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

PLoS ONE (2018) 13(1)
DOI: 10.1371/journal.pone.0191216
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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.

Figures

  • Fig 1. Mouse plasma antibody levels to MAA-LDL before immunization (week 0) and at the end of the study (week 39) in LDLR-/- mice immunized with saline, Rgp44, and heat-inactivated Pg. Each mouse plasma sample was measured in triplicate using chemiluminescence immunoassay. The antibody binding is expressed as mean ± SD in relative light units measured in 100 milliseconds (RLU/100ms). Plasma antibody levels as box-whisker plots represent 25%, 50% and 75% of the distribution, where the whiskers represent 10% and 90% distribution of the values and the cross represents the maximum and minimum range. The solid diamonds are the mean values. P-values less than 0.05 are regarded as statistically significant (nonparametric Mann-Whitney U test). p< 0.05, p< 0.01, p< 0.001.
  • Fig 2. Mouse plasma antibody levels to CuOx-LDL before immunization (week 0) and at the end of the study (week 39) in LDLR-/- mice immunized with saline, Rgp44, and heat-inactivated Pg. Each mouse plasma sample was measured in triplicate using chemiluminescence immunoassay. The antibody binding is expressed as mean ± SD in relative light units measured in 100 milliseconds (RLU/100ms). Plasma antibody levels as box-whisker plots represent 25%, 50% and 75% of the distribution, where the whiskers represent 10% and 90% distribution of the values and the cross represents the maximum and minimum range. The solid diamonds are the mean values. P-values less than 0.05 are regarded as statistically significant (nonparametric Mann-Whitney U test). p< 0.001.
  • Fig 3. Mouse plasma antibody levels to PCho before immunization (week 0) and at the end of the study (week 39) in LDLR-/- mice immunized with saline, Rgp44, and heat-inactivated Pg. Each mouse plasma sample was measured in triplicate using chemiluminescence immunoassay. The antibody binding is expressed as mean ± SD in relative light units measured in 100 milliseconds (RLU/100ms). Plasma antibody levels as box-whisker plots represent 25%, 50% and 75% of the distribution, where the whiskers represent 10% and 90% distribution of the values and the cross represents the maximum and minimum range. The solid diamonds are the mean values. P-values less than 0.05 are regarded as statistically significant (nonparametric Mann-Whitney U test). p< 0.05, p< 0.001.
  • Fig 4. Mouse plasma IgA levels to Rgp44, Pg, PCho, and Pg-LPS before immunization (week 0), before HFD (week 13), and at the end of the study (week 39) in LDLR-/- mice immunized with saline, Rgp44, and heatinactivated Pg. Each mouse plasma sample was measured in triplicate using chemiluminescence immunoassay. The IgA antibody binding is expressed as mean ± SD in relative light units measured in 100 milliseconds (RLU/ 100ms). P-values less than 0.05 are regarded as statistically significant (nonparametric Mann-Whitney U test).
  • Fig 5. Association of mouse plasma IgA and IgG levels with atherosclerotic plaque area in LDLR-/- mice immunized with saline, Rgp44, and heat-inactivated Pg. Plasma IgA and IgG to Rgp44 and Pg-LPS as well as plasma IgA to PCho were determined in triplicate by chemiluminescence immunoassay. The antibody level is expressed as relative light units measured in 100 milliseconds (RLU/100ms). Associations are determined using Spearman rank correlation coefficient (ρ). P-values (p) less than 0.05 are regarded as statistically significant.
  • Fig 6. Mouse plasma IL-5, IL-6, and IL-10 cytokine levels in LDLR-/- mice immunized with saline, Rgp44, and heat-inactivated Pg. Mouse plasma cytokine levels were determined with cytometric bead assay (CBA) from each mouse plasma sample and expressed as picograms per milliliter plasma (pg/mL). Samples at week 0 and week 13 were pooled together within each immunization group. At week 39 the plasma samples were not pooled, but measured as individuals. (A, C, E) Plasma cytokine levels at different time points within immunization groups (mean value). (B, D, F) Plasma cytokine levels at the end of the study (week 39) as box-whisker plots represent 25%, 50% and 75% of the distribution, where the whiskers represent 10% and 90% distribution of the values and the cross represents the maximum and minimum range. The solid diamonds are the mean values. p< 0.05, p< 0.01.
  • Fig 7. Association of mouse plasma IL-1α, IL-5, IL-10, and IL-22 cytokine levels with atherosclerotic plaque area in LDLR-/- mice immunized with saline, Rgp44, and heat-inactivated Pg. Mouse plasma cytokine levels were determined with cytometric bead assay (CBA) from each mouse plasma sample. They are expressed as picograms per milliliter plasma (pg/mL). Associations are determined using Spearman rank correlation coefficient (ρ). P-values (p) less than 0.05 are regarded as statistically significant.

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APA

Kyrklund, M., Kummu, O., Kankaanpää, J., Akhi, R., Nissinen, A., Pauliina Turunen, S., … Hörkkö, S. (2018). Immunization with gingipain A hemagglutinin domain of Porphyromonas gingivalis induces IgM antibodies binding to malondialdehyde-acetaldehyde modified low-density lipoprotein. PLoS ONE, 13(1). https://doi.org/10.1371/journal.pone.0191216

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