Korganow A S, Martin T, Weber J C, Lioure B, Lutz P, Knapp A M, Pasquali J L
Laboratory of Immunopathology, Hôpitaux Universitaires de Strasbourg, France.
Leuk Lymphoma. 1994 Jun;14(1-2):55-69. doi: 10.3109/10428199409049651.
Several genetic mechanisms have been shown to diversify the expressed antibody repertoire of committed B lymphocytes. These include V gene replacement, ongoing gene rearrangement and somatic hypermutation. These mechanisms may be operational at discrete points in the B cell differentiation pathway and generate idiotype diversity in various malignant B cell tumors. In particular, V region mutations have been established as a major mechanism of tumor escape from anti-idiotype immunotherapy in some lymphoma. On the other hand, previous studies on a few selected cases have shown that this mutation process does not affect the B cell clone during chronic lymphocytic leukemia. However, to what extent this intraclonal stability is a general phenomenon during B cell CLL is not clear. Therefore, we randomly selected 6 patients suffering from classical B cell CLL (sIgM (+), CD5 (+), CD19 (+)) at different stages of the disease and analysed the intraclonal variability of the expressed variable region of the heavy chain (VH). After PCR amplification of the cDNA corresponding to the rearranged VDJ regions, the products were cloned and sequenced. In five cases, multiple clone analysis did not show any intraclonal variability whatever the stage of the disease. Furthermore, in a single case, this intraclonal stability was confirmed during a three year period of time when the disease progressed. The sixth case behaved differently since we found multiple nucleotide substitutions, apparently accumulating as the malignant clone expanded. Besides the theoretical difficulties that these changes can induce during immunotherapy, two findings merit further discussion: 1) the distribution of the ongoing mutations affecting the VH region was not suggestive of an antigen driven selection, 2) this intraclonal variability was specific for the VH region, since the VL region showed no intraclonal variation.
几种遗传机制已被证明可使定向B淋巴细胞表达的抗体库多样化。这些机制包括V基因置换、持续的基因重排和体细胞超突变。这些机制可能在B细胞分化途径的不同阶段起作用，并在各种恶性B细胞肿瘤中产生独特型多样性。特别是，V区突变已被确定为某些淋巴瘤中肿瘤逃避抗独特型免疫治疗的主要机制。另一方面，先前对少数选定病例的研究表明，在慢性淋巴细胞白血病期间，这种突变过程不会影响B细胞克隆。然而，这种克隆内稳定性在B细胞慢性淋巴细胞白血病中在多大程度上是一种普遍现象尚不清楚。因此，我们随机选择了6例处于疾病不同阶段的经典B细胞慢性淋巴细胞白血病患者（sIgM(+)、CD5(+)、CD19(+)），并分析了重链可变区（VH）表达的克隆内变异性。在对与重排的VDJ区相对应的cDNA进行PCR扩增后，将产物克隆并测序。在5例病例中，无论疾病处于何阶段，多克隆分析均未显示任何克隆内变异性。此外，在1例病例中，在疾病进展的3年期间证实了这种克隆内稳定性。第6例病例表现不同，因为我们发现了多个核苷酸取代，显然随着恶性克隆的扩增而积累。除了这些变化在免疫治疗期间可能引发的理论难题外，有两个发现值得进一步讨论：1）影响VH区的持续突变的分布不提示抗原驱动的选择，2）这种克隆内变异性是VH区特有的，因为VL区未显示克隆内变异。
