He Bing, Chadburn Amy, Jou Erin, Schattner Elaine J, Knowles Daniel M, Cerutti Andrea
Departments of Pathology and Laboratory Medicine, Weill Medical College, Cornell University, New York, NY 10021, USA.
J Immunol. 2004 Mar 1;172(5):3268-79. doi: 10.4049/jimmunol.172.5.3268.
The mechanisms underlying the autonomous accumulation of malignant B cells remain elusive. We show in this study that non-Hodgkin's lymphoma (NHL) B cells express B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), two powerful B cell-activating molecules usually expressed by myeloid cells. In addition, NHL B cells express BAFF receptor, which binds BAFF, as well as transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation Ag (BCMA), which bind both BAFF and APRIL. Neutralization of endogenous BAFF and APRIL by soluble TACI and BCMA decoy receptors attenuates the survival of NHL B cells, decreases activation of the prosurvival transcription factor NF-kappaB, down-regulates the antiapoptotic proteins Bcl-2 and Bcl-x(L), and up-regulates the proapoptotic protein Bax. Conversely, exposure of NHL B cells to recombinant or myeloid cell-derived BAFF and APRIL attenuates apoptosis, increases NF-kappaB activation, up-regulates Bcl-2 and Bcl-x(L), and down-regulates Bax. In some NHLs, exogenous BAFF and APRIL up-regulate c-Myc, an inducer of cell proliferation; down-regulate p53, an inhibitor of cell proliferation; and increase Bcl-6, an inhibitor of B cell differentiation. By showing that nonmalignant B cells up-regulate BAFF and APRIL upon stimulation by T cell CD40 ligand, our findings indicate that NHL B cells deregulate an otherwise physiological autocrine survival pathway to evade apoptosis. Thus, neutralization of BAFF and APRIL by soluble TACI and BCMA decoy receptors could be useful to dampen the accumulation of malignant B cells in NHL patients.
恶性B细胞自主积累的潜在机制仍不清楚。我们在本研究中表明，非霍奇金淋巴瘤（NHL）B细胞表达肿瘤坏死因子家族的B细胞活化因子（BAFF）和增殖诱导配体（APRIL），这两种强大的B细胞活化分子通常由髓样细胞表达。此外，NHL B细胞表达与BAFF结合的BAFF受体，以及与BAFF和APRIL均结合的跨膜激活剂和钙调蛋白及亲环素配体相互作用分子（TACI）和B细胞成熟抗原（BCMA）。可溶性TACI和BCMA诱饵受体对内源性BAFF和APRIL的中和作用减弱了NHL B细胞的存活，降低了促生存转录因子NF-κB的激活，下调了抗凋亡蛋白Bcl-2和Bcl-x(L)，并上调了促凋亡蛋白Bax。相反，将NHL B细胞暴露于重组或髓样细胞来源的BAFF和APRIL可减弱细胞凋亡，增加NF-κB激活，上调Bcl-2和Bcl-x(L)，并下调Bax。在一些NHL中，外源性BAFF和APRIL上调细胞增殖诱导剂c-Myc；下调细胞增殖抑制剂p53；并增加B细胞分化抑制剂Bcl-6。通过显示非恶性B细胞在受到T细胞CD40配体刺激后上调BAFF和APRIL，我们的研究结果表明，NHL B细胞解除了原本生理性的自分泌存活途径的调控，以逃避细胞凋亡。因此，可溶性TACI和BCMA诱饵受体对BAFF和APRIL的中和作用可能有助于减少NHL患者中恶性B细胞的积累。
