Negative signaling in B cells by surface immunoglobulins.

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.