Department of Oncology and Hematology, Hubertus Wald Tumorzentrum/University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
PLoS One. 2010 Dec 30;5(12):e15992. doi: 10.1371/journal.pone.0015992.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Survival of CLL cells depends on their close contact with stromal cells in lymphatic tissues, bone marrow and blood. This microenvironmental regulation of CLL cell survival involves the stromal secretion of chemo- and cytokines as well as the expression of adhesion molecules. Since CLL survival may also be driven by antigenic stimulation through the B-cell antigen receptor (BCR), we explored the hypothesis that these processes may be linked to each other. We tested if stromal cells could serve as an antigen reservoir for CLL cells, thus promoting CLL cell survival by stimulation through the BCR. As a proof of principle, we found that two CLL BCRs with a common stereotyped heavy chain complementarity-determining region 3 (previously characterized as "subset 1") recognize antigens highly expressed in stromal cells--vimentin and calreticulin. Both antigens are well-documented targets of autoantibodies in autoimmune disorders. We demonstrated that vimentin is displayed on the surface of viable stromal cells and that it is present and bound by the stereotyped CLL BCR in CLL-stroma co-culture supernatant. Blocking the vimentin antigen by recombinant soluble CLL BCR under CLL-stromal cell co-culture conditions reduces stroma-mediated anti-apoptotic effects by 20-45%. We therefore conclude that CLL BCR stimulation by stroma-derived antigens can contribute to the protective effect that the stroma exerts on CLL cells. This finding sheds a new light on the understanding of the pathobiology of this so far mostly incurable disease.
慢性淋巴细胞白血病（CLL）是西方世界最常见的白血病。CLL 细胞的存活依赖于它们与淋巴组织、骨髓和血液中的基质细胞的紧密接触。这种 CLL 细胞存活的微环境调节涉及基质细胞分泌的趋化因子和细胞因子以及粘附分子的表达。由于 CLL 的存活也可能通过 B 细胞抗原受体（BCR）的抗原刺激驱动，我们探索了这样一种假设，即这些过程可能相互关联。我们测试了基质细胞是否可以作为 CLL 细胞的抗原库，从而通过 BCR 的刺激促进 CLL 细胞的存活。作为原理验证，我们发现两个具有共同刻板重链互补决定区 3（先前被表征为“亚组 1”）的 CLL BCR 识别高度表达在基质细胞中的抗原——波形蛋白和钙网蛋白。这两种抗原都是自身免疫性疾病中自身抗体的公认靶标。我们证明了波形蛋白在存活的基质细胞表面表达，并且在 CLL-基质共培养上清液中存在并被刻板的 CLL BCR 结合。在 CLL-基质细胞共培养条件下，用重组可溶性 CLL BCR 阻断波形蛋白抗原可使基质介导的抗凋亡作用降低 20-45%。因此，我们得出结论，基质衍生抗原对 CLL BCR 的刺激可以有助于基质对 CLL 细胞发挥的保护作用。这一发现为理解这种迄今为止基本上无法治愈的疾病的病理生物学提供了新的视角。
