Abstract
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.
Highlights
Atherosclerosis is a chronic inflammatory disease in which both innate and adaptive immune systems play an important role
Human umbilical cord blood plasma and maternal plasma were tested for IgG and IgM antibodies binding to MAA-low-density lipoprotein (LDL), Aa-Heat shock protein 60 (HSP60) and fish gelatin/phosphate-buffered saline (Fg-PBS) (Fig 1)
Neonates did have significant IgM levels to Aa-HSP60 and MAA-LDL when compared to fish gelatin (Fg)-PBS background controls (Fig 1B), suggesting that the IgM antibodies to Aa-HSP60 and MAA-LDL are already being produced by neonates before birth
Summary
Atherosclerosis is a chronic inflammatory disease in which both innate and adaptive immune systems play an important role. Aggregatibacter actinomycetemcomitans (Aa) is one of the most studied oral pathogens associated with periodontitis, a chronic inflammatory disease affecting tooth supporting tissue and alveolar bone. Heat shock proteins have a variety of different functions: intracellular folding, transportation, and working as chaperons [13] These proteins are vastly upregulated when cells are exposed to a stress factor, which leads further to T-cell activation. Antibodies to MAA-LDL and HSP60 are both associated with atherosclerosis and they are both produced under similar stressed conditions [13,16]. We cloned natural mouse monoclonal IgM antibody to MAA-LDL that bound to HSP60 of Aa bacteria [17]. We investigated whether human neonates have natural antibodies to Aa-HSP60 and whether the antibodies to Aa-HSP60 cross-react with MAA-LDL. Mouse experiments were carried out to verify the possible cross-reactions between HSP 60 and MAA-LDL antibodies as cross-reaction could be one possible mechanism in the progression of atherosclerosis and a potential link between atherosclerosis and periodontitis
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