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

Atherosclerosis is a chronic inflammatory disease and major cause of mortality worldwide. One of the crucial steps for atherosclerotic plaque development is oxidation of low-density lipoprotein (LDL). Through the oxidation, highly immunogenic epitopes are created and the immune system is activated. Association between atherosclerosis and periodontal diseases is well documented, and one of the main oral pathogens common in periodontitis is Aggregatibacter actinomycetemcomitans (Aa). Heat shock protein 60 (HSP60) is an important virulence factor for Aa bacteria and a strong activator of the immune system. Cross-reactivity of HSP60 and oxidized LDL (OxLDL) antibodies could be a potential mechanism in the progression of atherosclerosis and one possible link between atherosclerosis and periodontitis. Human plasma samples from neonates and mothers were analyzed to determine if antibody titer to Aa-HSP60 protein is already present in newborns. Further objectives were to characterize antibody response in Aa-HSP60 immunized mice and to determine possible antibody cross-reaction with oxidized LDL. We demonstrated that newborns already have IgM antibody levels to Aa-HSP60. We also showed that in mice, Aa-HSP60 immunization provoked IgG and IgM antibody response not only to Aa-HSP60 but also to malondialdehyde acetaldehyde-modified LDL (MAA-LDL). Competition assay revealed that the antibodies were specific to Aa-HSP60 and cross-reacted with MAA-LDL. Our results suggest a possibility of molecular mimicry between Aa-HSP60 and MAA-LDL, making it intriguing to speculate on the role of HSP60 protein in atherosclerosis that manifests at young age.

[1]  V. Dotz,et al.  Comparative Glycomics of Immunoglobulin A and G From Saliva and Plasma Reveals Biomarker Potential , 2018, Front. Immunol..

[2]  J. Kankaanpää,et al.  Immunization with gingipain A hemagglutinin domain of Porphyromonas gingivalis induces IgM antibodies binding to malondialdehyde-acetaldehyde modified low-density lipoprotein , 2018, PloS one.

[3]  Yingying Hu,et al.  Effects of oral and subcutaneous administration of HSP60 on myeloid-derived suppressor cells and atherosclerosis in ApoE-/- mice. , 2017, Biochemical and biophysical research communications.

[4]  M. Fornage,et al.  Heart Disease and Stroke Statistics—2017 Update: A Report From the American Heart Association , 2017, Circulation.

[5]  C. Wick.  Tolerization against atherosclerosis using heat shock protein 60 , 2016, Cell Stress and Chaperones.

[6]  U. Bergmann,et al.  Characterization of a natural mouse monoclonal antibody recognizing epitopes shared by oxidized low-density lipoprotein and chaperonin 60 of Aggregatibacter actinomycetemcomitans , 2016, Immunologic research.

[7]  Ahmad Karkhah,et al.  A potent multivalent vaccine for modulation of immune system in atherosclerosis: an in silico approach , 2016, Clinical and experimental vaccine research.

[8]  T. Mikuls,et al.  Aldehyde-modified proteins as mediators of early inflammation in atherosclerotic disease. , 2015, Free radical biology & medicine.

[9]  I. Mijakovic,et al.  Regulatory potential of post-translational modifications in bacteria , 2015, Front. Microbiol..

[10]  H. Sayles,et al.  Malondialdehyde‐Acetaldehyde Adducts and Anti–Malondialdehyde‐Acetaldehyde Antibodies in Rheumatoid Arthritis , 2015, Arthritis & rheumatology.

[11]  G. Hajishengallis,et al.  Periodontitis: from microbial immune subversion to systemic inflammation , 2014, Nature Reviews Immunology.

[12]  Ying Tan,et al.  Heat shock protein 65 promotes atherosclerosis through impairing the properties of high density lipoprotein. , 2014, Atherosclerosis.

[13]  H. Sayles,et al.  Unique Antibody Responses to Malondialdehyde-Acetaldehyde (MAA)-Protein Adducts Predict Coronary Artery Disease , 2014, PloS one.

[14]  C. Grundtman,et al.  The role of heat shock proteins in atherosclerosis , 2014, Nature Reviews Cardiology.

[15]  D. Tsiantoulas,et al.  B cells and humoral immunity in atherosclerosis. , 2014, Circulation research.

[16]  T. Kurita-Ochiai,et al.  Periodontal Pathogens and Atherosclerosis: Implications of Inflammation and Oxidative Modification of LDL , 2014, BioMed research international.

[17]  Chunguang Wang,et al.  Natural antibodies of newborns recognize oxidative stress-related malondialdehyde acetaldehyde adducts on apoptotic cells and atherosclerotic plaques. , 2013, International immunology.

[18]  Qingbo Xu,et al.  Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events. , 2012, Journal of the American College of Cardiology.

[19]  M. Baumann,et al.  Recognition of Porphyromonas gingivalis Gingipain Epitopes by Natural IgM Binding to Malondialdehyde Modified Low-Density Lipoprotein , 2012, PloS one.

[20]  L. Klassen,et al.  Malondialdehyde-acetaldehyde adduct is the dominant epitope after MDA modification of proteins in atherosclerosis. , 2010, Free radical biology & medicine.

[21]  C. Jackson,et al.  The Fat-Fed Apolipoprotein E Knockout Mouse Brachiocephalic Artery in the Study of Atherosclerotic Plaque Rupture , 2010, Journal of biomedicine & biotechnology.

[22]  V. Kakkar,et al.  Immunization with a combination of ApoB and HSP60 epitopes significantly reduces early atherosclerotic lesion in Apobtm2SgyLdlrtm1Her/J mice. , 2010, Atherosclerosis.

[23]  U. de Faire,et al.  Natural Antibodies against Phosphorylcholine in Cardiovascular Disease , 2009, Annals of the New York Academy of Sciences.

[24]  H. Björkbacka,et al.  Vaccines modulating lipoprotein autoimmunity as a possible future therapy for cardiovascular disease , 2009, Journal of internal medicine.

[25]  M. Clerici,et al.  Treatment of periodontal disease results in improvements in endothelial dysfunction and reduction of the carotid intima‐media thickness , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  A. Knowlton,et al.  HSP60 trafficking in adult cardiac myocytes: role of the exosomal pathway. , 2007, American journal of physiology. Heart and circulatory physiology.

[27]  L. Rauova,et al.  Immunization of low-density lipoprotein receptor deficient (LDL-RD) mice with heat shock protein 65 (HSP-65) promotes early atherosclerosis. , 2000, Journal of autoimmunity.

[28]  Qingbo Xu,et al.  Association of serum antibodies to heat-shock protein 65 with carotid atherosclerosis : clinical significance determined in a follow-up study. , 1999, Circulation.

[29]  Qingbo Xu,et al.  Myocardial injury leads to a release of heat shock protein (hsp) 60 and a suppression of the anti-hsp65 immune response. , 1999, Cardiovascular research.

[30]  D. Altschuh,et al.  Measurement of antigen–antibody interactions with biosensors , 1998, Journal of molecular recognition : JMR.

[31]  R. Young,et al.  Stress proteins, infection, and immune surveillance , 1989, Cell.

[32]  M. Nieminen,et al.  Association between dental health and acute myocardial infarction. , 1989, BMJ.

[33]  Steven A. Frank,et al.  Immunology and Evolution of Infectious Disease , 2002 .

[34]  E. Dennis,et al.  Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid-protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. , 1999, The Journal of clinical investigation.