VH gene use by HIV type 1-associated lymphoproliferations.
VH gene use by HIV type 1-associated lymphoproliferations.
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HIV 1 型相关淋巴细胞增殖使用 VH 基因。
DOI：
10.1089/aid.1997.13.135
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发表时间：
1997
期刊：
影响因子：
--
通讯作者：
McGrath,MS
中科院分区：
文献类型：
--
作者：
Ng,VL;Hurt,MH;Herndier,BG;Fry,KE;McGrath,MS
缺乏传统B细胞辅因子（即，Epstein-Barr病毒[EBV]感染，c-myc易位）知之甚少。一个多步骤的发病机制模型已被提出，其中多克隆淋巴瘤代表了一个早期阶段，在艾滋病毒相关的淋巴瘤发生之前出现的一个占主导地位的恶性克隆。慢性存在的抗原被认为是多克隆B细胞增殖的可能刺激物;如果是这样，多克隆淋巴瘤相关免疫球蛋白（Ig）应该有体细胞超变的分子证据，这是一个抗体亲和力成熟反应于慢性抗原刺激的过程。对缺乏EBV和c-myc重排的多克隆HIV相关大细胞淋巴瘤中B细胞使用的IG重链可变区（VH）基因进行了分子分析。从RT-PCR中随机选择18个克隆，得到15个独特的VH序列，所有这些都是最同源的，只有三个以前确定的生殖系VH 1基因。两组克隆（分别由三个和两个克隆组成）具有相同的VH基因序列，一对克隆具有相同的第三互补决定区（CDR 3），但VH基因序列不同; 8个克隆与其最相关的生殖系VH 1基因同源性<95%。我们比较了这些结果与IG VH 1基因的使用B细胞存在于反应性增生淋巴结从HIV-1感染的个人。从RT-PCR中随机选择15个克隆，得到15个独特的VH 1序列，所有这些序列与先前鉴定的5个生殖系VH 1基因最同源; 10个克隆与其最相关的生殖系基因的同源性<95%。二项式概率分析显示，15个独特的VH 1序列中只有1个来源于多克隆淋巴瘤（即，7%），相比之下，15个来源于反应性淋巴结的独特VH 1序列中有5个（即，33%），具有低概率随机发生（p<0.05）。这些数据提供了HIV相关多克隆淋巴瘤中多克隆性的分子证据，证明了与恶性与反应性B细胞淋巴增殖相关的IG VH基因体细胞超突变的质的差异，并支持HIV-1相关淋巴瘤发生的抗原介导的多步骤发病机制模型。
The pathogenesis of polyclonal HIV-associated lymphomas lacking traditional B cell cofactors (i.e., Epstein-Barr virus [EBV] infection, c-myctranslocations) is poorly understood. A multistep pathogenesis model has been proposed in which polyclonal lymphomas represent an earlier stage in HIV-associated lymphomagenesis before the emergence of a dominant malignant clone. Chronically present antigens have been proposed as a likely stimulus for polyclonal B cell proliferation; if so, polyclonal lymphoma--associated immunoglobulins (Igs) should have molecular evidence of somatic hypermutation, a process by which antibody affinity maturation in response to chronic antigenic stimulation occurs. Molecular analyses of Ig heavy chain variable (VH) gene use by B cells in a polyclonal HIV-associated large cell lymphoma lacking EBV and c-mycrearrangement was undertaken. Eighteen randomly selected clones generated from RT-PCR yielded 15 unique VHsequences, all of which were most homologous to only three previously identified germline VH1 genes. Two sets of clones (consisting of three and two clones, respectively) had identical VHgene sequences, and one pair of clones had identical third complementarity determining regions (CDR3s) but different VHgene sequences; eight clones were <95% homologous to their most related germline VH1 genes. We compared these results with Ig VH1 gene use by B cells present in a reactive hyperplastic lymph node obtained from an HIV-1-infected individual. Fifteen clones randomly selected from RT-PCRs yielded 15 unique VH1 sequences, all of which were most homologous to 5 previously identified germline VH1 genes; 10 clones were <95% homologous to their most related germline gene. Binomial probability analysis revealed that only 1 of the 15 unique VH1 sequences derived from the polyclonal lymphoma (i.e., 7%), as compared with 5 of 15 unique VH1 sequences derived from the reactive lymph node (i.e., 33%), had a low probability of occurrence by random chance (p<0.05). These data provide molecular evidence of polyclonality in an HIV-associated polyclonal lymphoma, demonstrate a qualitative difference in somatic hypermutations of Ig VHgenes associated with malignant versus reactive B cell lymphoproliferations, and support an antigen-mediated multistep pathogenesis model of HIV-1-associated lymphomagenesis.