title: Immune complex enhances tolerogenecity of immature dendritic cells via FcγRIIb and promotes FcγRIIb-overexpressing dendritic cells to attenuate lupus.
abstract: A balance of inhibitory and activating signals determines the function of dendritic cells (DCs) in the immune response, which may be regulatory or stimulatory. Defects of inhibitory receptor FcγRIIb are involved in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE), in which high levels of circulating immune complexes (IC) exist. Our previous study showed that IC/Ig can suppress TLR4-triggered inflammatory responses in macrophages via FcγRIIb. This led us to question whether IC/Ig can polarize FcγRIIb-overexpressing DCs (DC-FcγRIIb) to be tolerogenic, thus attenuating lupus progression once infused in vivo. First, we found that IC/Ig markedly inhibited LPS- or CpG-induced DC maturation, enhanced tolerogenicity of DCs via FcγRIIb, and induced massive prostaglandin E2 (PGE2) secretion from DCs, both contributing to T-cell hyporesponsiveness. Endogenous Ig and lupus-derived IC also exhibited the same effect. DC-FcγRIIb, transfected with recombinant adenovirus encoding FcγRIIb, displayed enhanced tolerogenic function and produced more PGE2 in the presence of IC, thus further inhibiting T-cell responses. Importantly, in vivo infusion with DC-FcγRIIb significantly reduced kidney damage and prolonged the survival of lupus-prone MRL/lpr mice either before or after the onset of clinic lupus. Therefore, administration of DC-FcγRIIb may be a new approach to attenuate lupus progression.
authors.affiliation: National Key Laboratory of Medical Immunology & Institute of Immunology, Second Military Medical University, Shanghai, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shuxun
authors.initials: S
authors.lastname: Liu
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Yu
authors.forename: Ting
authors.initials: T
authors.lastname: Zhang
authors.forename: Juan
authors.initials: J
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Shen
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D018450:Disease Progression; D007108:Immune Tolerance; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017452:Receptors, IgG / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D000936:Antigen-Antibody Complex; C080571:Fc gamma receptor IIB; D017452:Receptors, IgG; D051193:Toll-Like Receptors