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1、抗微生物免疫-抗菌免疫-抗病毒免疫,2023/3/31,1,感染与免疫之间的平衡关系与疾病,机体抗感染机制-共性-个性：不同微生物的特性和致病机制不同,抗感染免疫,2023/3/31,2,Spectrum of virulence,脊髓灰质炎0.1-1%显性感染,风疹50%显性感染,狂犬病100%显性感染,感染性疾病的“冰山”概念The iceberg concept of infectious disease,无症状感染,典型临床疾病表现,轻度疾病less severe disease,2023/3/31,3,微生物的结构与免疫应答-内部抗原-外部抗原-与致病性的关系（进入途径、感染部位全身
2、/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-诱导产生免疫应答的类型抗微生物感染免疫-天然免疫-特异性免疫 细胞免疫应答/体液免疫应答保护性免疫应答免疫损伤（超敏反应、自身免疫应答）,2023/3/31,4,微生物体积的大小不同,细菌,衣原体,病毒,体积微小,2023/3/31,5,Figure 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,2023/3/31,6,抗菌免疫Immunity to Bacteria基本原则1)抗菌免疫机制与细菌表面结构相关 细胞壁和细胞膜 包括 LPS-flagella(鞭毛)-fi
3、mbriae(菌毛)-capsules(荚膜),2023/3/31,7,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-激发炎性细胞因子(LPS,capsule,arabinoglactan/glycolipids),2023/3/31,8,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-细胞壁结构不同-致病性、致病机制不同-抗感染免疫不同,2023/3/31,9,G+金葡菌,G-大肠杆
4、菌,分枝杆菌,螺旋体,细菌细胞壁结构,2023/3/31,10,G+金葡菌,G-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-细胞壁成分-溶菌酶,2023/3/31,11,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,研究抗菌免疫时，需了解该菌结构,2023/3/31,12,2)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：Neutr
5、alization 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,2023/3/31,13,Adhesion/黏附toxin产生毒素,entryMultiplication繁殖,AdhesionMultiplication 繁殖Toxin 产生毒素,2023/3/31,14,3)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
6、细胞的内环境,2023/3/31,15,Extracellular versus Intracellular pathogenExtracellular pathogencapable of replicating outside of the host cellsdestroyed when phagocytoseddamaging tissues as they remain outside cellsinducing the production of opsonizing antibodies usually cause acute diseases of relatively sho
7、rt durationIntracellular pathogencan multiply within phagocytesfrequently cause chronic disease,2023/3/31,16,17,Extracellular pathogenRespiratory tract,cutaneous,infections:Streptococcus spp,Staphylococcus spp.Digestion tract infections:Salmonella spp.,Shigella spp.Intracellular pathogenRespiratory(
8、pneumopathies:immunosuppresive;children):Chlamydia,Legionella,Mycobateria.Sex-transmitted:Chlamydia trachomatis CNS+other sites:Listeria monocytogenes;Pregnant women;immunosuppressive patients,2023/3/31,18,Endosomes,Phagosomes,lysosomes,Phagolysosomes,军团菌衣原体,李斯特菌志贺菌,沙门菌结核菌,胞内寄生菌,Cytosol:pH=7Phagosom
9、e:pH=6Phagolysosome:pH=5,2023/3/31,Figure 10-4,胞外寄生菌,胞内寄生菌,感染部位,病原体,保护性免疫,2023/3/31,19,4)人体解剖结构与免疫-无/有菌状态的差异-免疫因子/细胞的差异-免疫应答的特点/差异,2023/3/31,20,Adenoid,Tonsil,Lymphnodes,Spleen,Peyers patches(small intestine),Appendix,Lymphaticvessels,Lymphnode,Masses ofdefensive cells,Bloodcapillary,Lymphaticvessel
10、,Tissuecells,Interstitial fluid,淋巴系统,2023/3/31,21,INNATE IMMUNITY,Recognition of traitsshared by broad rangesof pathogens,using asmall set of receptors,Rapid response,Recognition of traitsspecific to particularpathogens,using a vastarray of receptors,Slower response,ACQUIRED IMMUNITY,Pathogens(micro
11、organismsand viruses),Barrier defenses:SkinMucous membranesSecretions,Internal defenses:Phagocytic cellsAntimicrobial proteinsInflammatory responseNatural killer cells,Humoral response:Antibodies defend againstinfection in body fluids.,Cell-mediated response:Cytotoxic lymphocytes defendagainst infec
12、tion in body cells.,人体抗菌免疫的三道防线,2023/3/31,22,一般因素物理和化学屏障系统完整的皮肤和粘膜上皮细胞纤毛体液、胃酸、眼泪低 pH(皮肤,阴道,etc.)发热37 C年龄婴儿 vs.幼儿 vs.老人,2.人体抗菌免疫的第一道防线,2023/3/31,23,Lactobacillus acidophilus,Lactobacillus casei,Enterococcus faecium,Saccharomyces cerevisiae,营养状况激素孕妇感染 HEV-死亡率 遗传因子宿主种属的抗性共生菌-colicins,occupy ecological
13、niche益生菌（“probiotic”organisms）-lactobacilli etc.酸奶-保加利亚乳酸杆菌 嗜热链救菌 双岐杆菌 嗜酸乳杆菌,2023/3/31,24,Some protective factors found in body tissues and fluids,2023/3/31,25,Antimicrobial Peptides and Proteins,Peptides and proteins function in innate defense by attacking microbes directly or impeding their reprod
14、uctionAntimicrobial peptides：host defense peptidespart of theinnate immune responsefound among all classes of life.These peptides are potent,broad spectrumantibioticswhich demonstrate potential as novel potential therapeutic agents.-killGram negativeandGram positivebacteria,enveloped viruses,fungi a
15、nd even transformed or cancerous cells.-enhance immunity by functioning asimmunomodulatory.The complement system 30 proteins-lysis of invading cells-helps trigger inflammation,2023/3/31,26,Various structures of antimicrobial peptides,The modes of action by Antimicrobial peptides,Immunomodulatoryfunc
16、tions:Alter host gene expressionAct as chemokines and/or inducechemokineproductionInhibitingLPSinduced pro-inflammatorycytokineproductionPromoting wound healingModulating the responses ofdendritic cellsand cells of the adaptive immune response,2023/3/31,27,Figure 2-19,趋化,裂解,调理,补体的抗菌作用,2023/3/31,28,3
17、.人体抗菌免疫的第二道防线 识别细菌保守的“共有”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,2023/3/31,29,Outcome of Infection,Infection wins deathInfection loseslive(innate plus adaptive)Studied intenselyBest outcome isInfections killed quickly(innate only)Not well studied,How is it that most peo
18、ple are not perpetually sick?(Innate immunity squelching most infections),2023/3/31,30,微生物存活数量,天然免疫缺损小鼠,天然免疫正常小鼠,T、B细胞缺损小鼠,天然免疫在微生物感染中的作用,2023/3/31,31,天然免疫识别的细菌细胞壁的表面成分,G-bacteria,G+bacteria,脂多糖,脂蛋白,孔蛋白穿孔素,磷壁酸,肽聚糖,2023/3/31,32,物种演化中遗传的古老广谱抗微生物机制微生物的LPS,甘露糖等“pathogen-associated molecular patterns”PAM
19、Ps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”-MAMPs,Mannose binding lectinMBL belongs to the class of collectins in the
20、 C-type lectin superfamilyC-type lectin receptors(CLRs),CLR,2023/3/31,33,2023/3/31,34,不同Toll-like Receptors识别不同微生物的产物,2023/3/31,35,Toll-like Receptors识别微生物的表面产物/结构,2023/3/31,36,TLR4,TLR2,TLR6,TLR1,TLR5,TLR9,PeptidoglycanLipoproteinsLipoarabinomannan LPS(Leptospira)LPS(Porphyromonas)GPI(T.Cruzi)Zymos
21、an(Yeast),LPSLipoteichoic Acids,Flagellin,Unmethylated CpG DNA,dsRNA,CD14,TLR3,TLR7,ssRNA,TLR11,识别病毒,T.gondiProfilin,Toll-like Receptors 识别病毒,2023/3/31,37,吞噬细胞表面具有识别微生物成分的多种受体,2023/3/31,38,Phagocytosis and killing,Primary granules:Antimicrobial peptidesLysozyme(degrades peptidoglycan)Proteases(elast
22、ase,etc.),Secondary granules:phagocyte oxidase,New Science Press Ltd.2004,Primary granules,lysosome,Secondary granules,Lysosomes:Digestive enzymes,2023/3/31,39,Phagosytosis and destruction of bacteria,superoxide dismutase：superoxide(O2-),hydrogen peroxide(H2O2),and singlet oxygen,hydroxyl radicals m
23、yeloperoxidase（phagolysosome）,hydrogen peroxide+chlorine hypochlorite(toxic to bacteria),Oxygen-dependent bacteria-killing substance,2023/3/31,40,Effector Molecule,Function,Cationic proteins(cathepsin),Damage to microbial membranes,Lysozyme,Hydrolyses mucopeptides in the cell wall,Lactoferrin,Depriv
24、es pathogens of iron,Hydrolytic enzymes(proteases),Digests killed organisms,Oxygen Independent Killing in the Phago-lysosome,2023/3/31,41,趋化,吞噬,2023/3/31,42,There are different types of phagocytic cells:Neutrophils engulf and destroy microbesMacrophages are part of the lymphatic system and are found
25、 throughout the bodyDendritic cells stimulate development of acquired immunityEosinophils discharge destructive enzymes,2023/3/31,43,Neutrophil phagocytosing anthrax bacilli,Figure 2-15,2023/3/31,44,Figure 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,2023/3/31
26、,45,IFN-g 释放NK细胞激活,2023/3/31,46,inflammasome,Nod-like receptors(NLRs),2023/3/31,47,Inflammasome activation and diseases,Inflammatory Responses,Inflammation is a protective response that involves immune cells,blood vessels,and molecular mediators,Mast cell,-contains many granules rich in histamine an
27、d heparin,promotes changes in blood vessels,a part of the inflammatory responseIncrease local blood supply and allow more phagocytes and antimicrobial proteins to enter tissuesPus,a fluid rich in WBC,dead microbes,and cell debris,accumulates at the site of inflammation,2023/3/31,48,TNF,New Science P
28、ress Ltd.2000,or mast cell,2023/3/31,49,Fig.43-8-1,Pathogen,Splinter,Macrophage,Mast cell,Chemicalsignals,Capillary,Phagocytic cell,Red blood cells,2023/3/31,50,Inflammation:Neutrophils vs.Monocytes,Acute inflammation is initially characterized as rich in neutrophils;later it is more monocytes，contr
29、olled 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),interferon gamma(IFN-gamma),chemokines:C3a,C5a,Leukotriene B4,】Monocytes are multi-potential,depending on cytokine sig
30、nals:+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 phenotype and propagate adaptive immune priming,2023/3/31,51,Cytokine storm-sepsis syndrome,Bacterial septicemia l
31、eads to activation of TLRs on monocytes in the bloodSystemic release of TNF and IL-1 leads to“inflammation”all over the bodyShock from loss of blood pressure(vasodilation and leakage of fluid into tissues)TLRs also induce coagulation(via tissue factor)The combination of effects can lead to multi-org
32、an failure and death,2023/3/31,52,2023/3/31,53,通过多途径控制感染,TNF production,Induction of SignalingCascadesNF Activation,BIOLOGICAL EFFECTS,宿主抵抗LPS 的机制,2023/3/31,54,LBP 和 CD14 是内毒素的受体,Macrophages Endothelial cells,BiologicalActivities,2023/3/31,55,LPS Binding Protein/LPS结合蛋白(LBP)60-kDa血浆糖蛋白具有与LPS 高亲和力由肝细
33、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 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,2023/3/31,56,特异性抗菌免疫,2023/3/31,57,Figure 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,特异性抗菌免疫,2023/3/31,58,巨噬细胞与淋巴细胞相互作用,Cytokines are secreted by macrophages and
34、dendritic cells to recruit and activate lymphocytes,2023/3/31,59,A single B cell or T cell has about 100,000 identical antigen receptors,2023/3/31,60,Figure 9-5,T辅助细胞-B细胞激活，B细胞分化为浆细胞，分泌特异性抗体,2023/3/31,61,Figure 9-19 part 1 of 2,2023/3/31,62,Figure 9-19 part 2 of 2,2023/3/31,63,特异性体液免疫-抗胞外菌特异性抗体-毒素-中
35、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,调理,裂解,2023/3/31,64,抗黏附抗体阻断细菌定居,2023/3/31,65,Anti-Extracellular Bacteria,Extracellular BacteriaCapable of replicating outside of the host cells.They cause disease by two principle mechanisms.Induce inflammation Many of these bacteria produce toxins.Endotoxins E
36、xotoxins,2023/3/31,66,Innate immunity 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
37、TNF,IL-1,and chemokine:MCP-1,MIP-1a NK INF-gThe immune responses against extracellular bacteria-eliminating the bacteria-neutralizing the effects of toxins.,2023/3/31,67,Humoral immunity is the principle specific immune response against extracellular bacteria-Strong IgM responses are caused by polys
38、accharides.Antibodies IgM and IgG against 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
39、 opsonic)-IgA(local/mucosal immunity)block bacteria adhesionPrincipal injuries of host responses to extracellular bacteria:Inflammation&Septic shock,Specific Immunity Extracellular Bacteria,2023/3/31,68,69,Intracellular bacteria,No fusion,Lysozome,Phagosome,Fusion,Enter cytoplasm,Bacteria,Macrophage
40、 or neutrophil,Phagolysosomes,2023/3/31,70,Endosomes,Phagosomes,lysosomes,Phagolysosomes,军团菌衣原体,李斯特菌志贺菌,沙门菌结核菌,Anti-Intracellular Bacteria,Cytosol:pH=7Phagosome:pH=6Phagolysosome:pH=5,2023/3/31,1.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
41、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,2023/3/31,71,Anti-Intracellular Bacteria,Intercellular 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 immu
42、nity to intracellular Bacteria-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.,2023/3/31,72,Specific Immunity to Intracellular Bac
43、teria,Cell-mediated immune response is the major specific immune response against intracellular bacteria.Two types of cell-mediated reactions:Killing of phagocytosed intracellular bacteria as a result of macrophage activation by T cell derived cytokines,particularly IFN-gamma.Lysis of infected cells
44、 by CTLs.Tissue damage caused by macrophage activation that occurs in response to intracellular bacteria.,2023/3/31,73,抗胞内寄生菌的天然免疫和获得性免疫,活菌数,感染清除,感染控制,感染后天数,2023/3/31,74,Figure 1-26,2023/3/31,75,结核分枝杆菌的胞内感染,CD4 T cells 控制结核感染Immunity to the intracellular bacteria involves a DTH response 激活的巨噬细胞包裹感染灶
45、-结核球 tubercle.巨噬细胞释放的酶导致肺组织损伤,2023/3/31,76,细菌致病性免疫机制 白喉杆菌非侵袭性 毒素中和抗体霍乱弧菌非侵袭性毒素中和抗体、阻断细菌黏附奈瑟菌脑膜炎双球菌侵袭性 抗体、补体裂解、吞噬、调理金黄色葡萄球菌局部侵袭性+毒素抗体和补体的调理、吞噬、结核杆菌侵袭性、激发免疫病理巨噬细胞激活麻风杆菌侵袭性、激发免疫病理巨噬细胞激活,2023/3/31,77,78,EVASION STRATEGIES(1),2023/3/31,ref,79,EVASION STRATEGIES(2),2023/3/31,ref,病毒基本结构：核酸+蛋白 核酸+蛋白+包膜（含脂质和
46、糖蛋白）,抗病毒免疫,2023/3/31,80,病毒复制周期,吸附,穿入,脱衣壳,生化合成,装配,释放,出芽方式释放,细胞裂解释放,2023/3/31,81,Figure 2-49,病毒感染后体内免疫应答的动态变化,2023/3/31,82,干扰素细胞因子IFN-gCTL细胞增殖CTLT细胞增殖IFN-g，细胞因子抗体,天然免疫,获得性免疫,2023/3/31,83,屏障系统-respiratory epithelium and skin,etc.2.体液-stomach acid,tears,etc.3.干扰素4.NK 细胞5.巨噬细胞,抗病毒天然免疫,2023/3/31,84,干扰素Int
47、erferons(IFN)-第一个被发现的抗病毒因子-免疫调节剂-IFN alpha，beta，gamma IFN alpha 20 variants 白细胞 病毒 IFN beta 单个蛋白，纤维母细胞 病毒 IFN gamma 单个蛋白，NK 细胞，T 细胞抗原，mitogens,Type I,Type II,2023/3/31,85,干扰素诱生剂 IFN-alpha and IFN-beta 诱生剂：virus infection:-RNA viruses-DNA viruses are poor IFN inducers,with the exception of poxviruses
48、.-double stranded RNA-LPS,and components from some bacteriaIFN-gamma 诱生剂:-有丝分裂原mitogens-抗原antigen中草药,2023/3/31,86,Interferons 生物学活性-anti-viral activity 抗病毒-immunomodulate activity 免疫调节-regulation of cellular proliferation 调节细胞增殖,2023/3/31,87,IFN type I,II 不同受体 不同的激活途径调控不同生物学活性,型干扰素受体基因位于人染色体第21对染色体型
49、干扰素受体基因位于第6对染色体,2023/3/31,88,IFN的抗病毒作用,病毒,病毒复制,抑制病 毒复制,信号转导,IFN-a,IFN-诱导蛋白,诱导刺激,胞核,胞核,IFN 受体,细胞建立抗病毒状态,病毒感染细胞,2023/3/31,89,病毒易感患者：干扰素产生能力？受体变异？信号转导通路的改变/影响？,2023/3/31,90,IFN的临床应用,病毒感染乙型肝炎 丙型肝炎疣-人乳头瘤病毒/HPV呼吸道合胞病毒,肿瘤毛细胞白血病(90%有效)滤泡性淋巴瘤宫颈癌(HPV)基底细胞癌(80-90%)卡波济瘤(HHV type 8),Other conditions-慢性 肉芽肿病毒(IFN
50、-g)-多硬化症,2023/3/31,91,自然杀伤细胞(NK cell),病毒感染的靶细胞,2023/3/31,92,2023/3/31,93,Complementary activities of CTLsand NK cells,NK 细胞的效应机制,杀伤靶细胞的机制类似于 Tc cells杀伤靶细胞的活性为非 MHC限制对NK细胞敏感的靶细胞-MHC I 表达下调killer inhibitory receptors(KIR)on NK cells recognize class I MHC and prevent killingNK细胞表面具有FcRIII(CD16)可识别IgG-c
