Dendritic cells: an important link between antiphospholipid antibodies, endothelial dysfunction, and atherosclerosis in autoimmune and non-autoimmune diseases

Abstract

The presence of dendritic cells, antigen-presenting cells that link innate and adaptive immunity, is necessary to generate and maintain the production of antiphospholipid antibodies in response to exposed intracellular phospholipids on the outer surface of apoptotic cells. In turn, antiphospholipid antibodies enhance dendritic cell-induced inflammatory and proatherogenic responses in a number of conditions that are associated with accelerated atherosclerosis, including diabetes, chronic kidney disease, periodontal infections, and aging. While altering dendritic cells by modifying the ubiquitin-proteasome system enhances antiphospholipid antibody production and leads to development of accelerated atherosclerosis and autoimmune features, inducing tolerance by dendritic cell manipulation leads to decreased atherosclerosis and thrombosis. Therefore, further translational studies are needed to understand the interplay between dendritic cells and antiphospholipid antibodies, and to develop potential new therapies for antiphospholipid syndrome and atherosclerosis. Here we review current experimental and translational studies that have examined the role of dendritic cells in antiphospholipid antibody formation and in antiphospholipid-associated atherosclerosis and thrombosis.

Figure 1. Common pathways in antiphospholipid syndrome and in atherosclerosis

APLS and atherosclerosis share several common pathways including production of antibodies to phospholipids, heat shock proteins, and oxidized LDL; endothelial dysfunction; immune cell activation; oxidative stress; platelet activation and thrombus formation.

Figure 2. DCs are needed to develop anti - β2-GPI Abs

Early endothelial damage in the arterial vessels can lead to the exposure of phospholipids to the outer cell surface and aPL antibody formation. Opsonization of apoptotic cells with anti-β2-GPI Abs skews phagocytosis toward inflammation. DCs preferentially internalize apoptotic cells opsonized by anti-β2-GPI Abs, leading to sustained generation of anti-β2-GPI Abs.

Figure 3. Synergistic effects of aPL Abs and TLR7 on pDC maturation

aPL Abs work synergistically with TLR7 to promote pDC maturation and pro-inflammatory function by activating the NF-κB signaling pathway.

Figure 4. Interactions between DCs and aPL Abs may be enhanced by glycation and oxidation of aPL Abs

In atherosclerosis, diabetes and aging, the microenvironment predisposes local β₂GPI to glycation and/or oxidation, initiating a local autoimmune process leading to inflammation, endothelial dysfunction and accelerated atherosclerosis.

Figure 5. A possible link between periodontal disease, aPL Abs, DCs, and atherosclerosis

Bacteria associated with periodontal disease share homologous sequences with β₂GPI and promote formation of pathogenic aPL Abs, which cross react with oxLDL and form immune complexes that stimulate DCs and macrophages more robustly than bacteria or oxLDL alone.

Figure 6. Deubiquitination and tolerance induction may alter DCs to decrease DC-aPL interactions in APS and atherosclerosis

1. Dysregulation of the ubiquitin pathway may partly explain why only some individuals develop persistent aPL Abs, autoimmune features and atherosclerosis. Therefore, de-ubiquitination may decrease DC-aPL interactions. 2. DCs exposed to IL-10 decrease atherosclerotic plaque formation in mice and T-cell responses to b2GPI in APS.