Schuh Elisabeth, Musumeci Andrea, Thaler Franziska S, Laurent Sarah, Ellwart Joachim W, Hohlfeld Reinhard, Krug Anne, Meinl Edgar
Institute of Clinical Neuroimmunology, Biomedical Center and University Hospitals, LMU Munich, 82152 Planegg-Martinsried, Germany.
Institute for Immunology, Biomedical Center, LMU Munich, 82152 Planegg-Martinsried, Germany.
J Immunol. 2017 Apr 15;198(8):3081-3088. doi: 10.4049/jimmunol.1601746. Epub 2017 Mar 10.
The BAFF-APRIL system is best known for its control of B cell homeostasis, and it is a target of therapeutic intervention in autoimmune diseases and lymphoma. By analyzing the expression of the three receptors of this system, B cell maturation Ag (BCMA), transmembrane activator and CAML interactor, and BAFF receptor, in sorted human immune cell subsets, we found that BCMA was transcribed in plasmacytoid dendritic cells (pDCs) in both blood and lymphoid tissue. Circulating human pDCs contained BCMA protein without displaying it on the cell surface. After engagement of TLR7/8 or TLR9, BCMA was detected also on the cell surface of pDCs. The display of BCMA on the surface of human pDCs was accompanied by release of soluble BCMA (sBCMA); inhibition of γ-secretase enhanced surface expression of BCMA and reduced the release of sBCMA by pDCs. In contrast with human pDCs, murine pDCs did not express BCMA, not even after TLR9 activation. In this study, we extend the spectrum of BCMA expression to human pDCs. sBCMA derived from pDCs might determine local availability of its high-affinity ligand APRIL, because sBCMA has been shown to function as an APRIL-specific decoy. Further, therapeutic trials targeting BCMA in patients with multiple myeloma should consider possible effects on pDCs.
BAFF-APRIL系统因其对B细胞稳态的调控而最为人所知，它是自身免疫性疾病和淋巴瘤治疗干预的靶点。通过分析该系统的三种受体——B细胞成熟抗原（BCMA）、跨膜激活剂和CAML相互作用分子以及BAFF受体在分选的人类免疫细胞亚群中的表达，我们发现BCMA在血液和淋巴组织中的浆细胞样树突状细胞（pDC）中都有转录。循环中的人类pDC含有BCMA蛋白，但未在细胞表面显示。在TLR7/8或TLR9激活后，pDC的细胞表面也检测到了BCMA。人类pDC表面BCMA的显示伴随着可溶性BCMA（sBCMA）的释放；γ-分泌酶的抑制增强了BCMA的表面表达，并减少了pDC释放sBCMA。与人类pDC不同，小鼠pDC即使在TLR9激活后也不表达BCMA。在本研究中，我们将BCMA的表达谱扩展到了人类pDC。来自pDC的sBCMA可能决定其高亲和力配体APRIL的局部可用性，因为sBCMA已被证明可作为APRIL特异性诱饵发挥作用。此外，针对多发性骨髓瘤患者的BCMA治疗试验应考虑对pDC的可能影响。
