Sohn Hae Won, Pierce Susan K, Tzeng Shiang-Jong
Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
J Immunol. 2008 Jan 15;180(2):793-9. doi: 10.4049/jimmunol.180.2.793.
The FcgammaRIIB is a potent regulator of BCR signaling and as such plays a decisive role in controlling autoimmunity. The use of advanced imaging technologies has provided evidence that the earliest events in Ag-induced BCR signaling include the clustering of the BCR, the selective and transient association of the clustered BCR with raft lipids, and the concentration of BCR clusters in an immune synapse. That lipid rafts play a role in FcgammaRIIB's regulation of BCR signaling was suggested by recent studies showing that a lupus-associated loss of function mutation resulted in the receptor's exclusion from lipid rafts and the failure to regulate BCR signaling. In this study, we provide evidence from both biochemical analyses and fluorescence resonance energy transfer in conjunction with both confocal and total internal reflection microscopy in living cells that the FcgammaRIIB, when coligated with the BCR, associates with lipid rafts and functions both to destabilize the association of the BCR with raft lipids and to block the subsequent formation of the B cell's immune synapse. These results define new early targets of FcgammaRIIB inhibitory activity in the Ag-induced B cell activation pathway.
FcγRIIB是BCR信号传导的强效调节因子，因此在控制自身免疫中起决定性作用。先进成像技术的应用提供了证据，表明抗原诱导的BCR信号传导的最早事件包括BCR的聚集、聚集的BCR与脂筏脂质的选择性和短暂结合，以及BCR簇在免疫突触中的浓缩。最近的研究表明，狼疮相关的功能丧失突变导致该受体被排除在脂筏之外且无法调节BCR信号传导，这提示脂筏在FcγRIIB对BCR信号传导的调节中发挥作用。在本研究中，我们通过生物化学分析以及荧光共振能量转移，并结合共聚焦显微镜和活细胞中的全内反射显微镜，提供了证据，即FcγRIIB在与BCR共同结合时，会与脂筏结合，并起到破坏BCR与脂筏脂质结合以及阻止随后B细胞免疫突触形成的作用。这些结果确定了FcγRIIB在抗原诱导的B细胞活化途径中抑制活性的新早期靶点。
