变量免疫缺陷(CVID)和肉芽肿性和淋巴细胞性间质性肺疾病(GLILD)的患者具有发展为B细胞淋巴瘤和早期死亡的高风险。我们还发现，大多数CVID和GLILD(CVID-GLILD)患者感染了人类疱疹病毒8型(HHV8)。在目标1中，我们将确定在大量CVID患者和广泛的原发免疫缺陷患者中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感染的流行率，并通过聚合酶链式反应(PCR)扩增高度多态的HHV8 K1 ORF并对K1扩增片段进行DNA测序来确定HHV8在感染人群中的分子进化。在目标2中，我们将通过检查肺、肝或淋巴组织活检以寻找HHV8感染的证据，从而扩大我们对HHV8感染在CVID患者淋巴组织增生性疾病、肺和肝脏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确定CVID患者有感染HHV8的风险，并确定IL-6、TNF-1或IL-10基因的特定启动子多态性或TACI基因突变是否使CVID患者容易感染HHV8。 目的：确定HHV8在CVID患者中的分子系统发生，并确定在CVID和其他原发免疫缺陷患者中，HHV8是否是一种机会性病原体。 目的：探讨人类疱疹病毒8型(HHV8)感染在CVID患者肺、肝、淋巴组织增生性疾病病因中的作用。 目的：确定细胞因子基因启动子的多态、炎性细胞因子产生的失调、细胞免疫缺陷或TACI基因突变是否使CVID患者易感染HHV8。

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.