Regulation effects of fusion protein IgD-Fc-Ig targeting T cells via
IgD-IgDR-Lck-ZAP70-PI3K-NF-κB signaling in rheumatoid arthritis
Abstract
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.