Lymphoproliferative Disorders in Primary Immunodeficiencies

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疾病（GLILD）是高风险的， B细胞淋巴瘤的发展和早期死亡率。我们还发现，大多数患者 用人疱疹病毒8型（HHV 8）感染CVID和GLILD（CVID-GLILD）。在 目的1，我们将确定HHV 8感染的患病率在一个更大的队列患者， CVID和广谱原发性免疫缺陷患者。确定…的来源 HHV 8，我们将确定家庭成员和家庭中HHV 8感染的流行情况 感染和未感染CVID患者的接触者，并确定分子遗传学 通过PCR扩增高度多态性的HHV 8 K1 ORF来检测感染队列中的HHV 8，并 进行K1扩增子的DNA测序。在目标2中，我们将扩大我们的观察， HHV 8感染在淋巴组织增生性疾病、肺和肝脏疾病患者中作用 通过检查肺、肝或淋巴结组织活检的HHV 8证据， 感染在目标3中，我们将确定细胞免疫异常是否能识别出患有 CVID有感染HHV 8的风险，并确定IL-10基因中的特异性启动子多态性是否与CVID相关。 6、TNF-或IL-10基因或TACI基因突变使CVID患者易患 感染HHV 8。 目的1：确定HHV 8感染CVID患者的HHV 8分子遗传学， 在更大的CVID患者队列中确定HHV 8是否为机会致病菌， 其他原发性免疫缺陷。 目的2：明确HHV 8感染在肺部疾病、肝脏疾病、 CVID患者的淋巴组织增生性疾病。 目的3：确定细胞因子基因启动子多态性，失调的炎症反应， 细胞因子的产生和细胞免疫缺陷或TACI基因突变使 CVID患者感染HHV 8。

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-α 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.