Phosphorylcholine in atherosclerosis and immunity

Background

Atherosclerosis is a chronic inflammatory condition and the plques are characterized by accumulation of dead cells, oxidized LDL (OxLDL) in foam cells and activated immune competent cells. An interesting component in both OxLDL and dead cells is phosphorylcholine (PC) which is recognized when exposed, by antibodies (ant-PC). Extracellular vesicles (EVs) are important in the transport of cargo of proteins, metabolites, lipids and nucleic acids and are implicated in atherosclerosis.

PC is a major component in EV in our preliminary experiments. We demonstrated that oxidized LDL (oxLDL) cause dendritic cell (DC) and T cell activation in atherosclerotic plaques and that PC is of major importance and that IgM and IgG1 antibodies against PC (anti-PC) are inversely associated risk of atherosclerosis and CVD and more. We reported potential underlying mechanisms: anti-inflammatory, inhibition of uptake of oxLDL, increased clearance of dead cells and immunomodulation. We also identified Annexin A5 as anti-inflammatory, in the context of plaque inflammation.

Our aims are to: Investigate how PC can exert effects on immune competent cells, in different types of presentation, including by EVs. Further assess anti-PC as markers for atherosclerosis and vascular aging Develop a vaccine with PC as antigen, against atherosclerosis and complications Working plan

Effects of PC, with focus on PC in EVs on immune competent cells including DCs and plaque T cells in ex vivo studies are tested, with or without oxidation. Electron microscopy and lipidomics is used to study PC in EVs. Effects are inhibited by anti-PC, both our in house fully human anti-PC IgG1, and polyclonal IgM and IgG anti-PC.

We also test effects of Annexins, with focus on Annexin A5. Active immunization with PC with new carrier proteins will be developed, tested for antigenicity and then studied in mice models where effects on atherosclerosis will be evaluated. Antibodies against EVs and anti-PC is further evaluated in clinical settings.

Significance

We propose a novel paradigm: an insufficiently active natural immunity against PC predispose to atherosclerosis and CVD. Immunization with PC would be a major step forward if it works since atherosclerosis and ensuing CVD represent a major health problem in the world and is the largest cause of death. To reach this goal, also the underlying immunology, both innate immunity, B cells and T cells needs to be clarified.