title: The inhibiting Fc receptor for IgG, FcγRIIB, is a modifier of autoimmune susceptibility.
abstract: FcγRIIB-deficient mice generated in 129 background (FcγRIIB(129)(-/-)) if back-crossed into C57BL/6 background exhibit a hyperactive phenotype and develop lethal lupus. Both in mice and humans, the Fcγr2b gene is located within a genomic interval on chromosome 1 associated with lupus susceptibility. In mice, the 129-derived haplotype of this interval, named Sle16, causes loss of self-tolerance in the context of the B6 genome, hampering the analysis of the specific contribution of FcγRIIB deficiency to the development of lupus in FcγRIIB(129)(-/-) mice. Moreover, in humans genetic linkage studies revealed contradictory results regarding the association of "loss of function" mutations in the Fcγr2b gene and susceptibility to systemic lupus erythematosis. In this study, we demonstrate that FcγRIIB(-/-) mice generated by gene targeting in B6-derived ES cells (FcγRIIB(B6)(-/-)), lacking the 129-derived flanking Sle16 region, exhibit a hyperactive phenotype but fail to develop lupus indicating that in FcγRIIB(129)(-/-) mice, not FcγRIIB deficiency but epistatic interactions between the C57BL/6 genome and the 129-derived Fcγr2b flanking region cause loss of tolerance. The contribution to the development of autoimmune disease by the resulting autoreactive B cells is amplified by the absence of FcγRIIB, culminating in lethal lupus. In the presence of the Yaa lupus-susceptibility locus, FcγRIIB(B6)(-/-) mice do develop lethal lupus, confirming that FcγRIIB deficiency only amplifies spontaneous autoimmunity determined by other loci.
authors: Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
authors: Peter
authors: P
authors: Boross
authors: Victoria L
authors: VL
authors: Arandhara
authors: Javier
authors: J
authors: Martin-Ramirez
authors: Marie-Laure
authors: ML
authors: Santiago-Raber
authors: Francesco
authors: F
authors: Carlucci
authors: Roelof
authors: R
authors: Flierman
authors: Jos
authors: J
authors: van der Kaa
authors: Cor
authors: C
authors: Breukel
authors: Jill W C
authors: JW
authors: Claassens
authors: Marcel
authors: M
authors: Camps
authors: Erik
authors: E
authors: Lubberts
authors: Daniela
authors: D
authors: Salvatori
authors: Maria Pia
authors: MP
authors: Rastaldi
authors: Ferry
authors: F
authors: Ossendorp
authors: Mohamed R
authors: MR
authors: Daha
authors: H Terence
authors: HT
authors: Cook
authors: Shozo
authors: S
authors: Izui
authors: Marina
authors: M
authors: Botto
authors: J Sjef
authors: JS
authors: Verbeek
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease / Q000517:prevention & control*; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism*; D016130:Immunophenotyping; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C080571:Fc gamma receptor IIB; D007074:Immunoglobulin G; D017452:Receptors, IgG