临床免疫学-抗感染免疫-临床研究生-课件.ppt

1、抗微生物免疫抗微生物免疫-抗菌免疫抗菌免疫 -抗病毒免疫抗病毒免疫2022-12-201感染感染免疫力免疫力感染灶的范围感染灶的范围 x 毒力毒力免疫力免疫力疾病疾病=感染与免疫之间的平衡关系与疾病感染与免疫之间的平衡关系与疾病机体抗感染机制-共性共性-个性个性：不同微生物的特性和致病机制不同抗感染免疫2022-12-202Spectrum of virulence脊髓灰质炎脊髓灰质炎0.1-1%显性感染风疹风疹50%显性感染狂犬病100%显性感染感染性疾病的感染性疾病的“冰山冰山”概念概念The iceberg concept of infectious diseaseThe iceberg

2、 concept of infectious disease无症状感染无症状感染 典型临床疾病表现轻度疾病less severe disease 2022-12-203微生物的结构与免疫应答微生物的结构与免疫应答 -内部抗原内部抗原 -外部抗原外部抗原 -与致病性的关系（与致病性的关系（进入途径、感染部位全身/浅表、靶细胞/组织）-寄生的部位：细胞外；兼性细胞内；专性细胞内寄生寄生的部位：细胞外；兼性细胞内；专性细胞内寄生 -诱导产生免疫应答的类型诱导产生免疫应答的类型抗微生物感染免疫抗微生物感染免疫-天然免疫天然免疫-特异性免疫特异性免疫 细胞免疫应答细胞免疫应答/体液免疫应答体液免疫应答保

3、护性免疫应答保护性免疫应答免疫损伤免疫损伤 （超敏反应、自身免疫应答）（超敏反应、自身免疫应答）2022-12-204微生物体积的大小不同微生物体积的大小不同细菌衣原体病毒病毒体积微小体积微小2022-12-205Figure 2-1不同免疫应答的时间抗再次感染？抗再次感染？抗再次感染抗再次感染应答的时间初次感染2022-12-206抗菌免疫抗菌免疫Immunity to Bacteria1.基本原则基本原则1)抗菌免疫机制与细菌表面结构相关抗菌免疫机制与细菌表面结构相关 细胞壁和细胞膜细胞壁和细胞膜 包括包括 LPS -flagella(鞭毛鞭毛)-fimbriae(菌毛菌毛)-capsul

4、es(荚膜荚膜)2022-12-207细菌细胞表面结构：免疫系统作用的靶标细菌细胞表面结构：免疫系统作用的靶标细胞壁结构与细菌的抵抗力有关结核杆菌细胞壁的抵抗力强细菌荚膜抗吞噬 链球菌、炭疽杆菌有毒株具有荚膜细菌细胞壁成分佐剂活性细菌细胞壁成分佐剂活性-激发炎性细胞因子 (LPS,capsule,arabinoglactan/glycolipids)2022-12-208不同微生物具有不同的细胞壁结构不同微生物具有不同的细胞壁结构-革兰阳性细菌 （G+）-革兰阴性细菌（G-）-分支杆菌(结核分支杆菌)-Spriochaetes （螺旋体）不同的细菌不同的细菌-细胞壁结构不同-致病性、致病机制不

5、同-抗感染免疫不同2022-12-209G G+金葡菌金葡菌G G-大肠杆菌大肠杆菌分枝杆菌螺旋体细菌细胞壁结构2022-12-2010G G+金葡菌金葡菌G G-大肠杆菌大肠杆菌革兰阴性菌的脂质外膜-补体-裂解 -NK-杀伤-阳离子蛋白肽聚糖肽聚糖-细胞壁成分细胞壁成分 -溶菌酶溶菌酶2022-12-2011革兰阴性菌的脂质外膜（G-）-细胞壁成分-补体-裂解 -NK-杀伤-阳离子蛋白肽聚糖-细胞壁成分-溶菌酶鞭毛和菌毛-抗体菌细胞-吞噬细胞 细胞表面结构与免疫力细胞表面结构与免疫力研究抗菌免疫时，需了解该菌结构研究抗菌免疫时，需了解该菌结构2022-12-20122)抗菌免疫机制与细菌致病

6、性相关抗菌免疫机制与细菌致病性相关细菌的致病性 产生毒素,但不具侵袭力 毒素(Corynebacterium diphtheriae,Vibrio Cholerae)免疫力：Neutralization antibody/中和抗体 Anti-adhesion Ab/抗黏附抗体 具有侵袭力,但不产生毒素 酶类：扩散因子(tissue-degrading enzymes)免疫力：杀伤菌细胞 大多数细菌既产生毒素也具侵袭力 2022-12-2013Adhesion/黏附黏附toxin产生毒素产生毒素entryMultiplication繁殖繁殖AdhesionMultiplication 繁殖繁殖T

7、oxin 产生毒素产生毒素2022-12-20143)3)免疫机制与细菌赖于环境的生存能力相关免疫机制与细菌赖于环境的生存能力相关 胞外菌：葡萄球菌、链球菌 兼性胞内寄生菌：结核分枝杆菌 专性胞内寄生菌：衣原体、立克氏体 病毒等 -存活绝对依赖细胞的内环境 2022-12-2015Extracellular versus Intracellular pathogennExtracellular pathogenncapable of replicating outside of the host cellsndestroyed when phagocytosedndamaging tissue

8、s as they remain outside cellsninducing the production of opsonizing antibodies usually cause acute diseases of relatively short durationnIntracellular pathogenncan multiply within phagocytesnfrequently cause chronic disease2022-12-201617nExtracellular pathogennRespiratory tract,cutaneous,infections

9、:Streptococcus spp,Staphylococcus spp.nDigestion tract infections:Salmonella spp.,Shigella spp.nIntracellular pathogennRespiratory(pneumopathies:immunosuppresive;children):Chlamydia,Legionella,Mycobateria.nSex-transmitted:Chlamydia trachomatis nCNS+other sites:Listeria monocytogenes;Pregnant women;i

10、mmunosuppressive patients2022-12-2018EndosomesPhagosomeslysosomesPhagolysosomes军团菌军团菌衣原体衣原体李斯特菌李斯特菌志贺菌志贺菌沙门菌沙门菌结核菌结核菌胞内寄生菌胞内寄生菌nCytosol:pH=7nPhagosome:pH=6nPhagolysosome:pH=52022-12-20Figure 10-4胞胞外外寄生菌寄生菌胞胞内内寄生菌寄生菌感染感染部位部位病原体病原体保护性保护性免疫免疫2022-12-2019呼吸道消化道眼皮肤生殖道4)4)人体解剖结构与免疫人体解剖结构与免疫 -无/有菌状态的差异 -免疫

11、因子/细胞的差异 -免疫应答的特点/差异2022-12-2020AdenoidTonsilLymphnodesSpleenPeyers patches(small intestine)AppendixLymphaticvesselsLymphnodeMasses ofdefensive cellsBloodcapillaryLymphaticvesselTissuecellsInterstitial fluid淋巴系统2022-12-2021INNATE IMMUNITYRecognition of traitsshared by broad rangesof pathogens,using

12、asmall set of receptorsRapid responseRecognition of traitsspecific to particularpathogens,using a vastarray of receptorsSlower responseACQUIRED IMMUNITYPathogens(microorganismsand viruses)Barrier defenses:SkinMucous membranesSecretionsInternal defenses:Phagocytic cellsAntimicrobial proteinsInflammat

13、ory responseNatural killer cellsHumoral response:Antibodies defend againstinfection in body fluids.Cell-mediated response:Cytotoxic lymphocytes defendagainst infection in body cells.人体抗菌免疫的三道防线人体抗菌免疫的三道防线 2022-12-2022一般因素一般因素物理和化学屏障系统物理和化学屏障系统 完整的皮肤和粘膜完整的皮肤和粘膜 上皮细胞纤毛上皮细胞纤毛 体液、胃酸、眼泪体液、胃酸、眼泪 低低 pH(pH(

14、皮肤皮肤,阴道阴道,etc.),etc.)发热发热 37 37 C C年龄年龄 婴儿婴儿 vs.vs.幼儿幼儿 vs.vs.老人老人2.2.人体抗菌免疫的第一道防线人体抗菌免疫的第一道防线 2022-12-2023Lactobacillus acidophilusLactobacillus caseiEnterococcus faecium 营养状况营养状况激素激素 孕妇感染孕妇感染 HEV-死亡率死亡率 遗传因子遗传因子宿主种属的抗性宿主种属的抗性共生菌共生菌-colicins,occupy ecological niche益生菌（益生菌（“probiotic”organisms）-lact

15、obacilli etc.酸奶酸奶-保加利亚乳酸杆菌保加利亚乳酸杆菌 嗜热链救菌嗜热链救菌 双岐杆菌双岐杆菌 嗜酸乳杆菌嗜酸乳杆菌2022-12-2024GroupNameMajor SourcesActivity against EnzymesLysozymeSerum;leukocytesBacteria Basic peptides and proteinsb-lysin Phagocytin Leukin PlakinPlatelets Neutrophils NeutrophilsGram positive bacteria Iron binding proteinsTransfer

16、rin LactoferrinSerum,Leukocytes,milkBacteria Basic aminesSpermine;spermidinePancreas,kidney,prostateGram positive bacteria Complement componentsSerumBacteria,viruses,protozoa PeroxideMyeloperoxidase;xanthine oxidaseNeutrophils,milkBacteria,viruses,protozoa InterferonMost cells but not neutrophilsVir

17、uses,intracellular parasites,activation of macrophages Some protective factors found in body tissues and fluids2022-12-2025Antimicrobial Peptides and Proteins Peptides and proteins function in innate defense by attacking microbes directly or impeding their reproduction Antimicrobial peptides：host de

18、fense peptidespart of the innate immune response found among all classes of life.These peptides are potent,broad spectrum antibiotics which demonstrate potential as novel potential therapeutic agents.-kill Gram negative and Gram positive bacteria,enveloped viruses,fungi and even transformed or cance

19、rous cells.-enhance immunity by functioning as immunomodulatory.The complement system 30 proteins-lysis of invading cells-helps trigger inflammation2022-12-2026Various structures of antimicrobial peptidesThe modes of action by Antimicrobial peptidesImmunomodulatory functions:Alter host gene expressi

20、onAct as chemokines and/or induce chemokine productionInhibiting LPS induced pro-inflammatory cytokine productionPromoting wound healingModulating the responses of dendritic cells and cells of the adaptive immune response2022-12-2027Figure 2-19趋化趋化裂解裂解调理调理补体的抗菌作用2022-12-20283.3.人体抗菌免疫的第二道防线人体抗菌免疫的第二

21、道防线 识别细菌保守的识别细菌保守的“共有共有”成分成分 天然免疫/固有免疫/Innate Immunity 无记忆同一微生物每次感染后的免疫应答强度均相似 无多样性 免疫分子的基因不会出现重组2022-12-2029Outcome of Infection Infection wins death Infection loseslive(innate plus adaptive)Studied intenselyBest outcome is Infections killed quickly(innate only)Not well studied How is it that most

22、people are not perpetually sick?(Innate immunity squelching most infections)2022-12-2030微生物存活数量微生物存活数量天然免疫天然免疫缺损小鼠缺损小鼠天然免疫天然免疫正常小鼠正常小鼠T、B细胞细胞缺损小鼠缺损小鼠天然免疫在微生物感染中的作用天然免疫在微生物感染中的作用2022-12-2031天然免疫识别的细菌细胞壁的表面成分天然免疫识别的细菌细胞壁的表面成分G-bacteriaG+bacteria脂多糖脂蛋白孔蛋白穿孔素磷壁酸肽聚糖2022-12-2032物种演化中遗传的古老广谱抗微生物机制微生物的LPS,甘

23、露糖等“pathogen-associated molecular patterns”PAMPs识别PAMPs receptors:pattern recognition receptors(PRRs)，on membrane:Toll-like receptors(TLRs),C-type lectin receptors(CLRs),in cytoplasm:Nod-like receptors(NLRs);RIG-I-like receptors(RLRs)“microbe-associated molecular pattern”-MAMPsMBLMannose binding lec

24、tinMBL belongs to the class of collectins in the C-type lectin superfamilyC-type lectin receptors(CLRs)CLR2022-12-2033EXTRACELLULARFLUIDLipopolysaccharideFlagellinTLR4TLR5HelperproteinTLR9TLR3WHITEBLOODCELLVESICLECpG DNAds RNAInflammatoryresponsesPAMPsPRRs2022-12-2034受体受体(Pattern Recognition Recepto

25、rs)PPR配体配体(Pathogen-Associated Molecular Patterns)PAMPTLR1与与 TLR2形成异源二体形成异源二体TLR2PGN,some LPS,some LTA,lipoproteins,AraLAM/细菌细菌TLR3dsRNA 病毒病毒TLR4Gram(-)LPS,Taxol,some LTA/细菌细菌TLR5Flagellin /细菌细菌TLR6与与 TLR2形成异源二体形成异源二体TLR7ImidazoquinolineTLR9Bacterial DNA(CpG)/细菌细菌 TLR 8,10Unknown 不同不同Toll-like Recep

26、tors识别不同微生物的产物识别不同微生物的产物2022-12-2035TLR9Unmethylated CpG DNAdsRNATLR3TLR7ssRNATLR4TLR2TLR6TLR1TLR5LipoproteinsLipoarabinomannan Lipoteichoic AcidsZymosan(Yeast)LPSFlagellinCD14MD2TLR11T.gondiProfilin识别细菌识别细菌 Toll-like Receptors识别微生物的表面产物识别微生物的表面产物/结构结构2022-12-2036TLR4TLR2TLR6TLR1TLR5TLR9Peptidoglyca

27、nLipoproteinsLipoarabinomannan LPS(Leptospira)LPS(Porphyromonas)GPI(T.Cruzi)Zymosan(Yeast)LPSLipoteichoic AcidsFlagellinUnmethylated CpG DNAdsRNACD14TLR3TLR7ssRNAMD2TLR11识别病毒识别病毒T.gondiProfilinToll-like Receptors 识别病毒识别病毒2022-12-2037吞噬细胞表面具有识别微生物成分的多种受体吞噬细胞表面具有识别微生物成分的多种受体2022-12-2038Phagocytosis an

28、d killingPrimary granules:Antimicrobial peptidesLysozyme (degrades peptidoglycan)Proteases(elastase,etc.)Secondary granules:phagocyte oxidase New Science Press Ltd.2004MicrobesPHAGOCYTIC CELLVacuoleLysosomecontaining enzymesPrimary granuleslysosomeSecondary granulesLysosomes:Digestive enzymes2022-12

29、-2039Phagosytosis and destruction of bacteriasuperoxide dismutase：superoxide(O2-),hydrogen peroxide(H2O2),and singlet oxygen,hydroxyl radicals myeloperoxidase （phagolysosome）,hydrogen peroxide+chlorine hypochlorite(toxic to bacteria)Oxygen-dependent bacteria-killing substance2022-12-2040Effector Mol

30、eculeFunctionCationic proteins(cathepsin)Damage to microbial membranesLysozymeHydrolyses mucopeptides in the cell wallLactoferrinDeprives pathogens of ironHydrolytic enzymes(proteases)Digests killed organismsOxygen Independent Killing in the Phago-lysosome2022-12-2041趋化趋化吞噬吞噬 2022-12-2042 There are

31、different types of phagocytic cells:Neutrophils engulf and destroy microbes Macrophages are part of the lymphatic system and are found throughout the body Dendritic cells stimulate development of acquired immunity Eosinophils discharge destructive enzymes2022-12-2043Neutrophil phagocytosing anthrax

32、bacilli Figure 2-152022-12-2044Figure 2-5 part 1 of 2巨噬细胞表面表达多种受体细菌表面成分与巨噬细胞表面受体结合细菌与巨噬细胞表面受体结合后激发细胞因子/炎性因子的释放巨噬细胞吞噬细菌2022-12-2045IFN-g 释放NK细胞激活2022-12-2046inflammasome Nod-like receptors(NLRs)2022-12-2047Inflammasome activation and diseasesInflammatory Responses Inflammation is a protective respons

33、e that involves immune cells,blood vessels,and molecular mediators,Mast cell,-contains many granules rich in histamine and heparin,promotes changes in blood vessels,a part of the inflammatory response Increase local blood supply and allow more phagocytes and antimicrobial proteins to enter tissues P

34、us,a fluid rich in WBC,dead microbes,and cell debris,accumulates at the site of inflammation2022-12-2048TNF New Science Press Ltd.2000or mast cell2022-12-2049Fig.43-8-1PathogenSplinterMacrophageMast cellChemicalsignalsCapillaryPhagocytic cellRed blood cellsFluid2022-12-2050Inflammation:Neutrophils v

35、s.Monocytes Acute inflammation is initially characterized as rich in neutrophils;later it is more monocytes，controlled by chemokines expressed by the endothelial cells.Neutrophils are dedicated to killing bacteria and are short-lived，often damage host tissue as a byproduct.【interleukin-8(IL-8),inter

36、feron gamma(IFN-gamma),chemokines:C3a,C5a,Leukotriene B4,】Monocytes are multi-potential,depending on cytokine signals:+IFN-g:assume a vigorous killing phenotype similar to neutrophils +IL-10:assume a wound-healing type phenotype(to clean up after infection is cleared)+GM-CSF:assume a dendritic cell

37、phenotype and propagate adaptive immune priming2022-12-2051Cytokine storm-sepsis syndrome Bacterial septicemia leads to activation of TLRs on monocytes in the blood Systemic release of TNF and IL-1 leads to“inflammation”all over the body Shock from loss of blood pressure(vasodilation and leakage of

38、fluid into tissues)TLRs also induce coagulation(via tissue factor)The combination of effects can lead to multi-organ failure and death2022-12-20522022-12-2053通过多途径控制感染TNF productionInduction of SignalingCascadesNF ActivationBIOLOGICAL EFFECTSHow do macrophagesdetect LPS?宿主抵抗宿主抵抗LPS LPS 的机制的机制2022-12

39、-2054LBP 和和 CD14 是内毒素的受体是内毒素的受体Macrophages Endothelial cellsBiologicalActivitiesEarlier SignalingEvents?LBP-CD14Co-receptor(s)?2022-12-2055LPS Binding Protein/LPS结合蛋白结合蛋白(LBP)60-kDa血浆糖蛋白具有与LPS 高亲和力 由肝细胞合成的急性期蛋白(肝功能不全-LPS清除？)正常血清量 1 10 ug/ml 急性期血清含量 300 ug/ml 对少量LPS或革兰阴性菌快速反应，运输至巨噬细胞 LPS,上调 IL-1,IL-6

40、 and TNF表达.CD14 -巨噬细胞表面 -可溶性CD14-上皮细胞 -与LBP共同将LPS结合于细胞表面2022-12-2056特异性抗菌免特异性抗菌免疫疫2022-12-2057Figure 2-1不同免疫应答的时间抗再次感染抗再次感染应答的时间特异性抗菌免特异性抗菌免疫疫2022-12-2058巨噬细胞与淋巴细胞相互作用巨噬细胞与淋巴细胞相互作用巨噬细胞巨噬细胞 淋巴细胞淋巴细胞 细菌细菌Cytokines are secreted by macrophages and dendritic cells to recruit and activate lymphocytes2022-

41、12-2059 Antigen-bindingsite Antigen-binding siteAntigen-bindingsiteDisulfidebridge VariableregionsConstantregionsTransmembraneregionPlasmamembraneLightchainHeavy chainsT cell chain chainDisulfide bridgeCytoplasm of T cell(b)T cell receptorCytoplasm of B cell(a)B cell receptorB cellVVCCVVCCCCVVA sing

42、le B cell or T cell has about 100,000 identical antigen receptors2022-12-2060Figure 9-5T辅助细胞辅助细胞-B细胞激活，细胞激活，B细胞分化为浆细胞，分泌特异性抗体细胞分化为浆细胞，分泌特异性抗体2022-12-2061Figure 9-19 part 1 of 22022-12-2062Figure 9-19 part 2 of 22022-12-2063特异性体液免疫特异性体液免疫-抗胞外菌抗胞外菌特异性抗体-毒素-中和-菌细胞-调理 抗体+吞噬细胞-菌细胞-裂解 抗体+补体-阻断细菌黏附中和中和调理调理

43、裂解裂解2022-12-2064抗黏附抗体抗黏附抗体阻断细菌定居阻断细菌定居2022-12-2065Anti-Extracellular BacteriaExtracellular Bacteria Capable of replicating outside of the host cells.They cause disease by two principle mechanisms.Induce inflammation Many of these bacteria produce toxins.Endotoxins Exotoxins2022-12-2066Innate immunit

44、y to Extracellular BacteriaPhagocytosis by neutrophils,monocytes,and the tissue macrophages.Activation of the complement system(without antibody)Chemotaxis C3a,C5a,Opsonization C3b etc,lytic complex C5-9Chemotexis triggered by PAMPs,chemokine,C3a,C5a ectCytokines TNF,IL-1,and chemokine:MCP-1,MIP-1a

45、NK INF-gThe immune responses against extracellular bacteria-eliminating the bacteria-neutralizing the effects of toxins.2022-12-2067Humoral immunity is the principle specific immune response against extracellular bacteria-Strong IgM responses are caused by polysaccharides.Antibodies IgM and IgG agai

46、nst bacteria surface antigens and toxins stimulate three types of effector mechanisms:-opsonize bacteria and enhance phagocytosis -neutralize bacterial toxins-inhibit bacterial enzyme activities-limit the bacteria mobility -activate the complement system(lytic and opsonic)-IgA(local/mucosal immunity

47、)block bacteria adhesionPrincipal injuries of host responses to extracellular bacteria:Inflammation&Septic shockSpecific Immunity Extracellular Bacteria2022-12-206869Intracellular bacteriaNo fusionLysozomePhagosomeFusionEnter cytoplasmBacteriaMacrophage or neutrophilPhagolysosomes2022-12-2070Endosom

48、esPhagosomeslysosomesPhagolysosomes军团菌军团菌衣原体衣原体李斯特菌李斯特菌志贺菌志贺菌沙门菌沙门菌结核菌结核菌Anti-Intracellular BacterianCytosol:pH=7nPhagosome:pH=6nPhagolysosome:pH=52022-12-201.胞内寄生菌对宿主细胞几乎无/或无直接的毒性作用；但感染伴随迟发型超敏反应2.胞内寄生菌能与宿主长期共存，导致慢性感染；胞外菌引起急性感染3.胞内寄生菌感染的病理与免疫损伤有关，而胞外菌往往产生毒素直接造成组织损伤；4.T细胞是控制胞内寄生菌感染主要免疫因素；胞内寄生菌感染的特征胞内

49、寄生菌感染的特征2022-12-2071Anti-Intracellular BacteriaIntercellular bacteria have the ability to survive and even replicate within phagocytesImmune responses for elimination of intracellular bacteria-very different from the responses against extracellular bacteria.Innate immunity to intracellular Bacteria-

50、Intracellular bacteria are resistant to degradation within phagocytes.-Intracellular bacteria activate NK cells,either directly or by stimulating macrophages production of IL-12,a powerful NK cell activating cytokine.2022-12-2072Specific Immunity to Intracellular BacteriaCell-mediated immune respons