Innate Immune Response via Intracellular Receptor NODs and Periodontal Diseases

在先天免疫中，微生物的常见和特殊结构，病原体相关分子模式（PAMP），由宿主细胞中以Toll样受体（TLR）为代表的模式识别分子（PRM）识别。另一个细胞内PRM家族，NOD 1和NOD 2，识别细菌肽聚糖。我们通过各种细胞中的TLR和NOD检测先天免疫应答，以阐明先天免疫在口腔粘膜中的作用。在这些实验中，仅使用化学合成的配体来排除细菌制剂中的次要组分的影响;细菌脂肽Pam 3CSSNA（TLR 2配体）、大肠杆菌型脂质A LA-15-PP（TLR 4配体）、细菌CpG DNA（TLR 9配体）、MDP（NOD 2配体）和iE-DAP（NOD 1配体）。我们证明了NOD 1-或NOD 2-激动剂与各种TLR-激动剂的组合协同诱导培养的人单核细胞THP-1细胞中的炎性细胞因子。相同的组合刺激也诱导人树突状细胞中的Th 1-谱系应答。人类口腔上皮细胞也携带了迄今为止检测到的所有TLR和NOD分子。然而，通过相应配体的刺激不诱导炎性细胞因子，但明确诱导抗菌因子，如肽聚糖识别蛋白（PGRP-L，Iα，Iβ，S）和β-防御素2。考虑到所有这些发现，我们提出一个工作假设：口腔上皮细胞，与正常植物群中的各种细菌相互作用，积极产生抗菌因子。然而，这些细胞受到负控制，以防止诱导免疫和炎症反应。当负调节被关闭时，会发生过度的炎症反应，这反过来又会引发组织破坏。一旦粘膜屏障被破坏，积聚的巨噬细胞和树突状细胞启动Th 1谱系获得性免疫应答，这是以牙周病为代表的口腔粘膜疾病的典型特征。

In innate immunity, common and peculiar structures of microbes, pathogen-associated molecular patterns (PAMPs), are recognized by pattern-recognition molecules (PRMs) represented by Toll-like receptors (TLRs) in host cells. Another intracellular PRM family, NOD1 and NOD2, recognizes bacterial peptidoglycans. We examined innate immune responses through TLRs and NODs in various cells to elucidate the roles of innate immunity in the oral mucosa. In these experiments, only chemically synthesized ligands were used to rule out the influences of minor components in bacterial preparations ; bacterial lipopeptide Pam3CSSNA (TLR2 ligand), E.coli-type lipid A LA-15-PP (TLR4 ligand), bacterial CpG DNA (TLR9 ligand), MDP (NOD2 ligand) and iE-DAP (NOD1 ligand). We demonstrated that NOD1- or NOD2-agonist in combination with various TLR-agonists synergistically induced inflammatory cytokines in human monocytic THP-1 cells in culture. The same combinatory stimulation also induced Th1-lineage responses in human dendritic cells. Human oral epithelial cells also carried all of the TLR and NOD molecules examined to date. However, stimulation by the respective ligands did not induce inflammatory cytokines, but definitely induced anti-bacterial factors such as peptidoglycan recognition proteins (PGRP-L,Iα,Iβ,S) and β-defensin 2. Taking all of these findings in consideration, we postulate a working hypothesis : Oral epithelial cells, which interact with various bacteria in normal flora, actively produce anti-bacterial factors. The cells, however, are negatively controlled to prevent the induction of immune and inflammatory responses. When the negative regulation is turned off, excessive inflammatory responses occur, which in turn initiate tissue destruction. Once the mucosal barrier was broken, accumulated macrophages and dendritic cells initiate Th1-lineage acquired immune responses, which are were typical of oral mucosal disease represented by periodontal diseases.