Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia
Overexpression of the CXCR5 chemokine receptor, and its ligand, CXCL13 in B-cell chronic lymphocytic leukemia
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DOI：
10.1182/blood-2007-05-089409
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发表时间：
2007-11-01
期刊：
影响因子：
20.3
通讯作者：
Burger, Jan A.
中科院分区：
文献类型：
--
作者：
Buerkle, Andrea;Niedermeier, Matthias;Burger, Jan A.
CXCL13是一种稳态趋化因子，通过其同源受体CXCR5在次级淋巴组织的滤泡内进行淋巴细胞归巢和定位。此外，CXCR5-CXCL13轴在B1细胞的转运和归巢中起着独特的作用。在这里，我们报道慢性淋巴细胞白血病（CLL） B细胞表达高水平的功能性CXCR5。CXCR5在CLL B细胞和正常CD5(+) B细胞中的表达水平相似，与正常CD5(-) B细胞、滤泡B辅助T细胞（T- fh细胞）或其他B细胞肿瘤的肿瘤B细胞相比，CXCR5的表达水平更高。用CXCL13刺激CLL细胞可诱导肌动蛋白聚合、CXCR5内吞、趋化和p44/42丝裂原活化蛋白激酶的延长活化。抗CXCR5抗体、百日咳毒素和wortmannin抑制CXCL13的趋化性，证明Gi蛋白和P13激酶对CXCR5信号传导的重要性。此外，CLL患者血清CXCL13水平明显高于志愿者，且CXCL13水平与02微球蛋白相关。我们检测到CXCL13 mRNA在护士样细胞中的表达，并在CLL护士样细胞培养的上清液中检测到高水平的CXCL13蛋白。通过免疫组化，我们检测了CLL淋巴结内CD68（+）巨噬细胞原位表达CXCL13（+）。这些数据表明，CXCR5在CLL细胞定位以及CLL与淋巴组织中分泌cxcl13的CD68+附属细胞之间的同源相互作用中发挥作用。
CXCL13 is a homeostatic chemokine for lymphocyte homing and positioning within follicles of secondary lymphoid tissues, acting through its cognate receptor, CXCR5. Moreover, the CXCR5-CXCL13 axis plays a unique role in trafficking and homing of B1 cells. Here, we report that chronic lymphocytic leukemia (CLL) B cells express high levels of functional CXCR5. CXCR5 expression levels were similar on CLL B cells and normal CD5(+) B cells, and higher compared with normal CD5(-) B cells, follicular B-helper T cells (T-FH cells), or neoplastic B cells from other B-cell neoplasias. Stimulation of CLL cells with CXCL13 induces actin polymerization, CXCR5 endocytosis, chemotaxis, and prolonged activation of p44/42 mitogen-activated protein kinases. Anti-CXCR5 antibodies, pertussis toxin, and wortmannin inhibited chemotaxis to CXCL13, demonstrating the importance of Gi proteins and P13 kinases for CXCR5 signaling. Moreover, CLL patients had significantly higher CXCL13 serum levels than volunteers, and CXCL13 levels correlated with 02 microglobulin. We detected CXCL13 mRNA expression by nurselike cells, and high levels of CXCL13 protein in supernatants of CLL nurselike cell cultures. By immunohistochemistry, we detected CXCL13(+) expression by CD68(+) macrophages in situ within CLL lymph nodes. These data suggest that CXCR5 plays a role in CLL cell positioning and cognate interactions between CLL and CXCL13-secreting CD68+ accessory cells in lymphoid tissues.