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 6

Reduced FcγRIIB expression in MZ B cells from patients with SLE.

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Reduced FcγRIIB expression in MZ B cells from patients with SLE. High-di...
High-dimensional spectral flow cytometry was used to identify multiple B cell subsets within PBMCs from patients with SLE (n = 15) and healthy donors (HD) (n = 10). (A) Expression of CD32B/C in CD27– and CD27+ B cells. (B) Live B cells were clustered using FlowSOM and are shown in a UMAP plot. Live B cells from healthy donors and patients with SLE were concatenated from each donor (n = 250,000 cells per group). (C) Expression of CD32B/C among all B cell clusters in the UMAP plot. (D) Representative example of CD32B/C expression in MZ-like B cells from healthy donors and patients with SLE, including the FMO control. (E) Summary of CD32B/C expression in MZ B cells. (F) Summary of CD32B/C expression in cells in all FlowSOM clusters. (G) Expression of CD32B/C in MZP cells identified by manual gating as live CD19+CD27–IgD+CD38loCD21+CD24hi. (H) Representative examples of CD80 expression and gating in MZ B cells from healthy donors and patients with SLE. MZ B cells from healthy donors and patients with SLE were concatenated from each donor (n = 25,000 cells per group). (I) Summary of the percentage of CD80+ MZ B cells from healthy donors and patients with SLE. (J) Correlation of the percentage of CD80+ cells and CD32B/C MFI in MZ B cells. Data are shown as the median, with each symbol representing an individual donor (n = 10 for healthy donors; n = 15 for patients with SLE). **P < 0.01 (A) and other P values were determined by Mann-Whitney U test (E–G and I) or Spearman’s rank test (J). Act. Nv, activated naive; Rest. Nv, resting naive; Atyp. UnswM, atypical unswitched memory; Act. SwM, activated switched memory; Rest. SwM, resting switched memory; PB, plasmablast.