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

Mikael Kyrklund,Chunguang Wang,Sohvi Hörkkö,Jari Kankaanpää,S. Pauliina Turunen,Pirkko Pussinen,Outi Kummu,Ramin Akhi,Antti Nissinen,Cordula M. Stover

doi:10.1371/journal.pone.0191216

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.

Highlights

Atherosclerosis plays a major role in cardiovascular disease (CVD) and is the leading cause of death worldwide [1]
Immune response to Rgp44 and Porphyromonas gingivalis (Pg) in low-density lipoprotein receptor-deficient mice we aimed to investigate whether immunization with gingipain A hemagglutinin domain (Rgp44) would induce antibody responses to malondialdehyde acetaldehyde (MAA) adducts in mice
The experimental timeline is shown in S1 Fig. Recombinant gingipain A hemagglutinin domain (Rgp44) and heat-inactivated whole Pg bacteria (Pg) induced prominent immune responses in LDLR-/- mice

Summary

Introduction

Atherosclerosis plays a major role in cardiovascular disease (CVD) and is the leading cause of death worldwide [1]. It is considered a chronic inflammatory disease [2] whose recognized risk factors include environmental, genetic, and inflammatory elements [1]. Oxidative modification of LDL, which creates oxidized LDL particles (OxLDL) and formation of malondialdehyde-modified LDL (MDA-LDL), is the first step in the development of atherosclerosis. Phosphocholine (PCho) is another common epitope of oxidized phospholipids in OxLDL. It is exposed on some microorganisms, e.g. Streptococcus pneumoniae, and on apoptotic cells. Active immunization with PCho and passive immunization with anti-PCho ameliorate the development of atherosclerosis in apolipoprotein Enull mice [9]

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