Pathogenic immunity in systemic lupus erythematosus and atherosclerosis: common mechanisms and possible targets for intervention

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disorder that primarily affects young women and is characterized by inflammation in several organs including kidneys, skin, joints, blood and nervous system. Abnormal immune cellular and humoral responses play important roles in the development of the disease process. Impaired clearance of apoptotic material is a key factor contributing to the activation of self-reactive immune cells. The incidence of atherosclerotic cardiovascular disease (CVD) is increased up to 50-fold in patients with SLE compared to age- and gender-matched controls, and this can only partly be explained by traditional risk factors for CVD. Currently, there is no effective treatment to prevent CVD complications in SLE. Traditional preventive CVD therapies have not been found to significantly lower the incidence of CVD in SLE; therefore, there is a need for novel treatment strategies and increased understanding of the mechanisms involved in the pathogenesis of CVD complications in SLE. The pathogenic immune responses in SLE and development of atherosclerotic plaques share some characteristics, such as impaired efferocytosis and skewed T-cell activation, suggesting the possibility of identifying novel targets for intervention. As novel immune-based therapies for CVD are being developed, it is possible that some of these may be effective for the prevention of CVD and for immunomodulation in SLE. However, further understanding of the mechanisms leading to an increased prevalence of cardiovascular events in SLE is critical for the development of such therapies.

Keywords: CVD; SLE; immune mechanisms; immunotherapy.

Figure 1

Systemic lupus erythematous (SLE) disease mechanisms. Autoantigens released by apoptotic cells or other modified self-molecules can be taken up by antigen-presenting cells (APCs) or activating neutrophils, initiating different immune responses. Activated APCs will then activate T cells that start to produce cytokines, pro- or anti-inflammatory, and express co-stimulatory molecules to further activate other immune cells. Continued release of proinflammatory cytokines can induce damage of the surrounding tissue. T cells activated by autoantigens can further activate B cells leading to autoantibody production. Autoantibodies can then form immune complexes (ICs) with the respective autoantigen; after depositing the IC in tissues, inflammatory cells are recruited leading to tissue damage at the site of IC deposition. Activated neutrophils release proteins and reactive oxygen species with bactericidal properties. In addition to this, activated neutrophils extrude neutrophil extracellular traps (NETs) that have bactericidal functions, and the actions of activated neutrophils will lead to tissue damage during continued release of these lattices. Furthermore, NETs promote thrombosis leading to an increased risk of thrombus formation during inflammation. N, neutrophil; B, B cell; T, T cell; OxLDL, oxidized LDL; IFN; interferon; CD40L, CD40 ligand; FcR.

Figure 2

Potential future therapies targeting the immune system in systemic lupus erythematous (SLE) and cardiovascular disease (CVD).