Immunization with gingipain A hemagglutinin domain of Porphyromonas gingivalis induces IgM antibodies binding to malondialdehyde-acetaldehyde modified low-density lipoprotein

Abstract

Treatment of periodontitis has beneficial effects on systemic inflammation markers that relate to progression of atherosclerosis. We aimed to investigate whether immunization with A hemagglutinin domain (Rgp44) of Porphyromonas gingivalis (Pg), a major etiologic agent of periodontitis, would lead to an antibody response cross-reacting with oxidized low-density lipoprotein (OxLDL) and how it would affect the progression of atherosclerosis in low-density lipoprotein receptor-deficient (LDLR-/-) mice. The data revealed a prominent IgM but not IgG response to malondialdehyde-acetaldehyde modified LDL (MAA-LDL) after Rgp44 and Pg immunizations, implying that Rgp44/Pg and MAA adducts may share cross-reactive epitopes that prompt IgM antibody production and consequently confer atheroprotection. A significant negative association was observed between atherosclerotic lesion and plasma IgA to Rgp44 in Rgp44 immunized mice, supporting further the anti-atherogenic effect of Rgp44 immunization. Plasma IgA levels to Rgp44 and to Pg in both Rgp44- and Pg-immunized mice were significantly higher than those in saline control, suggesting that IgA to Rgp44 could be a surrogate marker of immunization in Pg-immunized mice. Distinct antibody responses in plasma IgA levels to MAA-LDL, to Pg lipopolysaccharides (Pg-LPS), and to phosphocholine (PCho) were observed after Rgp44 and Pg immunizations, indicating that different immunogenic components between Rpg44 and Pg may behave differently in regard of their roles in the development of atherosclerosis. Immunization with Rgp44 also displayed atheroprotective features in modulation of plaque size through association with plasma levels of IL-1α whereas whole Pg bacteria achieved through regulation of anti-inflammatory cytokine levels of IL-5 and IL-10. The present study may contribute to refining therapeutic approaches aiming to modulate immune responses and inflammatory/anti-inflammatory processes in atherosclerosis.

Humoral immune response to heat shock protein 60 of Aggregatibacter actinomycetemcomitans and cross-reactivity with malondialdehyde acetaldehyde-modified LDL

“…The mouse plasma IgM, but not IgG, in immunized mice recognizes apoptotic Jurkat cells. The result is consistent with the opinion that IgM antibodies to MAA-LDL may have a very important role in atheroprotection by inhibiting the macrophages uptake of the oxidized LDL, and by enhancing apoptotic cell clearance [3,4]. Little is known about the role of IgM antibodies to HSP60 in the development of atherosclerosis.…”

“…They cross-react, respectively, with a hemagglutinin domain of gingipain protease of Pg (Rgp44) and Aa-HSP60. We have also reported that immunization with Rgp44 reduces atherosclerosis in LDL receptor-deficient (LDLR -/-) mice and that increased IgM levels to MAA-LDL may contribute to atheroprotection [4]. Therefore, Aa-HSP60-induced antibody response to MAA-LDL may cross-react with virulence factors, such as Rgp44, from Pg bacteria.…”

“…The most studied pathogenic microbes are gram-negative bacteria, such as Aggregatibacter actinomycetemcomitans (Aa) and Porphyromonas gingivalis (Pg). Previous studies suggest that vaccination against virulence factors of the oral pathogens may confer disease resistance [4,25]. Similarly, OxLDLbased vaccinations have been developed to modulate the progression of atherosclerosis [26].…”

“…The exact role of antibodies to OxLDL in atherosclerosis remains elusive. IgM antibodies to OxLDL are considered to have protective properties, whereas IgG antibodies to OxLDL are more heterogeneous but mainly considered pro-atherogenic [3][4][5][6][7]. IgM antibodies to OxLDL inhibit the cholesterol uptake of macrophages through scavenger receptors, explaining the atheroprotective properties of IgM antibodies [8].…”

Mediators between oral dysbiosis and cardiovascular diseases

“…IgM that bind to these epitopes are already present before birth . A natural monoclonal IgM to MDA‐LDL has been shown to recognize arginine‐specific gingipain domains of P. gingivalis . Proteolytic enzymes of P. gingivalis , especially the arginine‐specific gingipain, are able to modify LDL particles, resulting in oxidation .…”