Guo Benchang, Zhang Lu, Chiorazzi Nicholas, Rothstein Thomas L
The Feinstein Institute for Medical Research, Manhasset, NY;
The Feinstein Institute for Medical Research, Manhasset, NY; Department of Medicine, North Shore University Hospital, Manhasset, NY; Department of Medicine, and Department of Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, NY.
Blood. 2016 Jul 28;128(4):553-62. doi: 10.1182/blood-2015-11-682997. Epub 2016 May 25.
Chronic lymphocytic leukemia (CLL) cells express poor levels of surface immunoglobulin (sIg), and many are minimally activated or anergic in response to B-cell receptor (BCR) crosslinking in vitro. Paradoxically, CLL cells in patients are highly activated through BCR signaling and expand in proliferation centers, suggesting that the function of sIg signaling is rescued. Here, we find that, compared with normal naïve B cells, CLL cells express a low level of total CD79b protein but normal levels of CD79a and IgM protein. Association of both CD79a and CD79b to IgM is markedly reduced. We further find that interleukin-4 (IL-4) markedly rescues CD79b and sIgM protein in CLL samples. These changes significantly enhance signaling in response to BCR crosslinking. Furthermore, we find that these changes are more pronounced in immunoglobulin heavy chain variable (IGHV)-unmutated CLL cells than IGHV-mutated CLL cells. The results described herein reveal that reduced sIgM is due to low expression of total CD79b protein in CLL cells. IL-4 substantially restores CD79b protein expression, sIgM expression, and BCR signaling.
慢性淋巴细胞白血病（CLL）细胞表面免疫球蛋白（sIg）表达水平较低，许多细胞在体外对B细胞受体（BCR）交联反应的激活程度极低或呈无反应状态。矛盾的是，患者体内的CLL细胞通过BCR信号通路被高度激活，并在增殖中心扩增，这表明sIg信号传导功能得以恢复。在此，我们发现，与正常幼稚B细胞相比，CLL细胞中总CD79b蛋白表达水平较低，但CD79a和IgM蛋白水平正常。CD79a和CD79b与IgM的结合均明显减少。我们进一步发现，白细胞介素-4（IL-4）可显著恢复CLL样本中的CD79b和sIgM蛋白水平。这些变化显著增强了对BCR交联的信号传导。此外，我们发现这些变化在免疫球蛋白重链可变区（IGHV）未突变的CLL细胞中比IGHV突变的CLL细胞中更为明显。本文所述结果表明，CLL细胞中sIgM减少是由于总CD79b蛋白表达水平较低所致。IL-4可显著恢复CD79b蛋白表达、sIgM表达及BCR信号传导。
