Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL

Abstract

During the progression of atherosclerosis, autoantibodies are induced to epitopes of oxidized low-density lipoprotein (oxLDL) and active immunization of hypercholesterolemic mice with oxLDL ameliorates atherogenesis. We unexpectedly found that many autoantibodies to oxLDL derived from 'naive' atherosclerotic mice share complete genetic and structural identity with antibodies from the classic anti-phosphorylcholine B-cell clone, T15, which protect against common infectious pathogens, including pneumococci. To investigate whether in vivo exposure to pneumococci can affect atherogenesis, we immunized Ldlr(-/-) mice with Streptococcus pneumoniae. This induced high circulating levels of oxLDL-specific IgM and a persistent expansion of oxLDL-specific T15 IgM-secreting B cells primarily in the spleen, which were cross-reactive with pneumococcal determinants. Pneumococcal immunization decreased the extent of atherosclerosis, and plasma from these mice had an enhanced capacity to block the binding of oxLDL to macrophages. These studies show molecular mimicry between epitopes of oxLDL and S. pneumoniae and indicate that these immune responses can have beneficial effects.

T-bet deficiency reduces atherosclerosis and alters plaque antigen-specific immune responses

“…Our studies have revealed a most interesting and previously undescribed impact of T-bet deficiency, namely a Th2 shift in the T cell response to hypercholesterolemia, and a linked enhancement of serum titers of atheroprotective EO6͞T15 natural IgM antibodies (19,30). EO6͞T15 IgM autoantibodies may exert atheroprotective effects by inhibiting the uptake of Ox-LDL by macrophage scavenger receptors.…”

“…In turn, it was shown that the IL-5 provided noncognate help to B-1 cells and expansion of EO6-secreting cells (19). Because we have recently shown that a near monoclonal expansion of EO6͞T15 antibodies in vivo, produced by immunization of mice with heat-killed Streptococcus pneumoniae, decreased the extent of atherosclerosis (30), the enhanced titer of EO6͞T15 we observed in the T-bet-deficient mice may well contribute in part to the atheroprotective effect observed with T-bet deficiency. Indeed, the enhanced IgM anti-Ox-LDL antibody titer observed in the T-bet-deficient mice may contain other such atheroprotective subsets of natural antibodies as well.…”

“…In brief, sera were diluted 1:100 in BSA-TBS, and binding of T15 clonotypic IgM antibodies (30) to wells coated with 2 g͞ml monoclonal anti-T15-idiotypic antibody AB1-2 (ATCC) was detected by using 0.1 g͞ml biotinylated AB1-2 followed by alkaline phosphatase-labeled NeutrAvidin.…”

High Levels of (Un)Switched Memory B Cells Are Associated With Better Outcome in Patients With Advanced Atherosclerotic Disease

“…Serum levels of IgM and IgG‐α‐oxLDL antibodies were measured as described previously 40, 43. In short, serum samples were diluted 500 times for IgM and 2000 times for IgG‐α‐oxLDL antibody measurements.…”

“…On the other hand, anti‐oxLDL autoantibodies have also been associated with lower oxLDL levels38 and decreased carotid atherosclerosis as well 39. In addition, vaccination with a pneumococcal vaccine, mimicking oxLDL epitopes, was shown to attenuate atherosclerotic lesion formation in mice40 and, according to a recent meta‐analysis, also prevents CVD in adults 41…”