Journal
ACTA PHARMACOLOGICA SINICA
Volume 43, Issue 2, Pages 387-400Publisher
NATURE PUBL GROUP
DOI: 10.1038/s41401-021-00665-w
Keywords
rheumatoid arthritis; immunoglobulin D; IgD-Fc-Ig; immunoglobulin D receptor; CD4(+) T cells; CD19(+) B cells
Funding
- National Natural Science Foundation of China [81603121, 81673444, 81973332]
- Key Projects of Natural Science Research of Anhui Colleges and Universities [KJ2020A0158]
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Rheumatoid arthritis is a chronic systemic autoimmune disease characterized by synovitis and small joint destruction. IgD stimulation may contribute to RA pathogenesis and IgD-Fc-Ig serves as a potential treatment by inhibiting T-cell activation and blocking the IgD-IgDR signaling pathway.
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-kappa B) 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 IgG(1) 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-kappa B 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-kappa B 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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