FcγRIIB-deficient mice generated in 129 background (FcγRIIB129−/−) 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 FcγRIIB129−/− 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 (FcγRIIBB6−/−), lacking the 129-derived flanking Sle16 region, exhibit a hyperactive phenotype but fail to develop lupus indicating that in FcγRIIB129−/− 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, FcγRIIBB6−/− mice do develop lethal lupus, confirming that FcγRIIB deficiency only amplifies spontaneous autoimmunity determined by other loci.

Fc receptors for IgG (FcγR) have been implicated in the development of arthritis. However, the precise contribution of the individual FcγR to joint pathology is unclear. In this study, the role of the different FcγR was assessed both in an active and in a passive mouse model of arthritis by analyzing disease development in double and triple knockout (KO) offspring from crosses of FcγRI KO, FcγRIII KO, FcγRI/III double KO, or FcR γ-chain KO with the FcγRII KO on C57BL6 background, which is susceptible for collagen-induced arthritis (CIA). In the active CIA model, onset was significantly delayed in the absence of FcγRIII, whereas incidence and maximum severity were significantly decreased in FcγRI/II/III triple KO but not in FcγRII/III double KO and FcγRI/II double KO mice as compared with FcγRII KO animals. Remarkably, fully destructive CIA developed in FcγRI/II/III triple KO mice. In contrast, FcR γ/FcγRII double KO mice were resistant to CIA. These findings were confirmed with the passive KRN serum-induced arthritis model. These results indicate that all activating FcγR play a role in the development of arthritis, mainly in the downstream effector phase. FcγRIII is critically required for early arthritis onset, and FcγRI can substantially contribute to arthritis pathology. Importantly, FcγRI and FcγRIII were together dispensable for the development of destructive arthritis but the FcR γ-chain was not, suggesting a role for another FcR γ-chain associated receptor, most likely FcγRIV. In addition, FcγRII plays a negative regulatory role in both the central and effector phase of arthritis.

No abstract

Analysis of host genetic polymorphisms is an increasingly important tool for understanding and predicting pathogenesis and treatment response of viral diseases. The gene locus of scavenger receptor class B type I (SR‐BI), encoding a cell entry factor and receptor for hepatitis C virus (HCV), contains several genetic polymorphisms. We applied a probe extension assay to determine the frequency of six single nucleotide polymorphisms (SNPs) within the SR‐BI gene locus in 374 individuals with history of HCV infection. In addition, SR‐BI messenger RNA (mRNA) levels were analyzed in liver biopsy specimens of chronically infected HCV subjects. The rs5888 variant allele T was present at a higher frequency in subjects with advanced fibrosis (χ2, p = 0.016) and after adjusting for age, duration of infection and alcohol intake as confounding factors. Haplotype analysis of SNP frequencies showed that a haplotype consisting of rs61932577 variant allele C and rs5888 variant allele T was associated with an increased risk of advanced liver fibrosis (defined by an Ishak score 4−6) (adjusted odds ratio 2.81; 95% confidence interval 1.06−7.46. p = 0.038). Carriers of the rs5888 variant allele T displayed reduced SR‐BI mRNA expression in liver biopsy specimens. In conclusion the rs5888 polymorphism variant is associated with decreased SR‐BI expression and an increased risk of development of advanced fibrosis in chronic HCV infection. These findings provide further evidence for a role of SR‐BI in HCV pathogenesis and provides a genetic marker for prediction of those infected individuals at greater risk of developing severe disease.