The inhibitory Fcgamma receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells.
Deletion of the gene encoding the Fc immunoglobulin G receptor IIB (FcgammaRIIB) results in a fulminant, lupus-like disease in C57BL/6 but not BALB/c mice. Here we have investigated this strain-specific, epistatic loss of tolerance using gene-targeted immunoglobulin variable heavy-chain (V(H)) alleles 3H9 or 56R, which encode DNA-specific heavy chains, expressed on the C57BL/6 or BALB/c background. The combination of C57BL/6 and V(H) 56R (B6.56R) resulted in a loss of tolerance; hybridoma and single-cell analysis indicated an FcgammaRIIB-independent difference in immunoglobulin light-chain usage, consistent with an alteration in receptor editing. FcgammaRIIB deficiency resulted in an increase in immunoglobulin G (IgG) antibodies to DNA in the serum, an increased frequency of anti-DNA-reactive IgG(+) B cells with a plasma cell phenotype and immune complex deposition in the glomeruli and renal disease in B6.56R mice. Thus, FcgammaRIIB provides a distal peripheral checkpoint to limit the accumulation of autoreactive plasma cells, thereby maintaining tolerance.
Fukuyama
Hidehiro
H
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York 10021, USA.
Nimmerjahn
Falk
F
Ravetch
Jeffrey V
JV
D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics; D015551:Autoimmunity; D004247:DNA / Q000276:immunology*; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000378:metabolism*; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D017452:Receptors, IgG / Q000502:physiology*
D000974:Antibodies, Antinuclear; C499172:Fcgr2b protein, mouse; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D017452:Receptors, IgG; D004247:DNA