PDF(Pubmed)
Abstract：
Antibody-producing plasma cells fuel humoral immune responses. They also contribute to autoimmune diseases such as systemic lupus erythematosus or IgA nephropathy. Interleukin-6 and the tumor necrosis factor (TNF) family ligands BAFF (B cell-activating factor) and APRIL (a proliferation-inducing ligand) participate in plasma cell survival. BAFF binds to three receptors, BAFFR (BAFF receptor), TACI (transmembrane activator and CAML interactor), and BCMA (B cell maturation antigen), while APRIL binds to TACI, BCMA, and proteoglycans. However, which ligand-receptor pair(s) are required to maintain plasma cells in different body locations remains unknown. Here, by combining mouse genetic and pharmacological approaches, we found that plasma cells required BCMA and/or TACI but not BAFFR. BCMA responded exclusively to APRIL, while TACI responded to both BAFF and APRIL, identifying three self-sufficient ligand-receptor pairs for plasma cell maintenance: BAFF-TACI, APRIL-TACI, and APRIL-BCMA. Together, these actors accounted for 90% of circulating antibodies. In BAFF-ko mice, the reduction of plasma cells upon APRIL inhibition indicated that APRIL could function in the absence of BAFF-APRIL heteromers. No evidence was found that in the absence of BCMA and TACI, binding of APRIL to proteoglycans would help maintain plasma cells. IL-6, alone or together with BAFF and APRIL, supported mainly splenic plasmablasts and plasma cells and contributed to circulating IgG but not IgA levels. In conclusion, survival factors for plasma cells can vary with body location and with the antibody isotype that plasma cells produce. To efficiently target plasma cells, in particular IgA-producing ones, dual inhibition of BAFF and APRIL is required.
摘要：
产生抗体的浆细胞促进体液免疫反应。它们还有助于自身免疫性疾病，例如系统性红斑狼疮或IgA肾病。白细胞介素-6和肿瘤坏死因子(TNF)家族配体BAFF(B细胞活化因子)和APRIL(增殖诱导配体)参与浆细胞存活。BAFF与三种受体结合,BAFFR（BAFF受体），TACI（跨膜激活剂和CAML相互作用剂），和BCMA（B细胞成熟抗原），而APRIL与TACI，BCMA，和蛋白聚糖。然而,在不同的身体位置维持浆细胞所需的配体-受体对仍然未知。这里,通过结合小鼠遗传和药理学方法，我们发现浆细胞需要BCMA和/或TACI,但不需要BAFFR.BCMA专门回应了4月，而TACI对BAFF和4月都做出了回应，确定三种自给自足的配体-受体对浆细胞维持：BAFF-TACI，APRIL-TACI和APRIL-BCMA。一起,这些参与者占循环抗体的90％。在BAFF-ko小鼠中,APRIL抑制后浆细胞的减少表明APRIL可以在不存在BAFF-APRIL异聚体的情况下发挥作用。没有发现在不存在BCMA和TACI的情况下,APRIL与蛋白聚糖的结合将有助于维持浆细胞的证据。IL-6，单独或与BAFF和4月一起，主要支持脾浆细胞和浆细胞，并有助于循环IgG而不是IgA水平。总之,浆细胞的存活因子可以随身体位置和浆细胞产生的抗体同种型而变化。为了有效地靶向浆细胞，特别是产生IgA的，需要BAFF和APRIL的双重抑制。
