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.

• Authors: Xiao-Xi Hu, Ai-Jun Zhang, Wen-Wen Pan, Qian-Ling Xin, Jing-Yu Chen, Ling-Ling Zhang, Yan Chang, Yu-Jing Wu, Wei Wei
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 43 Issue 2 Pg. 387-400 (Feb 2022) ISSN: 1745-7254 [Electronic] United States
• PMID: 33864023 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to CPS and SIMM.

Chemical References

• Immunoglobulin D
• Receptors, Fc
• Recombinant Proteins
• LCK protein, human
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck)

Topics

• Animals
• Arthritis, Rheumatoid (drug therapy)
• B-Lymphocytes (drug effects)
• Coculture Techniques
• Flow Cytometry
• Humans
• Immunoglobulin D (metabolism, therapeutic use)
• Lymphocyte Activation (drug effects)
• Lymphocyte Specific Protein Tyrosine Kinase p56(lck) (metabolism)
• Male
• Mice
• Mice, Inbred DBA
• Microscopy, Confocal
• Receptors, Fc (therapeutic use)
• Recombinant Proteins
• Signal Transduction (drug effects)
• T-Lymphocytes (drug effects)