The role of osteopontin in the induction of the CD40 ligand in Graves' disease

Abstract

Graves' disease (GD) is a common autoimmune disease involved autoantibody production. Although we previously reported that osteopontin (OPN), a proinflammatory protein, affected development of GD through NF-κB activation, little is known about the role of OPN in regulating immunoglobulin production in GD. CD40 Ligand (CD40L) is expressed on the surface of activated CD4+T cells and costimulates CD40 on B cells, stimulating production of immunoglobulins, a process which has been reported to play a vital role in immunological signalling transduction in several autoimmune diseases. This study sought to characterize the relationship between CD40L and GD development, as well as investigating the role of OPN in modulating immunoglobulin production in GD via CD40L. Forty incident patients with GD, twenty-one patients with GD in remission and twenty-seven healthy controls were recruited. Both membrane-bound and soluble forms of CD40L were measured, and their correlations with clinical parameters were studied. In addition, correlation between OPN and CD40L level was also examined. Furthermore, we studied the regulatory effect of OPN on CD40L in CD4+T cells. We demonstrated that the CD40L levels were enhanced in patients with GD and recovered in patients with GD in remission. CD40L levels correlated with clinical GD diagnostic parameters and OPN concentration. Moreover, human recombinant OPN and plasma samples from patients with GD increased CD40L expression, which could be significantly suppressed by OPN monoclonal antibody. In addition, CD40L antibody blocked the immunoglobulin production augmented by OPN in cultured peripheral blood mononuclear cells (PBMCs), isolated from patients with GD and healthy subjects. These results indicate that CD40L is induced by OPN and serves as the downstream effector of OPN for immunoglobulin production in GD development.