Autoantibody-associated kappa light chain variable region gene expressed in chronic lymphocytic leukemia with little or no somatic mutation. Implications for etiology and immunotherapy.
Autoantibody-associated kappa light chain variable region gene expressed in chronic lymphocytic leukemia with little or no somatic mutation. Implications for etiology and immunotherapy.
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DOI：
10.1084/jem.167.3.840
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发表时间：
1988-03-01
期刊：
影响因子：
--
通讯作者：
Carson DA
中科院分区：
文献类型：
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作者：
Kipps TJ;Tomhave E;Chen PP;Carson DA
最近，表达CD 5（Leu-1）抗原的次要B细胞亚群被认为是IgM自身抗体的来源。慢性淋巴细胞性白血病（CLL）是人类最常见的白血病，代表也表达CD 5抗原的小B淋巴细胞的恶性肿瘤。然而，关于这些恶性CD 5 B细胞所使用的抗体可变区基因（V基因）知之甚少。我们发现，相对高频率的CLL患者具有白血病B细胞，其表面免疫球蛋白（sIg）被17.109识别，17.109是一种鼠单克隆抗体，特异于与类风湿因子和其他IgM自身抗体相关的κ轻链相关交叉反应独特型（CRI）。流式细胞术分析表明，白血病B细胞中17.109-CRI的相对表达量与sIg κ轻链水平成正比，表明白血病人群中存在稳定的独特型表达。为了在分子水平上检验这一点，测定了编码两名携带17.109-CRI的sIG的不相关CLL患者的IG κ轻链的核酸序列。多个独立的κ轻链cDNA克隆的分析未显示CLL细胞群体中序列异质性的任何证据。此外，这两名患者的白血病细胞表达的核酸序列与从胎盘DNA中分离的种系V κ基因相同或非常同源，命名为Humanoid 325或“V κ RF”，因为它与IgM自身抗体相关。这项研究表明;（a）CLL中的恶性CD 5 + B淋巴细胞使用与IgM自身抗体高度相关的相同V κ基因，和（B）与迄今为止检查的其它B细胞恶性肿瘤相比，V基因的表达在CLL中是稳定的。我们提出，许多CLL的情况下，代表恶性肿瘤的自身反应性CD 5 B细胞，使用一组有限的保守的V基因。这种特性可能使CLL特别适合于用抗独特型抗体进行免疫治疗。
Recently the minor B cell subpopulation that expresses the CD5 (Leu-1) antigen has been implicated as a source of IgM autoantibodies. Chronic lymphocytic leukemia (CLL), the most common leukemia in humans, represents a malignancy of small B lymphocytes that also express the CD5 antigen. However, little is known concerning the antibody variable region genes (V genes) that are used by these malignant CD5 B cells. We have found that a relatively high frequency of CLL patients have leukemic B cells with surface immunoglobulin (sIg) recognized by 17.109, a murine mAb specific for a kappa light chain associated crossreactive idiotype (CRI) associated with rheumatoid factor and other IgM autoantibodies. Flow cytometric analyses revealed that the relative expression of the 17.109-CRI by circulating leukemic B cells was directly proportional to the levels of sIg kappa light chain, indicating that there exists stable idiotype expression in the leukemic population. To examine this at the molecular level, the nucleic acid sequences encoding the Ig kappa light chains of two unrelated patients with CLL bearing sIg with the 17.109-CRI were determined. Analyses of multiple independent kappa light chain cDNA clones did not reveal any evidence for sequence heterogeneity in the CLL cell population. Furthermore, the nucleic acid sequences expressed by the leukemic cells of these two patients were identical or very homologous to a germline V kappa gene isolated from placental DNA, designated Humkv 325, or "V kappa RF" because of its association with IgM autoantibodies. This study suggests; (a) that the malignant CD5+ B lymphocytes in CLL use the same V kappa gene that has been highly associated with IgM autoantibodies and (b) that the expression of V genes is stable in CLL, in contrast to other B cell malignancies examined to date. We propose that many CLL cases represent malignancies of autoreactive CD5 B cells that use a restricted set of conserved V genes. This property may render CLL particularly amenable to immunotherapy with antiidiotypic antibodies.