Novel immunological mechanisms and direction for new immunological therapies with focus on small lipid antigens

Background

We demonstrated that oxidized LDL (oxLDL) cause dendritic cell (DC) and T cell activation in atherosclerotic plaques and that a small lipid-related antigen, phosphorylcholine (PC) on inflammatory phospholipids is of major importance. IgM and IgG1 antibodies against PC (anti-PC) are inversely associated with atherosclerosis development, risk of CVD, also in SLE and uremia.

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 and PCSK9 as pro-inflammatory. Our aims are to:

Investigate how B cells can provide protection and dendritic cells (DC) and T cells in plaques are activated and how this activation can be modulated.

Further assess anti-PC as markers for atherosclerosis, vulnerable plaques and CVD (including different diagnoses of CVD). Develop therapies through active immunization with PC. Understand causes of low anti-PC, as low of exposure to PC bearing microorganisms. Working plan

Our research is translational, using a combination of cohort- and experimental studies, in vivo, ex vivo and in vitro. One focus is further delineation in large cohorts of the role of anti-PC, including genetics. We will study B cells, and how their anti-PC production can be increased or decreased.

We generated a panel of fully human anti-PC monoclonals, and will further characterize them and their properties. The effect on DC and T-cells activation by different activation methods, and modulation by anti-PC and other inhibitors as Annexin A5, PCSK9 antibodies, is further studied. Ex vivo experiments with T cells from atherosclerotic plaques is one focus, to find out how mode of presentation of PC can influence effects on T cells. Active immunization with PC will be tested in mice models.

Significance

We propose a novel paradigm: an insufficiently active natural immunity against PC in OxLDL and other compounds predispose to atherosclerosis and CVD. Anti-PC is a promising marker for atherosclerosis, vulnerable plaques and CVD, low levels associated with high risk and such prediction is much needed. Novel immunomodulatory methods with active immunization with PC would be a major step forward if it workd.

To reach this goal, also the underlying immunology, both innate immunity, B cells and T cells needs to be clarified.