Immunopathological aspect of cardiovascular disease in systemic lupus erythematosus (SLE)

Background and aims

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease involving most organ systems. Cardiovascular disease (CVD) is the leading cause of mortality in SLE and the increased risk is even more pronounced in younger women. Interferon-alpha (IFN-alpha), produced by plasmacytoid dendritic cells (pDCs) upon engulfment of ICs, is considered a key cytokine in SLE pathogenesis. IFN-alpha may be linked to CVD in SLE due to effects on endothelium since this cytokine seems to mediate imbalance between destruction and repair of the endothelial progenitor cells leading to endothelial dysfunction. Activated and/or NETting neutrophils are also main producers of S100A8/A9, which through interactions with RAGE and TLR4 induces systemic inflammation. SLE patients have a type I IFN signature in platelets associated with CVD.

The aims of the project are to analyse the proinflammatory protein complex S100A8/A9 and S100A12 as a marker of disease activity and of certain organ manifestations in SLE and to investigate S100A8/A9 and S100A12 as an indicator of CVD in SLE. Investigate the contribution of type I IFNs and the vasculoprotective apolipoprotein ApoM in development of endothelial dysfunction and CVD in SLE patients and assess the role of platelet activation in development of endothelial dysfunction, CVD and venous thrombosis in SLE.

Methods and Results

Study I

Serum levels of S100A8/A9 and S100A12 were measured with ELISA in 237 SLE patients with clinically inactive disease as well as in 100 healthy individuals. Cardiovascular manifestations were recorded. SLE patients with a history of CVD had increased serum levels of both S100A8/A9 and S100A12 compared with patients with no CVD. The presence of organ damage was associated with an increase in both S100A8/A9 and S100A12 serum levels.

Study II

Serum levels of S100A8/A9 and S100A12 were measured by ELISA in paired samples of 100 SLE patients at time points of higher and lower disease activity. Clinical data were recorded at time points of blood sampling. Serum levels of S100A8/A9 and S100A12 were increased in SLE patients with high disease activity compared to paired samples at low disease activity. Elevated levels of S100A8/A9 were particularly seen in patients with anti-dsDNA antibodies and glomerulonephritis.

Study III

SLE patients n=148 and 79 sex- and age matched healthy controls (HC) were tested. Endothelial dysfunction (ED) were measured by EndoPAT 2000 (Itamar Medical, Israel). A surrogate marker for ED; sVCAM-1 was measured with ELISA. Type I IFN activity was measured by a serum IFN-reporter gene expression assay (s-IFN score).Platelet activation was measured as levels of platelet C4d deposition, platelet- monocyte complex and platelet- granulocyte complex by flow cytometry. ED was seen in SLE patients with ongoing type I IFN activity compared to Healthy controls (HC). ED was seen in SLE patients with ongoing type I IFN activity compared to patients without type I IFN activity.  SLE patients with ED had more activated platelets than patients with normal endothelium.  

Study IV

The plasma concentrations of apoM were measured with an ELISA in 148 SLE patients and 79 healthy controls. Analyses of results ongoing.

Conclusions

Elevated serum levels of S100A8/A9 and S100A12 may be used as an indicator of CVD and severe disease in SLE and increased S100A8/A9 serum levels may be used to monitor disease activity in SLE, especially in patients with glomerulonephritis. SLE patients with activated type I IFN system have impaired endothelial function. This may act together with activated platelets due to injured endothelium, in the development of CVD in SLE.