CD154: an immunoinflammatory mediator in systemic lupus erythematosus and rheumatoid arthritis

Abstract

Systemic lupus erythematosus and rheumatoid arthritis are two major chronic inflammatory autoimmune diseases with significant prevalence rates among the population. Although the etiology of these diseases remains unresolved, several evidences support the key role of CD154/CD40 interactions in initiating and/or propagating these diseases. The discovery of new receptors (αIIbβ3, α5β1, and αMβ2) for CD154 has expanded our understanding about the precise role of this critical immune mediator in the physiopathology of chronic inflammatory autoimmune diseases in general, and in systemic lupus erythematosus and rheumatoid arthritis in particular. This paper presents an overview of the interaction of CD154 with its various receptors and outlines its role in the pathogenesis of systemic lupus erythematosus and rheumatoid arthritis. Moreover, the potential usefulness of various CD154-interfering agents in the treatment and prevention of these diseases is also discussed.

Figure 1

Biological function of the CD154/CD40 interaction. CD154 mediates numerous inflammatory functions on a wide variety of cell types by interacting with its classical CD40 receptor. These include T cell priming, B cell-dependent Ig class switching and germinal center formation, cell proliferation, regulation of apoptosis, release of proinflammatory cytokines, upregulation of adhesion molecules and costimulatory molecules, and production of cytotoxic radicals. FB: fibroblast, EC: endothelial cell, APC: antigen presenting cells, DC: dendritic cell, MC/Mac: monocyte/macrophage.

Figure 2

Structural and functional characteristics of CD154 receptors. Four receptors for CD154 have been identified, namely, CD40, αIIbβ3, α5β1, and αMβ2. These receptors are found on various cell types and induce different biological functions upon CD154 binding. APC: antigen presenting cells, DC: dendritic cells, MC: monocyte, EC: endothelial cell, FB: fibroblast, SMC: smooth muscle cell, Mac: macrophage, ICAM: intercellular adhesion molecule, GPIbα: glycoprotein Ibα, JAM-3: junctional adhesion molecule-3, MPO: myeloperoxidase.

Figure 3

CD154-dependent mechanistic events in SLE patients. High levels of membrane bound and sCD154 activate various immune cells in SLE, including T cells, B cells, and monocytes. These CD154 interactions induce the release of inflammatory mediators and the production of autoantibody and Igs, leading to the generation of immune complexes and the activation of the complement system at the forefront of many clinical manifestations in SLE patients.

Figure 4

Biological role of CD154 in RA. CD154 contributes to the pathogenesis of RA by stimulating expression of adhesion molecules, production of RF, release of inflammatory mediators including cytokines, chemokines, MMPs, and others.