RT Journal Article ID 75e91a7046557c26 A1 Mayumi, Mitsufumi A1 Ohshima, Yusei A1 Hata, Daisuke A1 Kim, Kwang-Myong A1 Heike, Toshio A1 Katamura, Kenji A1 Furusho, Kenshi T1 IgM-Mediated B Cell Apoptosis JF Critical Reviews™ in Immunology JO CRI YR 1995 FD 1995-12-01 VO 15 IS 3-4 SP 255 OP 269 K1 IgM K1 B cell K1 Apoptosis K1 CD40 K1 LFA-l/ICAM-1 AB Cross-linking of surface immunoglobulin M (slgM) on normal mature B cells induces different signaling consequences, including DNA synthesis (positive signaling) and cell cycle arrest and/or death by apoptosis (negative signaling). Presumably, the difference depends on the intensity of slgM cross-linking: relatively weak cross-linking induces DNA synthesis, moderate cross-linking induces DNA synthesis with cell cycle arrest at the G2/M interphase, and intense cross-linking induces apoptosis. In vivo experiments with transgenic mice have shown that relatively weak cross-linking of slgM by soluble antigens induces anergy in autoreactive B cells, whereas intense slgM cross-linking by membrane-bound forms of antigens induces deletion of them. However, it is still unknown whether the different intensities of slgM cross-linking generate qualitatively different signals responsible for DNA synthesis or cell death or whether they generate qualitatively the same but quantitatively different signals, and the quantitative difference is responsible for the induction of positive or negative signaling. The slgM-mediated negative signaling presumably plays an important role in the induction and maintenance of B cell tolerance, and slgD and slgG also possess the machinery necessary for negative signaling. Negative signaling through slgM is dependent on tyrosine kinase(s) and Ca2+ influx and is sensitive to cyclosporin A in certain types of B cells but not in all B cells. It has been suggested that there are different intracellular signaling pathways that transduce negative signaling via slgM, and that activation-induced B cell death by slgM cross-linking does not necessarily show DNA fragmentation and the morphology of apoptosis. On the other hand, slgM-mediated B cell death may be inhibited in the presence of appropriate co-stimulators such as IL-4, α-, and β-interferons and CD40-mediated signaling. The CD40-mediated signaling effectively inhibits slgM-mediated B cell apoptosis in many but not all experimental systems. Although homotypic cell adhesion through the LFA-1/ICAM-1 dependent pathway was shown to be involved in certain types of CD40-mediated inhibition of slgM-mediated negative signaling, it is still not known how the cytokines and CD40-mediated signaling inhibit slgM-mediated B cell death. The molecular mechanisms responsible for slgM-mediated negative signaling and for the inhibitory signaling against slgM-mediated negative signaling need further elucidation. PB Begell House LK https://www.dl.begellhouse.com/journals/2ff21abf44b19838,601751ce468f47e1,75e91a7046557c26.html