Abstract
Full activation of T lymphocytes requires signals from both T cell receptors and costimulatory molecules. In addition to CD28, several T cell molecules could deliver costimulatory signals, including CD154, which primarily interacts with CD40 on B-cells. CD40 is a critical molecule regulating several B-cell functions, such as antibody production, germinal center formation and cellular proliferation. Upregulated expression of CD40 and CD154 occurs in immune effector cells and non-immune cells in different autoimmune diseases. In addition, therapeutic benefits have been observed by blocking the CD40-CD154 interaction in animals with collagen-induced arthritis. Given the therapeutic success of the biologics abatacept, which blocks CD28 costimulation, and rituximab, which deletes B cells in the treatment of autoimmune arthritis, the inhibition of the CD40-CD154 axis has two advantages, namely, attenuating CD154-mediated T cell costimulation and suppressing CD40-mediated B-cell stimulation. Furthermore, blockade of the CD40-CD154 interaction drives the conversion of CD4+ T cells to regulatory T cells that mediate immunosuppression. Currently, several biological products targeting the CD40-CD154 axis have been developed and are undergoing early phase clinical trials with encouraging success in several autoimmune disorders, including autoimmune arthritis. This review addresses the roles of the CD40-CD154 axis in the pathogenesis of autoimmune arthritis and its potential as a therapeutic target.
Highlights
Patients with autoimmune arthritis, which is mainly comprised of rheumatoid arthritis (RA), psoriatic arthropathy (PsA) and ankylosing spondylitis (AS), suffer from aggressive and long-lasting joint destruction, and many of these patients end up with joint deformity and disability
The results suggested that TRAF1 plays important degradation of both TRAF2 and TRAF3 in response to CD40 stimulation [59]
TRAF3 is constitutively associated with NF-κB-inducing kinase (NIK), which is an important regulator of the noncanonical/NF-κB2 pathway induced by IL-1 or tumor necrosis factor (TNF) superfamily members [70,71], in a dynamic manner, and the TRAF3-NIK
Summary
Patients with autoimmune arthritis, which is mainly comprised of rheumatoid arthritis (RA), psoriatic arthropathy (PsA) and ankylosing spondylitis (AS), suffer from aggressive and long-lasting joint destruction, and many of these patients end up with joint deformity and disability. Early studies by Saito et al showed that the CD28-independent graft-vs-host disease (GVHD) reaction could be significantly attenuated by treatment with anti-CD154 mAb, suggesting the superiority of the CD40-CD154 axis among non-CD28 costimulatory pathways in regulating GVHD-mediated immune responses [16]. All of these findings suggest potential benefits of CD40-CD154 blockade in achieving effective control of inflammation because the inhibition of CD40/CD154 signaling decreases T cell costimulation and inhibits the stimulatory signal to B cells and to other CD40-expressing cells, such as fibroblasts, macrophages, and dendritic cells. In the major part of this review, we focus on discussing the potential of targeting the CD40-CD154 costimulatory pathway to develop therapeutics for patients with autoimmune arthritis
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