牙周病與免疫

1、五、牙周病與免疫五、牙周病與免疫 The oral cavity harbors more than 700 bacterial species, coexisting with probably millions of viral genomic copies. 口腔定居的細菌有口腔定居的細菌有700多種多種 與數(shù)百萬病毒基因組復制物共存與數(shù)百萬病毒基因組復制物共存 （A Tsuo Amano, 2010, Periodontology 2000） Oral bacteria 口腔中的細菌口腔中的細菌： - Free to saliva 在唾液中在唾液中 - Attachment in bi

2、ofilm 附著在生物膜附著在生物膜 Between closely related Saliva 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. 美國占美國占75%成年人群體不同程度患有牙周病成年人群體不同程度患有牙周病 1/3 children of 611years old, and 2/3 of adolesce

3、nt population have some degree of periodontal problems. 1/3的的611歲兒童，歲兒童，2/3青春期人群也有某種程度的青春期人群也有某種程度的 牙周問題牙周問題 Over 200 kinds of bacterial form dental plaque, adhere to the surface of the teeth and gums, and cause periodontal infections. 牙周感染細菌達牙周感染細菌達200余種余種 Periodontitis Gingivitis bleeding，Deep gin

4、gival Pocket 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 牙周袋是獨特的微環(huán)境牙周袋是獨特的微環(huán)境 escape the physical separation force 逃逸物理分離力逃逸物理分離力 hard ti

5、ssue surface 不剝脫更新的硬組織表面不剝脫更新的硬組織表面 junctional epithelialization, basically not differentiation 有結(jié)合上皮，基本上不分化有結(jié)合上皮，基本上不分化 non-keratinizing epithelium 無角化無角化 facultative anaerobic anaerobic 兼性厭氧兼性厭氧厭氧厭氧 nutrition, humidity, pH, Eh 營養(yǎng)、濕度、營養(yǎng)、濕度、pH、Eh 齦下細菌附著和聚集模式圖齦下細菌附著和聚集模式圖 Root surface Pellicle P.g P.

6、g P.g P.g P.g Subgingival biofilm formation 齦下生物膜形成齦下生物膜形成 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 nucleatum 1996 confirmed three bacteria for periodontal pathoge

7、ns : Actinobacillus actinomycetemcomitans (AA) Tannerella forsythia (TF) Porphyromonas gingivalis (Pg) 1996, 牙周致病菌牙周致病菌 AA，TF，Pg Recent views change, pathogenic capacity of AA and other culturable or non-culturable bacteria should be confirmed. 近期：近期：AA待證實待證實 50% oral microbial cannot be cultivated

8、and can be identified through extra methods: 口腔中有口腔中有50%微生物不能培養(yǎng)，可通過下述方法鑒定：微生物不能培養(yǎng)，可通過下述方法鑒定： quantitative RT-PCR 定量定量PCR phylogenetic 16s-rRNA gene clone library analysis 用基因組或用基因組或16s rRNA探針探針 checkerboard hybridization 棋盤雜交棋盤雜交 high-throughput fingerprint technology 高通量指紋技術(shù)高通量指紋技術(shù) pyrophosphate se

9、quencing 454技術(shù)（焦磷酸鹽測序）技術(shù)（焦磷酸鹽測序） metagenome technology 宏基因組技術(shù)宏基因組技術(shù) General view: Periodontitis is caused by endogenous G- periodontal bacteria. 目前普遍認為：牙周炎是由內(nèi)源性目前普遍認為：牙周炎是由內(nèi)源性G-牙周細菌所致牙周細菌所致 Red complex: Porphyromonas gingivalis 牙齦卟啉菌牙齦卟啉菌 Tannerella forsythia 弗賽菌弗賽菌 Treponema denticola 齒密螺旋體齒密螺旋體 Po

10、tential virulence factors 潛在毒力因子潛在毒力因子 Neutralization for local host defense mechanisms 中和局部宿主防御機制中和局部宿主防御機制 Destruction of periodontal tissue 破壞牙周組織破壞牙周組織 P. Gingivalis 牙齦卟啉菌牙齦卟啉菌 G-厭氧、桿狀、繖附著、與紅色菌群共同構(gòu)成生物膜厭氧、桿狀、繖附著、與紅色菌群共同構(gòu)成生物膜 adhere to host cells（integrins）通過整合素附著）通過整合素附著 Secretory proteinase 分泌蛋白

11、溶解酶、破壞牙齦附著分泌蛋白溶解酶、破壞牙齦附著 After invasion, association with the change of intracellular signaling pathways 入侵后改變信號通路入侵后改變信號通路 分泌脂多糖，是細菌內(nèi)毒素的主要成分分泌脂多糖，是細菌內(nèi)毒素的主要成分 畸形血管生成畸形血管生成 Tannerella forsythia 弗賽菌弗賽菌 厭氧厭氧G-菌，菌，cytophaga-Bacteroidetes family New pathogens through 16s rRNA detection 16s rRNA檢測檢測 分泌富含亮

12、氨酸的重復蛋白（分泌富含亮氨酸的重復蛋白（leucine-rich- repeat protein, BSPA ）, 使細菌容易附著，是使細菌容易附著，是 重要的毒力因子重要的毒力因子 啟動單核細胞釋放炎癥細胞因子，成骨細胞釋放啟動單核細胞釋放炎癥細胞因子，成骨細胞釋放 趨化因子，導致炎癥和骨吸收趨化因子，導致炎癥和骨吸收 G-口腔螺旋體家族，絕對厭氧，纖細、螺旋、能動、口腔螺旋體家族，絕對厭氧，纖細、螺旋、能動、 可彎曲可彎曲 Virulence factors 毒力因子毒力因子內(nèi)毒素內(nèi)毒素 Accumulation in gingival pocket, using a variety o

13、f nutrition ingredients 聚集于牙周袋聚集于牙周袋 Degradation of cytokines，inhibition of fibroblast migration, and prevention of healing 降解細胞因子降解細胞因子 Treponema denticola 齒密螺旋體齒密螺旋體 Because subgingival microbial between periodontal health and disease individuals are significant differences, simple pathogens mode

14、can not explain the etiology of periodontitis. Current theories tend to 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. 單一致病源不能解釋牙周病模式單一

15、致病源不能解釋牙周病模式 微生物交替可解釋牙周病病因微生物交替可解釋牙周病病因 Host - microorganisms interactions 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種基本性框架，寄生物相互作用已建立一種基本性框架， 可形成牙周炎癥，也提供了治療的可能性可形成牙周炎癥，也提供了治療的可能性 Subgingival infection

16、 齦下感染齦下感染 Bacteria adhesion - growth - biofilm formation- intrusion of host tissues - invasion of host immune system interface 細菌附著細菌附著粘附粘附細胞生長細胞生長生物膜形成生物膜形成 致病源入侵宿主細胞致病源入侵宿主細胞/組織組織侵犯宿主免疫系侵犯宿主免疫系 統(tǒng)界面統(tǒng)界面 Periodontal disease & host immunity 牙周病與宿主免疫牙周病與宿主免疫 46% people can be detected periodontal patho

17、gens. However, many individuals may limit the occurrence of periodontal disease. Many scholars have proposed the multiple etiology of periodontal disease: microbes, host immune response, environmental factors 46%檢測到牙周致病菌，但許多人不發(fā)病檢測到牙周致病菌，但許多人不發(fā)病 牙周病病因涉及牙周病病因涉及 微生物、宿主、環(huán)境微生物、宿主、環(huán)境 Although periodontal

18、disease is causeal by bacterial infection, the resulting tissue damage is due to the immune response. 牙周病損傷來自免疫反應牙周病損傷來自免疫反應 Individual immune responses to a large extent determine the severity of periodontal disease. 個體反應決定牙周損害程度個體反應決定牙周損害程度 Twin study confirms genetic hereditary effects on periodo

19、ntal disease clinical sensitivity up to 50%. 遺傳因素占遺傳因素占50% First is the innate immune response Bacterial uptake by macrophages cytoken release by macrophages 巨噬細胞釋放細胞因子巨噬細胞釋放細胞因子 causing periodontal diseases related to inflammation 炎癥炎癥 causing blood vessels to dilate, permeability increases 血管滲血管滲

20、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 response 固有免疫反應固有免疫反應 Acquired immune responses獲得性免疫反應獲得性免疫反應 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 DC Dendritic cells (DC) play a role in antige

21、n presentation Naive T cells stimulated DC 刺激幼稚刺激幼稚T細胞細胞 reaches the nearest lymph node activate T cells 到達附近淋巴結(jié)，激活到達附近淋巴結(jié)，激活T細胞細胞 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. 牙周致病菌進入細胞逃逸免疫監(jiān)視；病毒的作用牙周致病菌進入細胞逃逸免疫監(jiān)視；病毒的作用 Synergism 協(xié)同作用協(xié)同作用: Oral herpes virus,