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The inhibitory Fcγ receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells

Nature Immunology volume 6, pages 99–106 (2005)Cite this article

Abstract

Deletion of the gene encoding the Fc immunoglobulin G receptor IIB (FcγRIIB) 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 (VH) 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 VH 56R (B6.56R) resulted in a loss of tolerance; hybridoma and single-cell analysis indicated an FcγRIIB-independent difference in immunoglobulin light-chain usage, consistent with an alteration in receptor editing. FcγRIIB 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, FcγRIIB provides a distal peripheral checkpoint to limit the accumulation of autoreactive plasma cells, thereby maintaining tolerance.

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Figure 1: Emergence of anti-DNA in 56R Igh knock-in mice on the C57BL/6 background.
Figure 2: Anti-DNA antibodies are derived from the 56R Igh knock-in (IgMa) allele.
Figure 3: Vκ usage and receptor editing for the 56R Igh knock-in on the C57BL/6 and BALB/c backgrounds.
Figure 4: FcγRIIB deficiency enhances production of IgG anti-DNA in the serum of C57BL/6 mice carrying Igh knock-in allele.
Figure 5: Increased plasma cells in B6.56R Fcgr2b−/− mice.
Figure 6: IgG anti-DNA antibodies from B6.56R Fcgr2b−/− mice are sufficient to induce glomerulonephritis.

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Acknowledgements

We thank our colleagues, M. Nussenzweig, B. Diamond, M. Weigert and M. Madio for providing comments; P. Smith, C. Ryder, M. Patt, L. Josephs and P. Gel for technical assistance; and C. Ritter for administrative support. Supported by the National Institutes of Health and the Alliance for Lupus Research (J.V.R.), Yamada Science Foundation in Japan (H.F.) and Deutsche Forschungsgemeinschaft (F.N.; NI711/2-1).

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  1. Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, 10021, New York, USA

    Hidehiro Fukuyama, Falk Nimmerjahn & Jeffrey V Ravetch

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  1. Hidehiro Fukuyama
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Correspondence to Jeffrey V Ravetch.

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Supplementary information

Supplementary Fig. 1

Normal B cell development in B6.56R Fcgr2b−/− mice. (PDF 572 kb)

Supplementary Table 1

Primer list (PDF 43 kb)

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Fukuyama, H., Nimmerjahn, F. & Ravetch, J. The inhibitory Fcγ receptor modulates autoimmunity by limiting the accumulation of immunoglobulin G+ anti-DNA plasma cells. Nat Immunol 6, 99–106 (2005). https://doi.org/10.1038/ni1151

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