title: FcγRIIB regulation of BCR/TLR-dependent autoreactive B-cell responses.
abstract: Crosslinking of Fc γ receptor II B (FcγRIIB) and the BCR by immune complexes (IC) can downregulate antigen-specific B-cell responses. Accordingly, FcγRIIB deficiencies have been associated with B-cell hyperactivity in patients with systemic lupus erythematosus and mouse models of lupus. However, we have previously shown that murine IgG2a-autoreactive AM14 B cells respond robustly to chromatin-associated IC through a mechanism dependent on both the BCR and the endosomal TLR9, despite FcγRIIB coexpression. To further evaluate the potential contribution of FcγRIIB to the regulation of autoreactive B cells, we have now compared the IC-triggered responses of FcγRIIB-deficient and FcγRIIB-sufficient AM14 B cells. We find that FcγRIIB-deficient cells respond significantly better than FcγRIIB-sufficient cells when stimulated with DNA IC that incorporate low-affinity TLR9 ligand (CG-poor dsDNA fragments). AM14 B cells also respond to RNA-associated IC through BCR/TLR7 coengagement, but such BCR/TLR7-dependent responses are normally highly dependent on IFN-α costimulation. However, we now show that AM14 FcγRIIB(-/-) B cells are very effectively activated by RNA IC without supplemental IFN-α priming. These results demonstrate that FcγRIIB can effectively modulate both BCR/TLR9 and BCR/TLR7 endosomal-dependent activation of autoreactive B cells.
authors.affiliation: Department of Microbiology, Boston University School of Medicine, Boston, MA 01655, USA. Ann.Rothstein@umassmed.edu
authors.forename: Ana M
authors.initials: AM
authors.lastname: Avalos
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Uccellini
authors.forename: Petar
authors.initials: P
authors.lastname: Lenert
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Viglianti
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D017452:Receptors, IgG / Q000276:immunology*; D013047:Specific Pathogen-Free Organisms; D051217:Toll-Like Receptor 9 / Q000276:immunology*
chemical_list: D000936:Antigen-Antibody Complex; D001324:Autoantigens; C499172:Fcgr2b protein, mouse; D011947:Receptors, Antigen, B-Cell; D017452:Receptors, IgG; D051217:Toll-Like Receptor 9
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