Ricerc@Sapienza

Atherosclerosis is a chronic inflammatory disease driven by lipids and particularly by immunogenic oxidation-specific epitopes (OSEs) of oxidated LDL (oxLDL). A number of studies have provided evidence that anti-oxLDL natural IgM antibodies, mostly produced by innate marginal zone (MZ) B cells, are atheroprotective in hyperlipidemic ApoE-/- or Ldlr-/- mice. The production of protective anti-oxLDL IgM antibodies can be boosted in mice by immunization with OSEs displayed by phosphorylcholine (PC), by apoptotic cells, or by killed pneumococci through the polysaccharide-associated PC. The latter finding prompts the appealing possibility of making use of the current pneumococcal polysaccharide vaccines for inducing atheroprotective antibodies in humans but attempts with a 13-valent vaccine (Prevenar) have so far failed to yield robust anti-oxLDL responses. A likely reason for this failure is that human autoreactive MZ B cells continually exposed to autoantigen, as it is the case for anti-oxLDL B cells, largely become anergic ¿CD21low¿ B cells with unresponsive B cell receptors (BCR). Importantly, it is known that the contemporaneous engagement of the BCR and of Toll-like receptors (TLR) 9 or 7 can overcome anergy in these cells; thus, while the immunogens used in mouse studies simultaneously provide OSEs that stimulate the BCR and ligands (bacterial or cellular DNA, CpG) that stimulate TLR9, polysaccharide vaccines used in human studies stimulate only the BCR. Thus, formulations of pneumococcal polysaccharide adjuvated by TLR9 or TLR7 ligands are expected to induce robust, potentially atheroprotective, anti-oxLDL responses.

The objective of the project is to determine the functional status of human oxLDL-specific B cells in healthy donors and in patients with hyperlipidemia and diffuse atherosclerosis, and the optimal conditions in vitro of costimulation with TLR9 or TLR7 ligands and pneumococcal polysaccharide for inducing an IgM anti-oxLDL antibody response.