Defective Fc gamma RII gene expression in macrophages of NOD mice: genetic linkage with up-regulation of IgG1 and IgG2b in serum.
A quantitative trait locus for increased IgG serum levels in the NOD mouse strain was mapped to distal chromosome 1, close to the fcgr2 locus encoding the low-affinity type II receptor for the Fc portion of IgG (Fc gamma RII). Expression of membrane-inserted (b2) and soluble (b3) isoforms of Fc gamma RII was strongly decreased in macrophages of NOD compared with C57BL/6 (B6) mice. In contrast, B cell-specific (Fc gamma RIIb1) isoform was only slightly decreased and Fc gamma RIII was not altered. This Fc gamma RII regulatory defect was cis-encoded by fcgr2 or by a closely linked locus, occurred at the mRNA level, and was associated with multiple mutations in the fcgr2 gene promoter. In relation with this defect, binding of IgG1- and IgG2b- but not IgG2a-opsonized RBC by macrophages of NOD and congenic B6.NOD-fcgr2 mice was severely impaired, but was normal in macrophages of NOD.B6-fcgr2 congenic mice, indicating that Fc gamma RII plays a nondispensable role in binding of IgG1 and IgG2b isotypes. Likewise, serum levels of IgG1 and IgG2b but not IgG2a were up-regulated in NOD compared with NOD.B6-fcgr2 congenic mice. These findings indicate that macrophage Fc gamma RII may regulate serum IgG1 and IgG2b through their catabolism, and validate the NOD strain as a model to investigate the functions of Fc gamma RII isoforms.
INSERM Unit 25 and Necker Institute, Paris, France.
J J
JJ
Luan
R C
RC
Monteiro
C
C
Sautès
G
G
Fluteau
L
L
Eloy
W H
WH
Fridman
J F
JF
Bach
H J
HJ
Garchon
D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D005786:Gene Expression Regulation / Q000276:immunology*; D005803:Genes, Immunoglobulin; D008040:Genetic Linkage / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood* / Q000235:genetics*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D017452:Receptors, IgG / Q000096:biosynthesis* / Q000235:genetics*; D015854:Up-Regulation / Q000276:immunology*
D007074:Immunoglobulin G; D017452:Receptors, IgG