Genetic Dissection of the Effects of Stimulatory and Inhibitory IgG Fc Receptors on Murine Lupus

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.

In vivo enzymatic modulation of IgG glycosylation inhibits autoimmune disease in an IgG subclass-dependent manner

“…After the abrogation of treatment the mice started succumbing to disease although 40% of the animals were still alive after 55 weeks of age. Interestingly, BXSB mice deficient in the common FcR ␥-chain (BXSB-␥ Ϫ/Ϫ ), which lack all functional activating Fc␥Rs and therefore represent the maximal effects that can be achieved by interfering with antibody-Fc␥R interactions, showed a similar survival pattern, with the first mice dying at 30 weeks of age (27).…”

Inhibitory IgG Fc receptor promoter region polymorphism is a key genetic element for murine systemic lupus erythematosus

“…The B6-type Fcgr2b promoter region-bearing BXSB strain (BXSB.IIB B6 ) was established by microsatellite marker-assisted selective backcrossing of (BXSB Â B6.FcRg-/-) F1 to BXSB over 30 generations, as described previously (Fig. 1A) [18]. All mice used were housed under identical conditions and all experiments were performed in accordance with our institutional guidelines.…”

“…To dissect the role of polymorphic Fcgr2b in the susceptibility to SLE, we took advantage of the congenic BXSB strain (BXSB.IIB B6 ) [18], in which Fcgr2b is of C57BL/6 (B6) origin, but other potent downstream autoimmune-susceptibility genes, such as Slam/Cd2, Ifi202, and Cr2, are of BXSB type (Fig. 1A).…”

“…For monocyte analysis, spleen cells A) The gene segment shown by the black bar was introduced into the BXSB background from the FcRg-deficient B6 strain. Genotypes were determined by analysis of microsatellite marker polymorphisms, Fcgr2b allele polymorphism, and the defective FcRg chain gene (Fcer1g), and it was confirmed that the Fcgr2b allele was derived from the B6 strain and the Fcer1g allele was derived from the BXSB strain in the congenic BXSB.IIB B6 strain [18]. B) The genotyping of the boundary between Fcgr2b and Slam/Cd2 was confirmed by SSCP for polymorphic Fcgr2b and two members of the Slam/Cd2 family (Cd229 and Cd84).…”

“…Because BXSB mice carry the autoimmune-type Fcgr2b polymorphism, it was assumed that expression of FcgRIIB on such activated self-reactive B cells is selectively down-regulated, resulting in extensive proliferation and maturation of self-reactive B cells in BXSB males. Indeed, we earlier found that SLE phenotypes including the production of pathogenic autoantibodies observed in BXSB males were all almost completely inhibited in the congenic BXSB (BXSB.IIB B6 ) males carrying the wild C57/BL6 (B6)-type Fcgr2b [18]. As BXSB females with autoimmune-type Fcgr2b but not Yaa mutation did not develop severe SLE [19], it was suggested that the autoimmune-type Fcgr2b shows a strong epistatic interaction with Yaa mutation in SLE susceptibility and that the wild-type Fcgr2b preferentially inhibits Yaa-mediated SLE susceptibility.…”