Journal
NATURE IMMUNOLOGY
Volume 6, Issue 1, Pages 99-106Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni1151
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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.
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