Mayumi M, Sumimoto S, Kanazashi S, Hata D, Yamaoka K, Higaki Y, Ishigami T, Kim K M, Heike T, Katamura K
Department of Pediatrics, Faculty of Medicine, Kyoto University, Japan.
J Allergy Clin Immunol. 1996 Dec;98(6 Pt 2):S238-47. doi: 10.1016/s0091-6749(96)70072-6.
Cross-linking of surface immunoglobulins generates negative signals that cause B-cell death unless appropriate rescue signals are provided. Surface IgM is the main transducer of the negative signaling, but surface IgD and IgG may also transduce negative signaling when cross-linked intensively. In the surface IgM+, IgD+ human malignant B lymphoma cell lines B104 and DND-39, cross-linking of surface IgM by anti-IgM antibodies induced cell death. Anti-IgM antibody-induced B104 cell death was inhibited by stimulation with alpha- and beta-interferons but not stimulation with anti-CD40 antibody or IL-4, whereas anti-IgM antibody-induced DND-39 cell death was inhibited by stimulation with anti-CD40 antibody but not stimulation with alpha- and beta-interferons. Anti-IgM antibody-stimulated B104 cells had morphologic features compatible with necrosis, whereas anti-IgM antibody-stimulated DND-39 cells showed morphologic features of apoptosis. CD11a/CD54-dependent cell adhesion induced by stimulation with anti-CD40 antibody was involved in anti-CD40 antibody-mediated inhibition of anti-IgM antibody-induced DND-39 cells. In normal human mature B cells, cross-linking of surface IgM induced different signaling consequences, including DNA synthesis or cell division (positive signaling) or cell cycle arrest or death (negative signaling). In this system, too, CD40-transduced signal inhibited anti-IgM antibody-induced negative signaling, and CD11a/CD54-dependent cell adhesion played a role in the rescue process. It is suggested that quantitatively different intensities of surface IgM cross-linking induce qualitatively different signaling consequences; relatively weak cross-linking may induce DNA synthesis; moderate cross-linking may induce DNA synthesis with cell cycle arrest at the G2/M interphase; and intense cross-linking may induce apoptotic cell death. The reasons for this difference are not yet known. Further elucidation of the molecular mechanisms responsible for surface IgM-mediated negative signaling and its rescue signaling may contribute toward development of therapy for allergic disorders by artificial modulation of specific immunoglobulin production.
表面免疫球蛋白的交联会产生负向信号，导致B细胞死亡，除非提供适当的拯救信号。表面IgM是负向信号的主要传导分子，但当表面IgD和IgG被强烈交联时，它们也可能传导负向信号。在表面IgM+、IgD+的人恶性B淋巴瘤细胞系B104和DND - 39中，抗IgM抗体交联表面IgM会诱导细胞死亡。α-干扰素和β-干扰素刺激可抑制抗IgM抗体诱导的B104细胞死亡，但抗CD40抗体或IL - 4刺激则不能；而抗CD40抗体刺激可抑制抗IgM抗体诱导的DND - 39细胞死亡，但α-干扰素和β-干扰素刺激则不能。抗IgM抗体刺激的B104细胞具有与坏死相符的形态学特征，而抗IgM抗体刺激的DND - 39细胞则表现出凋亡的形态学特征。抗CD40抗体刺激诱导的CD11a/CD54依赖性细胞黏附参与了抗CD40抗体介导的对抗IgM抗体诱导的DND - 39细胞的抑制作用。在正常人成熟B细胞中，表面IgM的交联会诱导不同的信号转导结果，包括DNA合成或细胞分裂（正向信号）或细胞周期停滞或死亡（负向信号）。在这个系统中，CD40转导的信号也抑制抗IgM抗体诱导的负向信号，并且CD11a/CD54依赖性细胞黏附在拯救过程中发挥作用。提示表面IgM交联强度的定量差异会诱导信号转导结果的定性差异；相对较弱的交联可能诱导DNA合成；中等程度的交联可能诱导DNA合成并使细胞周期停滞在G2/M期；而强烈的交联可能诱导凋亡性细胞死亡。这种差异的原因尚不清楚。进一步阐明负责表面IgM介导的负向信号及其拯救信号的分子机制，可能有助于通过人工调节特异性免疫球蛋白的产生来开发过敏性疾病的治疗方法。
