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1、五、牙周病与免疫五、牙周病与免疫The oral cavity harbors more than 700 bacterial species, coexisting with probably millions of viral genomic copies.口腔定居的细菌有口腔定居的细菌有700多种多种与数百万病毒基因组复制物共存与数百万病毒基因组复制物共存（A Tsuo Amano, 2010, Periodontology 2000）Oral bacteria 口腔中的细菌口腔中的细菌： - Free to saliva 在唾液中在唾液中 - Attachment in biofilm
2、 附着在生物膜附着在生物膜 Between closely relatedSaliva as a carrier, is conducive to horizontal and vertical transmission of bacteria In United States, 75 per cent of adult populations suffer from periodontal disease. 美国占美国占75%成年人群体不同程度患有牙周病成年人群体不同程度患有牙周病1/3 children of 611years old, and 2/3 of adolescent popu
3、lation have some degree of periodontal problems. 1/3的的611岁儿童，岁儿童，2/3青春期人群也有某种程度的青春期人群也有某种程度的牙周问题牙周问题Over 200 kinds of bacterial form dental plaque, adhere to the surface of the teeth and gums, and cause periodontal infections. 牙周感染细菌达牙周感染细菌达200余种余种Periodontitis Gingivitis bleeding，Deep gingival Pock
4、et 3mm Periodontitis bleeding，swelling，initial bone loss, Deep periodontal Pocket = 5mm major stage bleeding，swelling，major bone loss， Deep periodontal Pocket 6mm Periodontal Pocket: a unique micro-environment牙周袋是独特的微环境牙周袋是独特的微环境escape the physical separation force 逃逸物理分离力逃逸物理分离力hard tissue surface
5、不剥脱更新的硬组织表面不剥脱更新的硬组织表面junctional epithelialization, basically not differentiation有结合上皮，基本上不分化有结合上皮，基本上不分化non-keratinizing epithelium 无角化无角化facultative anaerobic anaerobic 兼性厌氧兼性厌氧厌氧厌氧nutrition, humidity, pH, Eh 营养、湿度、营养、湿度、pH、Eh龈下细菌附着和聚集模式图龈下细菌附着和聚集模式图RootsurfacePellicleP.gP.gP.gP.gP.gSubgingival bi
6、ofilm formation龈下生物膜形成龈下生物膜形成 Initial colonization早期定居者早期定居者： actinomyces, streptococci succeeded colonization 微生物交替后：微生物交替后： periodontal pathogens 致病微生物定植致病微生物定植 Pg，AA, forsythia, T. denticole Fusobacterium nucleatum1996 confirmed three bacteria for periodontal pathogens : Actinobacillus actinomyce
7、temcomitans (AA) Tannerella forsythia (TF) Porphyromonas gingivalis (Pg) 1996, 牙周致病菌牙周致病菌 AA，TF，PgRecent views change, pathogenic capacity of AA and other culturable or non-culturable bacteria should be confirmed. 近期：近期：AA待证实待证实50% oral microbial cannot be cultivated and can be identified through ex
8、tra methods:口腔中有口腔中有50%微生物不能培养，可通过下述方法鉴定：微生物不能培养，可通过下述方法鉴定：quantitative RT-PCR 定量定量PCRphylogenetic 16s-rRNA gene clone library analysis 用基因组或用基因组或16s rRNA探针探针checkerboard hybridization 棋盘杂交棋盘杂交high-throughput fingerprint technology 高通量指纹技术高通量指纹技术pyrophosphate sequencing 454技术（焦磷酸盐测序）技术（焦磷酸盐测序）metage
9、nome technology 宏基因组技术宏基因组技术General view: Periodontitis is caused by endogenous G- periodontal bacteria. 目前普遍认为：牙周炎是由内源性目前普遍认为：牙周炎是由内源性G-牙周细菌所致牙周细菌所致 Red complex:Porphyromonas gingivalis 牙龈卟啉菌牙龈卟啉菌Tannerella forsythia 弗赛菌弗赛菌Treponema denticola 齿密螺旋体齿密螺旋体Potential virulence factors 潜在毒力因子潜在毒力因子Neutra
10、lization for local host defense mechanisms中和局部宿主防御机制中和局部宿主防御机制Destruction of periodontal tissue 破坏牙周组织破坏牙周组织P. Gingivalis 牙龈卟啉菌牙龈卟啉菌G-厌氧、杆状、繖附着、与红色菌群共同构成生物膜厌氧、杆状、繖附着、与红色菌群共同构成生物膜adhere to host cells（integrins）通过整合素附着）通过整合素附着Secretory proteinase 分泌蛋白溶解酶、破坏牙龈附着分泌蛋白溶解酶、破坏牙龈附着After invasion, association
11、 with the change of intracellular signaling pathways 入侵后改变信号通路入侵后改变信号通路分泌脂多糖，是细菌内毒素的主要成分分泌脂多糖，是细菌内毒素的主要成分畸形血管生成畸形血管生成Tannerella forsythia 弗赛菌弗赛菌厌氧厌氧G-菌，菌，cytophaga-Bacteroidetes familyNew pathogens through 16s rRNA detection 16s rRNA检测检测分泌富含亮氨酸的重复蛋白（分泌富含亮氨酸的重复蛋白（leucine-rich-repeat protein, BSPA ）,
12、使细菌容易附着，是使细菌容易附着，是重要的毒力因子重要的毒力因子启动单核细胞释放炎症细胞因子，成骨细胞释放启动单核细胞释放炎症细胞因子，成骨细胞释放趋化因子，导致炎症和骨吸收趋化因子，导致炎症和骨吸收G-口腔螺旋体家族，绝对厌氧，纤细、螺旋、能动、口腔螺旋体家族，绝对厌氧，纤细、螺旋、能动、可弯曲可弯曲Virulence factors 毒力因子毒力因子内毒素内毒素Accumulation in gingival pocket, using a variety of nutrition ingredients 聚集于牙周袋聚集于牙周袋Degradation of cytokines，inhib
13、ition of fibroblast migration, and prevention of healing 降解细胞因子降解细胞因子Treponema denticola 齿密螺旋体齿密螺旋体Because subgingival microbial between periodontal health and disease individuals are significant differences, simple pathogens mode can not explain the etiology of periodontitis.Current theories tend t
14、o apply microorganism succession to explain the etiology of periodontitis, i.e. benign bacteria reducing results in the increase of pathogen bacteria. In some degree, the whole microbial community is its pathogen.单一致病源不能解释牙周病模式单一致病源不能解释牙周病模式微生物交替可解释牙周病病因微生物交替可解释牙周病病因Host - microorganisms interaction
15、s has established the basic framework, which can form a periodontal inflammation, but also offers the possibility of treatment.宿主宿主寄生物相互作用已建立一种基本性框架，寄生物相互作用已建立一种基本性框架，可形成牙周炎症，也提供了治疗的可能性可形成牙周炎症，也提供了治疗的可能性Subgingival infection 龈下感染龈下感染 Bacteria adhesion - growth - biofilm formation- intrusion of host
16、tissues - invasion of host immune system interface 细菌附着细菌附着粘附粘附细胞生长细胞生长生物膜形成生物膜形成致病源入侵宿主细胞致病源入侵宿主细胞/组织组织侵犯宿主免疫系侵犯宿主免疫系统界面统界面Periodontal disease & host immunity牙周病与宿主免疫牙周病与宿主免疫46% people can be detected periodontal pathogens. However, many individuals may limit the occurrence of periodontal disease.
17、Many scholars have proposed the multiple etiology of periodontal disease: microbes, host immune response, environmental factors46%检测到牙周致病菌，但许多人不发病检测到牙周致病菌，但许多人不发病牙周病病因涉及牙周病病因涉及 微生物、宿主、环境微生物、宿主、环境Although periodontal disease is causeal by bacterial infection, the resulting tissue damage is due to the
18、 immune response.牙周病损伤来自免疫反应牙周病损伤来自免疫反应Individual immune responses to a large extent determine the severity of periodontal disease. 个体反应决定牙周损害程度个体反应决定牙周损害程度Twin study confirms genetic hereditary effects on periodontal disease clinical sensitivity up to 50%. 遗传因素占遗传因素占50% First is the innate immune r
19、esponse Bacterial uptake by macrophages cytoken release by macrophages 巨噬细胞释放细胞因子巨噬细胞释放细胞因子 causing periodontal diseases related to inflammation 炎症炎症 causing blood vessels to dilate, permeability increases 血管渗血管渗 透性增加透性增加 local blood flow increases, creating inflammation 血流量增加血流量增加Innate immune resp
20、onse 固有免疫反应固有免疫反应Acquired immune responses获得性免疫反应获得性免疫反应Pg is the most of bacteria related to periodontal inflammation, can sensitized and activate DC Pg 致敏并激活致敏并激活 DCDendritic cells (DC) play a role in antigen presentation Naive T cells stimulatedDC 刺激幼稚刺激幼稚T细胞细胞 reaches the nearest lymph node acti
21、vate T cells到达附近淋巴结，激活到达附近淋巴结，激活T细胞细胞Immune escape 免疫逃逸免疫逃逸Pathogenic bacteria of periodontitis may enter cells, escape immune surveillance, and form ecological balance with host. Once balance damage, periodontal disease can happen. 牙周致病菌进入细胞逃逸免疫监视；病毒的作用牙周致病菌进入细胞逃逸免疫监视；病毒的作用Synergism 协同作用协同作用: Oral
22、herpes virus, EB virus and bacterial CD4+ T cells appearance is the main cause of periodontal bone loss. CD4+ T细胞细胞Th2 cells activate B cells to produce antibodies. Th2 激活激活B细胞细胞Epithelial cells in periodontitis patients contain high levels IgA and IgG, and IgM can be found in deep periodontal pocke
23、t. 上皮细胞含上皮细胞含IgA、G、MBone loss 骨丧失骨丧失 Periodontal disease - related systemic diseases including cardiovascular disease and, preterm birth and other issuesPeriodontal inflammation enables individuals more sensitive to periodontal diseases and vascular sclerosis. 血管硬化血管硬化Inflammatory Cytokines, particularly IL-1 beta, PGE2 and TNF-alpha, can affect the cardiovascular and placenta. 心血管和胚胎心血管和胚胎Systemic reaction 全身反应全身反应
