Fais F, Sellars B, Ghiotto F, Yan X J, Dono M, Allen S L, Budman D, Dittmar K, Kolitz J, Lichtman S M, Schulman P, Schuster M, Vinciguerra V P, Rai K, Stevenson F K, Gregersen P K, Ferrarini M, Chiorazzi N
Department of Medicine, North Shore University Hospital and Cornell University Medical College, Manhasset, New York 11030, USA.
J Clin Invest. 1996 Oct 1;98(7):1659-66. doi: 10.1172/JCI118961.
Chronic lymphocytic leukemia (CLL) usually involves the expansion of a clone of CD5+ B cells synthesizing IgM antibodies. These B cells appear to be blocked at the antigen receptor-expressing stage of B cell differentiation and are thought not to undergo an isotype class switch to IgG or IgA production. In vivo and in vitro studies suggest, however, that in some instances terminal differentiation and isotype switching can occur. To test the hypothesis that in vivo isotype class switching occurs in IgM+ B-type CLL cells, we analyzed the PBMC of 19 CLL patients for the presence of transcripts encoding the rearranged CLL V(H)DJ(H) associated with either gamma or alpha H chains. The molecular data indicate that approximately 50% of B-CLL patients have amplifications of IgM+ B cells that undergo an isotype class switch. Switching to IgA appears to occur more often than to IgG; also, switching can involve different IgG subclasses in individual patients. In many instances, these CLL-related gamma and alpha transcripts are much more plentiful than those of normal B cells that produce the same isotype. These switched transcripts do not reveal evidence for the accumulation of significant numbers of new V(H) gene mutations. The cellular data indicate that B cells with lesser amounts of surface membrane IgD and higher IgM/IgD ratios are more likely to undergo this switching process. Furthermore, B cells expressing IgG and IgA of the same idiotype or V(H) family and the same CDR3 length as those of the CLL IgM+ clone can be identified in the blood of patients studied using multiparameter immunofluorescence analyses. Collectively, these data suggest that not all members of a B-CLL clone are frozen at the surface membrane Ig-expressing stage of B cell maturation, and that some members can switch to the production of non-IgM isotypes. The occurrence of switching without the accumulation of V gene mutations indicates that the processes of differentiation and diversification are not linked.
慢性淋巴细胞白血病（CLL）通常涉及合成IgM抗体的CD5 + B细胞克隆的扩增。这些B细胞似乎在B细胞分化的抗原受体表达阶段被阻滞，并且被认为不会经历向IgG或IgA产生的同种型类别转换。然而，体内和体外研究表明，在某些情况下可以发生终末分化和同种型转换。为了检验IgM + B型CLL细胞在体内发生同种型类别转换的假说，我们分析了19例CLL患者的外周血单核细胞（PBMC）中是否存在与γ或α重链相关的重排CLL V(H)DJ(H)编码转录本。分子数据表明，约50%的B - CLL患者有经历同种型类别转换的IgM + B细胞扩增。向IgA的转换似乎比向IgG的转换更常见；此外，在个体患者中，转换可涉及不同的IgG亚类。在许多情况下，这些与CLL相关的γ和α转录本比产生相同同种型的正常B细胞的转录本丰富得多。这些转换后的转录本没有显示出大量新的V(H)基因突变积累的证据。细胞数据表明，表面膜IgD含量较少且IgM/IgD比值较高的B细胞更有可能经历这种转换过程。此外，使用多参数免疫荧光分析可以在研究患者的血液中鉴定出表达与CLL IgM +克隆相同独特型或V(H)家族以及相同CDR3长度的IgG和IgA的B细胞。总体而言，这些数据表明并非B - CLL克隆的所有成员都停滞在B细胞成熟的表面膜Ig表达阶段，并且一些成员可以转换为产生非IgM同种型。在没有V基因突变积累的情况下发生转换表明分化和多样化过程没有关联。
