Objective. Lupus-prone BXSB mice develop monocytosis characterized by selective accumulation of the Gr-1-monocyte subset. The aim of this study was to explore the possible role of activating IgG Fc receptors (Fc␥R) in the development of monocytosis and to characterize the functional phenotype of the Gr-1-subset that accumulates in lupus-prone mice bearing the NZBtype defective Fcgr2b allele for the inhibitory Fc␥RIIB.Methods. The development of monocytosis was analyzed in BXSB and anti-IgG2a rheumatoid factortransgenic C57BL/6 mice deficient in activating Fc␥R. Moreover, we assessed the expression levels of activating Fc␥R and inhibitory Fc␥RIIB on Gr-1؉ and Gr-1-monocyte subsets in C57BL/6 mice bearing the C57BL/ 6-type or the NZB-type Fcgr2b allele.Results. We observed monocytosis with expansion of the Gr-1-subset in anti-IgG2a-transgenic C57BL/6 mice expressing IgG2a, but not in those lacking IgG2a. Moreover, monocytosis barely developed in BXSB and anti-IgG2a-transgenic C57BL/6 mice deficient in activating Fc␥R. The Gr-1-subset that accumulated in lupus-prone mice displayed a unique hyperactive phenotype. It expressed very low levels of inhibitory Fc␥RIIB, due to the presence of the NZB-type Fcgr2b allele, but high levels of activating Fc␥RIV. This was in contrast to high levels of Fc␥RIIB expression and no Fc␥RIV expression on the Gr-1؉ subset. Conclusion. Our results demonstrated a critical role of activating Fc␥R in the development of monocytosis and in the expansion of a Gr-1-Fc␥RIIB lowFc␥RIV؉ hyperactive monocyte subset in lupus-prone mice. Our findings further highlight the importance of the NZB-type Fcgr2b susceptibility allele in murine lupus, the presence of which induces increased production of hyperactive monocytes as well as dysregulated activation of autoreactive B cells.

The diverse roles of monocytes in SLE and RA

Objective. Fc␥ receptor type IIb (Fc␥RIIb) is a major negative regulator of B cells, and the lack of Fc␥RIIb expression has been reported to induce systemic lupus erythematosus (SLE) in mice of the C57BL/6 (B6) genetic background. The 129 strainderived Sle16 locus on the telomeric region of chromosome 1 including polymorphic Fcgr2b confers the predisposition to systemic autoimmunity when present on the B6 background. We undertook this study to examine the effect of the Sle16 locus on autoimmune disease in Fc␥RIIb-deficient B6 mice.Methods. We established 2 lines of Fc␥RIIb-deficient B6 congenic mouse strains (KO1 and KO2) by selective backcrossing of the originally constructed Fc␥RIIb-deficient mice on a hybrid (129 ؋ B6) background into a B6 background. Although both lack Fc␥RIIb expression, the KO1 and KO2 strains carry different lengths of the 129 strain-derived telomeric chromosome 1 segment flanked to the null-mutated Fcgr2b gene; the KO1 strain carries a 129 strainderived ϳ6.3-Mb interval distal from the null-mutated Fcgr2b gene within the Sle16 locus, while this interval in the KO2 strain is of B6 origin.Results. Unexpectedly, both strains failed to develop SLE; instead, the KO1 strain, but not the KO2 strain, spontaneously developed severe rheumatoid arthritis (RA) with an incidence reaching >90% at age 12 months.Conclusion. The current study shows evidence that the epistatic interaction between the Fcgr2b-null mutation and a polymorphic gene(s) in the 129 strainderived interval located in the distal Sle16 locus contributes to RA susceptibility in a new mouse model with the B6 genetic background, although the participation of other genetic polymorphisms cannot be totally excluded.

No abstract

Immune complex (IC)-mediated tissue inflammation is controlled by stimulatory and inhibitory IgG Fc receptors (FcγRs). Systemic lupus erythematosus is a prototype of IC-mediated autoimmune disease; thus, imbalance of these two types of FcγRs is probably involved in pathogenesis. However, how and to what extent each FcγR contributes to the disease remains unclear. In lupus-prone BXSB mice, while stimulatory FcγRs are intact, inhibitory FcγRIIB expression is impaired because of promoter region polymorphism. To dissect roles of stimulatory and inhibitory FcγRs, we established two gene-manipulated BXSB strains: one deficient in stimulatory FcγRs (BXSB.γ−/−) and the other carrying wild-type Fcgr2b (BXSB.IIBB6/B6). The disease features were markedly suppressed in both mutant strains. Despite intact renal function, however, BXSB.γ−/− had IC deposition in glomeruli associated with high-serum IgG anti-DNA Ab levels, in contrast to BXSB.IIBB6/B6, which showed intact renal pathology and anti-DNA levels. Lymphocytes in BXSB.γ−/− were activated, as in wild-type BXSB, but not in BXSB.IIBB6/B6. Our results strongly suggest that both types of FcγRs in BXSB mice are differently involved in the process of disease progression, in which, while stimulatory FcγRs play roles in effecter phase of IC-mediated tissue inflammation, the BXSB-type impaired FcγRIIB promotes spontaneous activation of self-reactive lymphocytes and associated production of large amounts of autoantibodies and ICs.