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An IgD-Fc-Ig fusion protein restrains the activation of T and B cells by inhibiting IgD-IgDR-Lck signaling in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovitis and the destruction of small joints. Emerging evidence shows that immunoglobulin D (IgD) stimulation induces T-cell activation, which may contribute to diseases pathogenesis in RA. In this study, we investigated the downstream signaling pathways by which IgD activated T cells as well as the possible role of IgD in the T–B interaction. Peripheral blood mononuclear cells were isolated from peripheral blood of healthy controls and RA patients. We demonstrated that IgD activated T cells through IgD receptor (IgDR)-lymphocyte-specific protein tyrosine kinase (Lck)-zeta-associated protein 70 (ZAP70)/phosphatidylinositol 3-kinase (PI3K)/nuclear factor kappa-B (NF-κB) signaling pathways; IgD-induced CD4+ T cells promoted the proliferation of CD19+ B cells in RA patients. A novel fusion protein IgD-Fc-Ig (composed of human IgD-Fc domain and IgG1 Fc domain, which specifically blocked the IgD–IgDR binding) inhibited the coexpression of IgDR and phosphorylated Lck (p-Lck) and the expression levels of p-Lck, p-ZAP70, p-PI3K on CD4+ T cells, and decreased NF-κB nuclear translocation in Jurkat cells. Meanwhile, IgD-Fc-Ig downregulated the expression levels of CD40L on CD4+ T cells as well as CD40, CD86 on CD19+ B cells in RA patients and healthy controls. It also decreased the expression levels of CD40L on CD4+ T cells and CD40 on CD19+ B cells from spleens of collagen-induced arthritis (CIA) mice and reduced IL-17A level in mouse serum. Moreover, administration of IgD-Fc-Ig (1.625–13 mg/kg, iv, twice a week for 4 weeks) in CIA mice dose-dependently decreased the protein expression levels of CD40, CD40L, and IgD in spleens. IgD-Fc-Ig restrains T-cell activation through inhibiting IgD-IgDR-Lck-ZAP70-PI3K-NF-κB signaling, thus inhibiting B-cell activation. Our data provide experimental evidences for application of IgD-Fc-Ig as a highly selective T cell-targeting treatment for RA.

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Fig. 1: Effects of IgD-Fc-Ig (DG) on the IgDR-p-Lck interaction on CD4+ T cells in healthy controls induced by IgD.
Fig. 2: Effects of IgD-Fc-Ig (DG) on the protein expression of p-Lck, ZAP70, p-ZAP70, PI3K, and p-PI3K.
Fig. 3: Image Stream fluorescence imaging of NF-κB nuclear translocation in Jurkat cells after IgD induction and incubation with IgD-Fc-Ig (DG) and the Lck inhibitor A770041.
Fig. 4: Effects of IgD on CD4+ T-cell and CD19+ B-cell activities in healthy controls.
Fig. 5
Fig. 6: Effects of IgD-Fc-Ig (DG) on CD40, CD40L, and IgD expression in the spleens of CIA mice in vivo.
Fig. 7: Effects of IgD-Fc-Ig (DG) on CD4+ T-cell and CD19+ B-cell actions in CIA mice in vitro.
Fig. 8: Hypothetical schematic diagram of the IgD-Fc-Ig mechanism. IgD induces the abnormal activation of T cells by affecting IgDR-Lck-ZAP70-PI3K-NF-κB signaling in T cells, which can upregulate the expression of CD40L on CD4+ T cells.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (Nos. 81603121; 81673444; 81973332) and the Key Projects of Natural Science Research of Anhui Colleges and Universities (No. KJ2020A0158). The authors acknowledge Professors Li Si and Doctor Fang Wang in the First Affiliated Hospital of Anhui Medical University, for their help in healthy and RA donors recruiting.

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XXH performed the experiments and wrote the paper. AJZ and WWP participated in the experiments, collected the samples and performed immunohistochemistry experiments. QLX and JYC took part in FACS Aria cell sorting. LLZ and YC helped to revise the paper. YJW designed the study, participated in the experiments, and revised the paper. WW conceived of the study and revised the paper. All authors read and approved the final paper.

Corresponding authors

Correspondence to Yu-jing Wu or Wei Wei.

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Hu, Xx., Zhang, Aj., Pan, Ww. et al. An IgD-Fc-Ig fusion protein restrains the activation of T and B cells by inhibiting IgD-IgDR-Lck signaling in rheumatoid arthritis. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-021-00665-w

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Keywords

  • rheumatoid arthritis
  • immunoglobulin D
  • IgD-Fc-Ig
  • immunoglobulin D receptor
  • CD4+ T cells
  • CD19+ B cells

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