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. 2011 Nov 15;108(46):18772-7.
doi: 10.1073/pnas.1111810108. Epub 2011 Nov 7.

Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system in vivo

Affiliations

Fcγ receptor IIB (FcγRIIB) maintains humoral tolerance in the human immune system in vivo

Anne Baerenwaldt et al. Proc Natl Acad Sci U S A. .

Erratum in

Abstract

Maintenance of immunological tolerance is crucial to prevent development of autoimmune disease. The production of autoantibodies is a hallmark of many autoimmune diseases and studies in mouse model systems suggest that inhibitory signaling molecules may be important checkpoints of humoral tolerance. By generating humanized mice with normal and functionally impaired Fcγ receptor IIB (FcγRIIB) variants, we show that the inhibitory Fcγ-receptor is a checkpoint of humoral tolerance in the human immune system in vivo. Impaired human FcγRIIB function resulted in the generation of higher levels of serum immunoglobulins, the production of different autoantibody specificities, and a higher proportion of human plasmablasts and plasma cells in vivo. Our results suggest that the inhibitory FcγRIIB may be an important checkpoint of humoral tolerance in the human immune system.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
FcγRIIB expression and function in humanized mice. (A) Presence of human cells in the blood of humanized mice 4 mo after transplantation with HSC carrying the FcγRIIB-232I/I (232I/I), -232I/T (232I/T), or -232T/T alleles. (B) Expression of FcγRIIB on CD19+ B cells of humans and humanized mice in the peripheral blood. (C) Assessment of FcγRIIB function in the peripheral blood of humanized mice with the indicated FcγRIIB genotypes by calcium flux analysis after cross-linking the B-cell receptor either alone (red line) or in combination with FcγRIIB (blue line). (D–F) Expression of FcγRIIB on different B-cell developmental stages in the bone marrow (D) and spleen (E and F) of humanized mice. Expression level of FcγRIIB is shown as mean fluorescence intensity (MFI). *P < 0.05, **P < 0.01, ***P < 0.001.
Fig. 2.
Fig. 2.
Development of autoantibodies in humanized mice. (A and B) The levels of serum IgM and serum IgG were analyzed in humanized mice carrying the different FcγRIIB allelic variants at 4 and 6 mo of age. (C–F) Detection of IgM autoantibody responses to dsDNA (anti-DNA), anti-GPI, RF, and anti-CCP in humanized mice at 16 and 24 wk of age. The level of autoantibody production is shown as arbitrary units (AU) for anti-DNA, -GPI, and RF responses and as OD for anti-CCP responses. Statistical significance was calculated with the Mann–Whitney U test. *P < 0.05. Datapoints of mice that received human HSC from the same donor are depicted in the same color.
Fig. 3.
Fig. 3.
Influence of HLA and activating FcγR alleles on autoantibody production. (A) Humanized mice with FcγRIIB-232T/T or FcγRIIB-232I/I alleles were grouped according to the indicated HLA haplotypes (DR*03, 15/DQ*02, 06, DR*15/DQ*06, and DR*03/DQ*02) and according to the absence of these HLA haplotypes (others). (B) Humanized mice with the indicated FcγRIIB alleles were genotyped for the presence of the FcγRIIA-131 histidine (IIA:H) or arginine (IIA:R) allele and the FcγRIIIA-158 valine (IIIA:V) or phenylalanine (IIIA:F) allele and grouped according to their FcγRIIA/FcγRIIIA genotype. The level of autoantibody production is shown as arbitrary units (AU) for anti-DNA, -GPI, and -RF responses and as OD for anti-CCP responses.
Fig. 4.
Fig. 4.
Identification of autoantibody producing B cells in humanized mice with different FcγRIIB alleles. (A) Identification and quantification of IgM+ or IgM plasmablasts in the spleen of 6-mo-old humanized mice with the FcγRIIB-232I/I, -232I/T, or -232T/T genotype. B cells were identified by gating on CD19. (B) Identification and quantification of CD138+ plasma cells in the spleen of 6-mo-old humanized mice with the FcγRIIB-232I/I or -232T/T genotype. B cells were identified by gating on CD19. Bars indicate the median of the group and statistical significance was evaluated with the Student's T-test. *P < 0.05. (C and D) Identification (C) and quantification (D) of IgM-producing B cells, IgM anti-GPI, and IgM anti-DNA–producing B cells obtained from the bone marrow by ELISpot analysis of 6-mo-old humanized mice with the FcγRIIB-232I/I or -232T/T genotype.

References

    1. Nashi E, Wang Y, Diamond B. The role of B cells in lupus pathogenesis. Int J Biochem Cell Biol. 2010;42:543–550. - PMC - PubMed
    1. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008;8:34–47. - PubMed
    1. Takai T. Roles of Fc receptors in autoimmunity. Nat Rev Immunol. 2002;2:580–592. - PubMed
    1. Wardemann H, Nussenzweig MC. B-cell self-tolerance in humans. Adv Immunol. 2007;95:83–110. - PubMed
    1. Grimaldi CM, Hicks R, Diamond B. B cell selection and susceptibility to autoimmunity. J Immunol. 2005;174:1775–1781. - PubMed

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