Genetic dissection of the effects of stimulatory and inhibitory IgG Fc receptors on murine lupus.
Immune complex (IC)-mediated tissue inflammation is controlled by stimulatory and inhibitory IgG Fc receptors (FcgammaRs). Systemic lupus erythematosus is a prototype of IC-mediated autoimmune disease; thus, imbalance of these two types of FcgammaRs is probably involved in pathogenesis. However, how and to what extent each FcgammaR contributes to the disease remains unclear. In lupus-prone BXSB mice, while stimulatory FcgammaRs are intact, inhibitory FcgammaRIIB expression is impaired because of promoter region polymorphism. To dissect roles of stimulatory and inhibitory FcgammaRs, we established two gene-manipulated BXSB strains: one deficient in stimulatory FcgammaRs (BXSB.gamma(-/-)) and the other carrying wild-type Fcgr2b (BXSB.IIB(B6/B6)). The disease features were markedly suppressed in both mutant strains. Despite intact renal function, however, BXSB.gamma(-/-) had IC deposition in glomeruli associated with high-serum IgG anti-DNA Ab levels, in contrast to BXSB.IIB(B6/B6), which showed intact renal pathology and anti-DNA levels. Lymphocytes in BXSB.gamma(-/-) were activated, as in wild-type BXSB, but not in BXSB.IIB(B6/B6). Our results strongly suggest that both types of FcgammaRs in BXSB mice are differently involved in the process of disease progression, in which, while stimulatory FcgammaRs play roles in effecter phase of IC-mediated tissue inflammation, the BXSB-type impaired FcgammaRIIB promotes spontaneous activation of self-reactive lymphocytes and associated production of large amounts of autoantibodies and ICs.
Lin
Qingshun
Q
Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Xiu
Yan
Y
Jiang
Yi
Y
Tsurui
Hiromichi
H
Nakamura
Kazuhiro
K
Kodera
Sanki
S
Ohtsuji
Mareki
M
Ohtsuji
Naomi
N
Shiroiwa
Wakana
W
Tsukamoto
Kazuyuki
K
Amano
Hirofumi
H
Amano
Eri
E
Kinoshita
Katsuyuki
K
Sudo
Katsuko
K
Nishimura
Hiroyuki
H
Izui
Shozo
S
Shirai
Toshikazu
T
Hirose
Sachiko
S
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D001792:Blood Platelets / Q000276:immunology; D004247:DNA / Q000276:immunology; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D008181:Lupus Nephritis / Q000097:blood / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D010587:Phagocytosis / Q000235:genetics; D011961:Receptors, Fc / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D013163:Splenomegaly / Q000276:immunology / Q000473:pathology; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics / Q000276:immunology
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D011961:Receptors, Fc; D017452:Receptors, IgG; D004247:DNA