Molecular basis of host immune responses to periodontal disease

慢性牙周炎是一种与细菌有关的炎症性疾病。最近的流行病学研究表明慢性牙周病与心血管疾病风险增加之间存在联系。牙龈蛋白酶是由牙龈卟啉单胞菌（Porphyromonas gingivalis）产生的半胱氨酸蛋白酶，牙龈卟啉单胞菌是一种与慢性牙周炎相关的革兰氏阴性厌氧菌，与细菌的广泛毒力有关，目前将其分为两种类型的蛋白酶，Arg-gingipains（Rgp）和Lys-gingipain（Kgp）。另一方面，组织蛋白酶E是一种主要在免疫系统细胞中表达的内溶酶体天冬氨酸蛋白酶，并参与针对细菌感染的免疫防御反应。由于牙周炎的发生是细菌感染与宿主防御平衡的结果，因此研究这些蛋白酶在牙周病中的病理生理作用以及开发新的治疗牙周炎的药物具有重要意义 ...更多信息 疗法通过本工作获得的发现如下：（1）我们首先纯化了660-kDa的细胞相关牙龈菌蛋白酶复合物，该复合物作为两个催化活性单体的同源二聚体存在，包括Rgp和Kgp的催化和粘附结构域，并发现该复合物在逃避宿主防御机制和宿主组织分解中起重要作用。(2)We首次设计并合成了一系列能够抑制Rgp或Kgp的肽类似物，这些肽类似物基于每种酶对组胺的切割位点特异性。在这一系列化合物中，我们发现KYT-1和KYT-36分别对Rgp和Kgp具有最有效和选择性的抑制活性，并且它们可用于评估每种酶的病理生理功能。(3)We提供证据表明，Rgp对LDL颗粒的唯一蛋白组分apoB-100的蛋白水解裂解对于牙龈卟啉单胞菌感染促进动脉粥样硬化至关重要。(4)We证明组织蛋白酶E在抵抗包括牙龈卟啉单胞菌在内的入侵微生物的免疫防御中起重要作用。少

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