FcγRIIB-mediated dissociation of BCR-CD19 microclusters and hyperreactivity of lupus B cells (HUM7P.303)

Abstract

Abstract B cell activation is regulated through the interplay between the B cell receptor (BCR) and the inhibitory co-receptor FcγRIIB or activating co-receptor CD19. Recent studies suggest that the BCR microcluster is converted to a signaling active state upon its colocalization with CD19 microclusters to activate B cells. Here using TIRF microscopy-based live cell imaging techniques, we show that FcγRIIB can inhibit B cell activation by a previously uncharacterized mechanism of blocking the spatial-temporal colocalization of BCR and CD19 microclusters within the immunological synapse (IS). This inhibitory function of FcγRIIB mainly relies on its transmembrane domain (TM). Indeed, human primary B cells from SLE patients homozygous for the gene encoding FcγRIIB-I232T lose the ability to block the synaptic colocalization of BCR with CD19, leading to the dis-regulated recruitment of pCD19, pSyk and pPI3K to membrane proximal signalosome. Furthermore, FcγRIIB-I232T homozygous SLE patients are more likely to develop severe clinical symptoms characterized by high anti-ds DNA antibody titers and the involvement of kidney, central nervous system, gastrointestinal tract, lung and heart compared to patients carrying either one or both WT copies of FcγRIIB. These observations may explain the hyper-reactive features of SLE patient B cells and provide a potential target through FcγRIIB for the prophylactic diagnosis, evaluation of disease progression and potential therapies.