Ng V L, Hurt M H, Herndier B G, Fry K E, McGrath M S
Department of Laboratory Medicine, University of California School of Medicine, San Francisco, USA.
AIDS Res Hum Retroviruses. 1997 Jan 20;13(2):135-49. doi: 10.1089/aid.1997.13.135.
The pathogenesis of polyclonal HIV-associated lymphomas lacking traditional B cell cofactors (i.e., Epstein-Barr virus [EBV] infection, c-myc translocations) 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 (V(H)) gene use by B cells in a polyclonal HIV-associated large cell lymphoma lacking EBV and c-myc rearrangement was undertaken. Eighteen randomly selected clones generated from RT-PCR yielded 15 unique V(H) sequences, all of which were most homologous to only three previously identified germline V(H)1 genes. Two sets of clones (consisting of three and two clones, respectively) had identical V(H) gene sequences, and one pair of clones had identical third complementarity determining regions (CDR3s) but different V(H) gene sequences; eight clones were <95% homologous to their most related germline V(H)1 genes. We compared these results with Ig V(H)1 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 V(H)1 sequences, all of which were most homologous to 5 previously identified germline V(H)1 genes; 10 clones were <95% homologous to their most related germline gene. Binomial probability analysis revealed that only 1 of the 15 unique V(H)1 sequences derived from the polyclonal lymphoma (i.e., 7%), as compared with 5 of 15 unique V(H)1 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 V(H) genes associated with malignant versus reactive B cell lymphoproliferations, and support an antigen-mediated multistep pathogenesis model of HIV-1-associated lymphomagenesis.
缺乏传统B细胞辅助因子（即爱泼斯坦 - 巴尔病毒[EBV]感染、c - myc易位）的多克隆HIV相关淋巴瘤的发病机制尚不清楚。有人提出了一种多步骤发病机制模型，其中多克隆淋巴瘤代表HIV相关淋巴瘤发生过程中在显性恶性克隆出现之前的早期阶段。长期存在的抗原被认为是多克隆B细胞增殖的可能刺激因素；如果是这样，多克隆淋巴瘤相关免疫球蛋白（Igs）应该有体细胞超突变的分子证据，体细胞超突变是一个抗体亲和力成熟以应对慢性抗原刺激的过程。对一例缺乏EBV和c - myc重排的多克隆HIV相关大细胞淋巴瘤中的B细胞使用免疫球蛋白重链可变区（V(H)）基因进行了分子分析。从逆转录聚合酶链反应（RT - PCR）产生的18个随机选择的克隆中获得了15个独特的V(H)序列，所有这些序列与仅三个先前鉴定的种系V(H)1基因最同源。两组克隆（分别由三个和两个克隆组成）具有相同的V(H)基因序列，一对克隆具有相同的第三个互补决定区（CDR3）但V(H)基因序列不同；八个克隆与其最相关的种系V(H)1基因的同源性小于95%。我们将这些结果与从一名HIV - 1感染个体获得的反应性增生性淋巴结中的B细胞使用的免疫球蛋白V(H)1基因进行了比较。从RT - PCR中随机选择的15个克隆产生了15个独特的V(H)1序列，所有这些序列与5个先前鉴定的种系V(H)1基因最同源；10个克隆与其最相关的种系基因的同源性小于95%。二项式概率分析显示，多克隆淋巴瘤来源的15个独特V(H)1序列中只有1个（即7%），与反应性淋巴结来源的15个独特V(H)1序列中的5个（即33%）相比，随机出现的概率较低（p < 0.05）。这些数据为HIV相关多克隆淋巴瘤中的多克隆性提供了分子证据，证明了与恶性和反应性B细胞淋巴增殖相关的免疫球蛋白V(H)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多步骤发病机制模型。
