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五、牙周病与免疫
1Theoralcavityharborsmorethan700bacterialspecies,coexistingwithprobablymillionsofviralgenomiccopies.口腔定居的细菌有700多种与数百万病毒基因组复制物共存（ATsuoAmano,2010,Periodontology2000）
2Oralbacteria口腔中的细菌：--Freetosaliva在唾液中--Attachmentinbiofilm附着在生物膜BetweencloselyrelatedSalivaasacarrier,isconducivetohorizontalandverticaltransmissionofbacteria
3InUnitedStates,75percentofadultpopulationssufferfromperiodontaldisease.美国占75%成年人群体不同程度患有牙周病1/3childrenof6~11yearsold,and2/3ofadolescentpopulationhavesomedegreeofperiodontalproblems.1/3的6~11岁儿童，2/3青春期人群也有某种程度的牙周问题
4Over200kindsofbacterialformdentalplaque,adheretothesurfaceoftheteethandgums,andcauseperiodontalinfections.牙周感染细菌达200余种PeriodontitisⅠGingivitisbleeding，DeepgingivalPocket<3mmⅡPeriodontitisbleeding，swelling，initialboneloss,DeepperiodontalPocket=5mmⅢmajorstagebleeding，swelling，majorboneloss，DeepperiodontalPocket＞6mm
5PeriodontalPocket:auniquemicro-environment牙周袋是独特的微环境escapethephysicalseparationforce逃逸物理分离力hardtissuesurface不剥脱更新的硬组织表面junctionalepithelialization,basicallynotdifferentiation有结合上皮，基本上不分化non-keratinizingepithelium无角化facultativeanaerobic→anaerobic兼性厌氧→厌氧nutrition,humidity,pH,Eh营养、湿度、pH、Eh
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7龈下细菌附着和聚集模式图RootsurfacePellicleP.gP.gP.gP.gP.g
8Subgingivalbiofilmformation龈下生物膜形成Initialcolonization早期定居者：actinomyces,streptococcisucceededcolonization微生物交替后：periodontalpathogens致病微生物定植Pg，AA,forsythia,T.denticoleFusobacteriumnucleatum
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101996confirmedthreebacteriaforperiodontalpathogens:Actinobacillusactinomycetemcomitans(AA)Tannerellaforsythia(TF)Porphyromonasgingivalis(Pg)1996,牙周致病菌AA，TF，PgRecentviewschange,pathogeniccapacityofAAandotherculturableornon-culturablebacteriashouldbeconfirmed.近期：AA待证实
1150%oralmicrobialcannotbecultivatedandcanbeidentifiedthroughextramethods:口腔中有50%微生物不能培养，可通过下述方法鉴定：quantitativeRT-PCR定量PCRphylogenetic16s-rRNAgeneclonelibraryanalysis用基因组或16srRNA探针checkerboardhybridization棋盘杂交high-throughputfingerprinttechnology高通量指纹技术pyrophosphatesequencing454技术（焦磷酸盐测序）metagenometechnology宏基因组技术
12Generalview:PeriodontitisiscausedbyendogenousG-periodontalbacteria.目前普遍认为：牙周炎是由内源性G-牙周细菌所致Redcomplex:Porphyromonasgingivalis牙龈卟啉菌Tannerellaforsythia弗赛菌Treponemadenticola齿密螺旋体Potentialvirulencefactors潜在毒力因子Neutralizationforlocalhostdefensemechanisms中和局部宿主防御机制Destructionofperiodontaltissue破坏牙周组织
13P.Gingivalis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adheretohostcells（integrins）通过整合素附着Secretoryproteinase分泌蛋白溶解酶、破坏牙龈附着Afterinvasion,associationwiththechangeofintracellularsignalingpathways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畸形血管生成
14Tannerellaforsythia弗赛菌厌氧G-菌，cytophaga-BacteroidetesfamilyNewpathogensthrough16srRNAdetection16srRNA检测分泌富含亮氨酸的重复蛋白（leucine-rich-repeatprotein,BSPA）,使细菌容易附着，是重要的毒力因子启动单核细胞释放炎症细胞因子，成骨细胞释放趋化因子，导致炎症和骨吸收
15G-口腔螺旋体家族，绝对厌氧，纤细、螺旋、能动、可弯曲Virulencefactors毒力因子——内毒素Accumulationingingivalpocket,usingavarietyofnutritioningredients聚集于牙周袋Degradationofcytokines，inhibitionoffibroblastmigration,andpreventionofhealing降解细胞因子Treponemadenticola齿密螺旋体
16Becausesubgingivalmicrobialbetweenperiodontalhealthanddiseaseindividualsaresignificantdifferences,simplepathogensmodecannotexplaintheetiologyofperiodontitis.Currenttheoriestendtoapplymicroorganismsuccessiontoexplaintheetiologyofperiodontitis,i.e.benignbacteriareducingresultsintheincreaseofpathogenbacteria.Insomedegree,thewholemicrobialcommunityisitspathogen.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
17Host-microorganismsinteractionshasestablishedthebasicframework,whichcanformaperiodontalinflammation,butalsooffersthepossibilityoftreatment.宿主—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
18Subgingivalinfection龈下感染Bacteriaadhesion-growth-biofilmformation-intrusionofhosttissues-invasionofhostimmunesysteminterface细菌附着—粘附—细胞生长—生物膜形成—致病源入侵宿主细胞/组织—侵犯宿主免疫系统界面
19Periodontaldisease&hostimmunity牙周病与宿主免疫
2046%peoplecanbedetectedperiodontalpathogens.However,manyindividualsmaylimittheoccurrenceofperiodontaldisease.Manyscholarshaveproposedthemultipleetiologyofperiodontaldisease:microbes,hostimmuneresponse,environmentalfactors…46%检测到牙周致病菌，但许多人不发病牙周病病因涉及微生物、宿主、环境
21Althoughperiodontaldiseaseiscausealbybacterialinfection,theresultingtissuedamageisduetotheimmuneresponse.牙周病损伤来自免疫反应
22Individualimmuneresponsestoalargeextentdeterminetheseverityofperiodontaldisease.个体反应决定牙周损害程度Twinstudyconfirmsgenetichereditaryeffectsonperiodontaldiseaseclinicalsensitivityupto50%.遗传因素占50%
23FirstistheinnateimmuneresponseBacterialuptakebymacrophages→cytokenreleasebymacrophages巨噬细胞释放细胞因子→causingperiodontaldiseasesrelatedtoinflammation炎症→causingbloodvesselstodilate,permeabilityincreases血管渗透性增加→localbloodflowincreases,creatinginflammation血流量增加Innateimmuneresponse固有免疫反应
24Acquiredimmuneresponses获得性免疫反应Pgisthemostofbacteriarelatedtoperiodontalinflammation,cansensitizedandactivateDCPg致敏并激活DCDendriticcells(DC)playaroleinantigenpresentation→NaiveTcellsstimulatedDC→刺激幼稚T细胞→reachesthenearestlymphnode→activateTcells到达附近淋巴结，激活T细胞
25Immuneescape免疫逃逸Pathogenicbacteriaofperiodontitismayentercells,escapeimmunesurveillance,andformecologicalbalancewithhost.Oncebalancedamage,periodontaldiseasecanhappen.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:Oralherpesvirus,EBvirusandbacterial
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27CD4+Tcellsappearanceisthemaincauseofperiodontalboneloss.CD4+T细胞Th2cellsactivateBcellstoproduceantibodies.Th2激活B细胞EpithelialcellsinperiodontitispatientscontainhighlevelsIgAandIgG,andIgMcanbefoundindeepperiodontalpocket.上皮细胞含IgA、G、MBoneloss骨丧失
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29Periodontaldisease-relatedsystemicdiseasesincludingcardiovasculardiseaseand,pretermbirthandotherissues…Periodontalinflammationenablesindividualsmoresensitivetoperiodontaldiseasesandvascularsclerosis.血管硬化InflammatoryCytokines,particularlyIL-1beta,PGE2andTNF-alpha,canaffectthecardiovascularandplacenta.心血管和胚胎Systemicreaction全身反应
