Molecular basis of host immune responses to periodontal disease

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Chronic periodontitis is an inflammatory disease associated with bacteria. Recent epidemiological studies have suggested a link between chronic periodontal disease and an increased risk of cardiovascular disease. Gingipains are cysteine proteinases produced by Porphyromonas gingivalis, a Gram-negative anaerobic bacterium associated with chronic periodontitis and implicated in a wide range of virulence of the bacterium, which are now classified into two types of proteinases, Arg-gngipains (Rgps) and Lys-gingipain (Kgp). On the other hand, cathepsin E is an endolysosomal aspartic proteinase predominantly expressed in immune system cells and implicated in immune defense responses against bacterial infection. As the development of periodontitis is a result of the balance between bacterial infection and host defense, it is of particular importance for us to investigate pathophysiological roles of these proteinases in periodondal disease and to develop new promising agents for periodontitis … More therapy. The findings obtained through this work are as follows : (1)we first purified a 660-kDa cell associated gingipain complex existing as a homodimer of two catalytically active monomers comprising the catalytic and adhesin domains of Rgp and Kgp and found the complex to play an important role in evasion of host defense mechanisms and host tissue breakdown. (2)We designed and synthesized for the first time a series of peptide analogs able to inhibit Rgp or Kgp on the basis of the cleavage site specificity of histatins by each enzyme. Among this series of compounds, we found that KYT-1 and KYT-36 had the most potent and selective inhibitory activities of Rgp and Kgp, respectively, and that they are useful in assessing the pathophysiological functions of each enzyme. (3)We provide evidence that the proteolytic cleavage of apoB-100, the only protein component of LDL particles, by Rgp is crucial for the promotion of atherosclerosis by P.gingivalis infection. (4)We demonstrate that cathepsin E plays an essential role in immune defense against invaded microorganisms including P.gingivalis. Less