Genetically determined aberrant down-regulation of FcgammaRIIB1 in germinal center B cells associated with hyper-IgG and IgG autoantibodies in murine systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is a multigenic disease associated with IgG hypergammaglobulinemia, IgG anti-nuclear antibodies and immune complex (IC)-type glomerulonephritis. In both human and murine SLE, one susceptibility allele has been mapped to the interval linked to the IgG Fc receptor II (FcgammaRII) gene on chromosome 1. In spontaneous SLE models of NZB and (NZB x NZW) F(1) mice, expression of FcgammaRIIB1, which acts as a negative regulator for B cells, was abnormally down-regulated in follicular germinal center B cells from aged mice, compared to findings in non-SLE NZW, while levels in non-germinal center B cells were practically identical. Such strain differences were also evident in young mice upon in vivo stimulation with foreign antigens. In the FcgammaRIIB promoter region, the NZB allele has two deletion sites, including transcription factor-binding sites. Analyses using (NZB x NZW) F(1) x NZW backcross mice showed that this NZB allele was significantly linked to hyper-IgG, irrespective of the MHC haplotype, while high levels of IgG antibodies specific for DNA were regulated by a combinatorial effect of the F(1)-unique MHC haplotype and the NZB FcgammaRIIB allele. Therefore, the FcgammaRIIB promoter polymorphism may possibly predispose to SLE through germinal center B cells abnormally down-regulating FcgammaRIIB1 expression upon autoantigen stimulations and thus escaping negative signals for IgG production.
Jiang
Y
Y
Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
Hirose
S
S
Sanokawa-Akakura
R
R
Abe
M
M
Mi
X
X
Li
N
N
Miura
Y
Y
Shirai
J
J
Zhang
D
D
Hamano
Y
Y
Shirai
T
T
D000367:Age Factors; D000483:Alleles; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D004247:DNA / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation; D005260:Female; D005838:Genotype; D018858:Germinal Center / Q000166:cytology*; D007074:Immunoglobulin G / Q000097:blood*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008285:Major Histocompatibility Complex / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D012313:RNA / Q000032:analysis; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D013154:Spleen / Q000166:cytology / Q000276:immunology
D001323:Autoantibodies; D007074:Immunoglobulin G; D017452:Receptors, IgG; D012313:RNA; D004247:DNA