Background and Purpose Neutrophils and the release of neutrophil extracellular traps (NETs) play important roles in the pathogenesis of RA. However, IgD, which was abnormally higher in RA, has not been studied for its pathological role in neutrophil activation and NETs formation. Experimental Approach Peripheral blood of RA patients and healthy controls were collected and adjuvant-induced arthritis (AA) rat models were established. Body weights, the severity of arthritis of AA rats were monitored regularly. After being stimulated with IgD, expression of FcδR on neutrophils and NETs formation were analyzed with multiple approaches such as flow cytometry, scanning electron microscopy, western blot, and qPCR. IgD-Fc-Ig were used to block interactions between IgD-FcδR. Additionally, the effect of IgD-induced neutrophils or NETs on FLS was assayed. Key Results As a specific marker of NETs, the level of citrullinated histone H3 was positively correlated with sIgD and FcδR in RA patients. IgD enhances the release of NETs by activating neutrophils. IgD-Fc-Ig could significantly reduce NETs formation and FcδR expression on neutrophils in vitro. In vivo, IgD-Fc-Ig treatment significantly regulates the neutrophil activity and NETs formation. IgD-Fc-Ig could restrain IgD-induced neutrophil activation and NETs formation, thus inhibiting FLS proliferation. Conclusions and Implications Neutrophils were activated by IgD, which suggests that neutrophils play a role in inducing FLS proliferation in RA patients who have abnormally higher IgD levels, there by increasing the severity of the disease. Blocking FcδR inhibited neutrophil activation and may represent an additional attractive novel therapeutic strategy for the treatment of RA.

Rheumatoid arthritis(RA) is a chronic systemic autoimmunediseasecharacterized by synovitis and the destruction of small joints.Emerging evidence had shown thatthe stimulation of immunoglobulin D (IgD) induced T cell activation which may contribute to diseases pathogenesis in RA.In this study we demonstrated that IgD could induce the activation of T cells through affecting IgDR-Lck-ZAP70- PI3K-NF-κB signaling, IgD-induced CD4+T cells promoted the proliferation of CD19+B cells in RA patients. IgD-Fc-Ig fusion protein (composed of human IgD Fc domain and IgG1 Fc domain, specifically blocks the IgD-IgDR pathway)inhibited the co-expression of IgDR and p-Lck and the expressions of p-Lck, p-ZAP70, p-PI3K on CD4+T cells, and decreased NF-κB nuclear translocation in Jurkat cells. Meanwhile, IgD-Fc-Ig down-regulated the protein expressions of CD40L on CD4+T cells and CD40, CD86 on CD19+B cells in RA patients and healthy controls. It also decreased the protein expressions of CD40L on CD4+T cellsand CD40 on CD19+B cells from spleens of CIA mice and reduced IL-17A level in mouse serum. Moreover, in vivo, IgD-Fc-Ig administration dose-dependently down-regulated the protein expressions of CD40, CD40L and IgD in spleens from CIA mice. IgD-Fc-Ig restrains the activations of T cells through inhibiting IgD-IgDR-Lck-ZAP70- PI3K-NF-κB signaling, thus inhibiting the activation of B cells.Our data provides experimental evidence for application prospect of IgD-Fc-Ig as a highly selective targeting T cell treatment for RA.