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

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-KB 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.