FcγRIIB regulates autoantibody responses by limiting marginal zone B cell activation
Ashley N. Barlev, Susan Malkiel, Izumi Kurata-Sato, Annemarie L. Dorjée, Jolien Suurmond, Betty Diamond
Ashley N. Barlev, Susan Malkiel, Izumi Kurata-Sato, Annemarie L. Dorjée, Jolien Suurmond, Betty Diamond
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Research Article Autoimmunity Immunology

FcγRIIB regulates autoantibody responses by limiting marginal zone B cell activation

Abstract

FcγRIIB is an inhibitory receptor expressed throughout B cell development. Diminished expression or function is associated with lupus in mice and humans, in particular through an effect on autoantibody production and plasma cell (PC) differentiation. Here, we analyzed the effect of B cell–intrinsic FcγRIIB expression on B cell activation and PC differentiation. Loss of FcγRIIB on B cells in Fcgr2b–conditional KO (Fcgr2b-cKO) mice led to a spontaneous increase in autoantibody titers. This increase was most striking for IgG3, suggestive of increased extrafollicular responses. Marginal zone (MZ) B cells had the highest expression of FcγRIIB in both mice and humans. This high expression of FcγRIIB was linked to increased MZ B cell activation, Erk phosphorylation, and calcium flux in the absence of FcγRIIB triggering. We observed a marked increase in IgG3+ PCs and B cells during extrafollicular PC responses in Fcgr2b-cKO mice. The increased IgG3 response following immunization of Fcgr2b-cKO mice was lost in MZ-deficient Notch2 Fcgr2b–double KO mice. Importantly, patients with systemic lupus erythematosus (SLE) had a decrease in FcγRIIB expression that was strongest in MZ B cells. Thus, we present a model in which high FcγRIIB expression in MZ B cells prevented their hyperactivation and ensuing autoimmunity.

Authors

Ashley N. Barlev, Susan Malkiel, Izumi Kurata-Sato, Annemarie L. Dorjée, Jolien Suurmond, Betty Diamond

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Figure 1

Increased spontaneous autoantibody IgG3 responses in Fcgr2b-cKO mice.

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Increased spontaneous autoantibody IgG3 responses in Fcgr2b-cKO mice. Fe...
Female control (Ctr) and Fcgr2b-cKO mice were bred and maintained until experiments at 10–12 months of age, at which point (auto)antibodies in serum and PCs in spleen were characterized. ANA reactivity of PCs was established using flow cytometry. (A and B) dsDNA ELISA for total IgG and IgG subclasses in serum from Fcgr2b-cKO mice. (C) Representative example of ANA staining in IgG and IgM PCs in spleen. (D and E) Frequency of ANA+ IgG+ PCs in spleen, total IgG (D), and by IgG subclass (E). (F) Representative example of IgM and IgG3 staining in total PCs. IgG3+ cells are indicated in green. (G) Frequency of IgG+ PCs in spleen separated by subclass. (H) Frequency of IgG3+ B cells in control and Fcgr2b-cKO mice. (I) Representative example of staining strategy for B-1 and B-2 cells in spleen. (J) Percentage of splenic IgG3+ B cells with a B-1 or B-2 phenotype, respectively, gated as in I. (K) Representative example of staining for B220 and CD5 in total IgG3+ B cells compared with B-1, FO, and MZ B cells in spleen. Data are shown as the median, with each symbol representing an individual mouse (A, B, D, E, G, H, and J) (n = 12–17 per group pooled from 2–3 independent experiments). *P < 0.05 and ***P < 0.001, by Mann-Whitney U test.