Lymphoproliferative Disorders in Primary Immunodeficiencies

描述（由申请方提供）：我们证明了普通变异型免疫缺陷（CVID）和肉芽肿性和淋巴细胞性间质性肺病（GLILD）患者发生B细胞淋巴瘤和早期死亡的风险较高。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（HHV 8）。在目标1中，我们将确定HHV 8感染在更大的CVID和广谱原发性免疫缺陷患者队列中的患病率。为了确定HHV 8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HHV 8感染的患病率，并通过PCR扩增高度多态性的HHV 8 K1 ORF并对K1扩增子进行DNA测序来确定感染队列中HHV 8的分子遗传学。在目标2中，我们将通过检查肺、肝脏或淋巴结组织活检来寻找HHV 8感染的证据，扩大我们对HHV 8感染在CVID患者淋巴增生性疾病、肺部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可识别存在HHV 8感染风险的CVID患者，并确定IL- 6、TNF-1或IL-10基因的特异性启动子多态性或TACI基因的突变是否使CVID患者易感染HHV 8。 目标1：在感染HHV 8的CVID患者中确定HHV 8的分子遗传学，并确定HHV 8是否是CVID和其他原发性免疫缺陷患者的更大队列中的机会病原体。 目的2：探讨HHV 8感染在CVID患者肺部、肝脏、淋巴组织增生性疾病中的作用。 目标3：确定细胞因子基因启动子多态性、炎症细胞因子产生失调、细胞免疫缺陷或TACI基因突变是否使CVID患者易感染HHV 8。 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。在本申请中，我们将尝试确定原发性免疫缺陷患者发生癌症的原因。

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.