title: Analysis of a wild mouse promoter variant reveals a novel role for FcγRIIb in the control of the germinal center and autoimmunity.
abstract: Genetic variants of the inhibitory Fc receptor FcγRIIb have been associated with systemic lupus erythematosus in humans and mice. The mechanism by which Fcgr2b variants contribute to the development of autoimmunity is unknown and was investigated by knocking in the most commonly conserved wild mouse Fcgr2b promoter haplotype, also associated with autoimmune-prone mouse strains, into the C57BL/6 background. We found that in the absence of an AP-1-binding site in its promoter, FcγRIIb failed to be up-regulated on activated and germinal center (GC) B cells. This resulted in enhanced GC responses, increased affinity maturation, and autoantibody production. Accordingly, in the absence of FcγRIIb activation-induced up-regulation, mice developed more severe collagen-induced arthritis and spontaneous glomerular immune complex deposition. Our data highlight how natural variation in Fcgr2b drives the development of autoimmune disease. They also show how the study of such variants using a knockin approach can provide insight into immune mechanisms not possible using conventional genetic manipulation, in this case demonstrating an unexpected critical role for the activation-induced up-regulation of FcγRIIb in controlling affinity maturation, autoantibody production, and autoimmunity.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 OXY, England, UK.
authors.forename: Marion
authors.initials: M
authors.lastname: Espéli
authors.forename: Menna R
authors.initials: MR
authors.lastname: Clatworthy
authors.forename: Susanne
authors.initials: S
authors.lastname: Bökers
authors.forename: Kate E
authors.initials: KE
authors.lastname: Lawlor
authors.forename: Antony J
authors.initials: AJ
authors.lastname: Cutler
authors.forename: Frank
authors.initials: F
authors.lastname: Köntgen
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lyons
authors.forename: Kenneth G C
authors.initials: KG
authors.lastname: Smith
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D055879:Gene Knock-In Techniques; D014644:Genetic Variation; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D008156:Luciferases; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D018709:Statistics, Nonparametric; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D017931:DNA Primers; C499172:Fcgr2b protein, mouse; D017452:Receptors, IgG; D018808:Transcription Factor AP-1; D008156:Luciferases