Molecular Immunology Group, Cancer Sciences Division, University of Southampton, School of Medicine, Southampton SO16 6YD, United Kingdom.
Proc Natl Acad Sci U S A. 2010 Oct 26;107(43):18587-92. doi: 10.1073/pnas.1009388107. Epub 2010 Oct 11.
Surface Ig (sIg) of follicular lymphoma (FL) is vital for tumor cell survival. We found previously that the Ig in FL is unusual, because the variable region genes carry sequence motifs for N-glycan addition. These are introduced by somatic mutation and are tumor specific. Unexpectedly, added glycans terminate at high mannose, suggesting a potentially important interaction of FL cells with mannose-binding lectins of the innate immune system. We have now identified mannosylated IgM at the surface of primary lymphoma cells. Recombinant lectin domains of the mannose receptor (MR) or DC-SIGN bind mannosylated Igs in vitro and bind to FL cells, signaling sIgM-associated increases in intracellular Ca(2+). Lectins also bind to normal B cells but fail to signal. In contrast, anti-Ig signaled similarly in both FL and normal B cells. Mannosylation patterns were mimicked by FL Ig-derived single-chain Fvs (scFv), providing probes for potential receptors. Mannosylated scFv bound specifically to the lectin domains of the MR and DC-SIGN and blocked signaling. Mannosylated scFv also bound to DC-SIGN on the surface of dendritic cells. This unique lymphoma-specific interaction of sIg with lectins of innate immunity reveals a potential route for microenvironmental support of tumor cells, mediated via the key B-cell receptor.
滤泡性淋巴瘤（FL）的表面免疫球蛋白（sIg）对肿瘤细胞的存活至关重要。我们之前发现，FL 中的 Ig 是不寻常的，因为可变区基因携带 N-糖基化添加的序列基序。这些是由体细胞突变引入的，并且是肿瘤特异性的。出乎意料的是，添加的糖基终止于高甘露糖，这表明 FL 细胞与先天免疫系统中甘露糖结合凝集素之间存在潜在的重要相互作用。我们现在已经在原发性淋巴瘤细胞的表面上鉴定出了糖基化的 IgM。甘露糖受体（MR）或 DC-SIGN 的重组凝集素结构域在体外与糖基化的 Ig 结合，并与 FL 细胞结合，引发 sIgM 相关的细胞内 Ca(2+)增加。凝集素也与正常 B 细胞结合，但不能发出信号。相比之下，抗 Ig 在 FL 和正常 B 细胞中都发出类似的信号。FL Ig 衍生的单链 Fv（scFv）模拟了糖基化模式，为潜在的受体提供了探针。糖基化的 scFv 特异性结合 MR 和 DC-SIGN 的凝集素结构域，并阻断信号转导。糖基化的 scFv 也与树突状细胞表面的 DC-SIGN 结合。sIg 与先天免疫凝集素的这种独特的淋巴瘤特异性相互作用揭示了肿瘤细胞微环境支持的潜在途径，这是通过关键的 B 细胞受体介导的。
