Przybylski G K, Goldman J, Ng V L, McGrath M S, Herndier B G, Schenkein D P, Monroe J G, Silberstein L E
Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia 19104-6082, USA.
Blood. 1996 Dec 15;88(12):4620-9.
To investigate the origin and pathogenesis of acquired immunodeficiency syndrome (AIDS)-related lymphoma (ARL), we studied 14 cases in which Epstein-Barr virus (EBV) infection was not an etiologic factor. By histology, 8 of the specimens were of the small noncleaved cell type and 6 consisted of the large diffuse cell type. Southern analysis using a J(H) probe was consistent with a monoclonal B-cell tumor in 13 cases. To characterize the expressed Ig genes, we performed reverse transcriptase-polymerase chain reaction (RT-PCR) and direct sequencing of PCR products. Eight cases expressed IgM and 1 case expressed IgG. V(H)3 genes were found in 5 cases, V(H)4 genes in 3 cases, V(H)1 genes in 2 cases, and a V(H)7 gene in 1 case. The nucleotide homology to known germline V(H) genes ranged from 80% to 97%, suggesting significant somatic diversification of expressed V(H) genes. The large proportion of V(H)3-expressing lymphomas in this series corresponds to the frequency of V(H)3-expressing B cells in the peripheral blood from healthy and (recent) human immunodeficiency virus (HIV)-seropositve individuals and contrasts with the V(H)3 clonal deficit observed in late stages of HIV infection. Similar to the Ig heavy chain genes, the corresponding Ig light chain genes showed significant deviation from known germline gene sequences. The large proportion of V(H)3-expressing lymphomas as well as the high degree of somatic deviation from germline suggest that these EBV-negative lymphomas might arise from antigen-selected expanded B-cell clones before transformation. Further support for this hypothesis is provided by sequential Ig sequence analysis in 1 patient with large-cell lymphoma. It was shown that 3 years before the diagnosis of axillary lymphoma, there existed several B-cell clones in this patient's bone marrow. One of these clones present in the bone marrow expressed the same rearranged V(H) gene as the axillary lymphoma. Taken together, the current findings from Ig gene analyses suggest that activation of B cells in the early phase of HIV infection may be a predisposing factor for subsequent B-cell transformation.
为了研究获得性免疫缺陷综合征（AIDS）相关淋巴瘤（ARL）的起源和发病机制，我们研究了14例其中爱泼斯坦-巴尔病毒（EBV）感染并非病因的病例。通过组织学检查，8份标本为小无裂细胞型，6份由大弥漫细胞型组成。使用J(H)探针的Southern分析在13例病例中与单克隆B细胞肿瘤一致。为了表征表达的Ig基因，我们进行了逆转录酶-聚合酶链反应（RT-PCR）并对PCR产物进行直接测序。8例表达IgM，1例表达IgG。5例中发现V(H)3基因，3例中发现V(H)4基因，2例中发现V(H)1基因，1例中发现V(H)7基因。与已知种系V(H)基因的核苷酸同源性范围为80%至97%，表明表达的V(H)基因存在显著的体细胞多样化。该系列中表达V(H)3的淋巴瘤比例较高，与健康人和（近期）人类免疫缺陷病毒（HIV）血清阳性个体外周血中表达V(H)3的B细胞频率相对应，与HIV感染晚期观察到的V(H)3克隆缺陷形成对比。与Ig重链基因类似，相应的Ig轻链基因显示出与已知种系基因序列的显著偏差。表达V(H)3的淋巴瘤比例较高以及与种系的高度体细胞偏差表明，这些EBV阴性淋巴瘤可能在转化前源于抗原选择的扩增B细胞克隆。1例大细胞淋巴瘤患者的连续Ig序列分析为这一假设提供了进一步支持。结果显示，在诊断腋窝淋巴瘤前3年，该患者骨髓中存在多个B细胞克隆。骨髓中存在的这些克隆之一表达与腋窝淋巴瘤相同的重排V(H)基因。综上所述，Ig基因分析的当前发现表明，HIV感染早期B细胞的激活可能是随后B细胞转化的一个易感因素。
