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1、胃肠道黏膜先天性免疫应答,刘占举 M.D.,Ph.D郑州大学第二附属医院消化内科,Innate Immunity in gut mucosa,介绍胃肠道先天性免疫防御机制。了解胃肠道先天免疫系统如何识别肠道病原微生物。病原体识别信号系统。病原微生物感染引起肠道黏膜炎症应答。,Lecture aims,消化道是外界抗原或病原微生物进入体内的门户。有生理性和生物学屏障阻挡着这些抗原的侵入，并保持着肠道粘膜组织“内环境”的稳定。1年内有30 kg食物蛋白通过肠道；每天有130190g抗原被吸收进入机体。每克粪便1012个微生物，这些微生物抗原可通过肠道粘膜吸收进入机体引起免疫反应。,消化道也是免疫器
2、官，有许多免疫细胞参与了肠道粘膜免疫应答。当食物或细菌抗原接触胃肠道后，抗原成分被肠粘膜Peyers patches表面的M细胞吸收，引起一系列的免疫反应，出现免疫耐受，即对食物抗原不应答；否则引起食物过敏反应或炎症应答。,Gastric mucosal protective factors,病原微生物进入体内后识别免疫应答（先天性、获得性）清除免疫病理（过敏、感染、炎症）,Pathogenic infection,Immune response,Innate immunity(non specific),先天性与获得性免疫应答,Adaptive immunity(Ag specific),I
3、nflammation,Memory of infection,获得性免疫应答：Ag特异性防御机制，抗原刺激数天后形成免疫保护，以排除体内特异性抗原。终生伴随。,先天性免疫应答：Ag非特异性防御机制，遇到任何抗原后迅速或数小时后形成，以清除病原体，是机体先天固有的。,先天性免疫组成-生理性屏障-补体系统-细胞组成-细胞因子、炎症反应病原体识别-Pathogen-associated molecular patterns(PAMPs)-Pattern recognition receptors(PRRs)-Toll-like receptors(TLR)-NF-kB activation-TLR
4、 signaling-Nod proteins病原识别及炎症反应异常引起的疾病-Nod and Crohns disease-Celiac disease-Bacterial infection,先天性免疫应答,Cells types involved in innate immunity,Neutrophils,Monocytes/Macrophages,NK cells,Dendritic cells,Functions,Killing by Phagocytosis,Reactive oxygen species,Antimicrobial peptides,Extracellular
5、traps,Killing by Phagocytosis,Inflammation mediators,Reactive oxygen species,Complt proteins,Ag presentation,Ag presentation,Costimulatory signals,Cytokines,Lysis of viral infected cells,Activation of macrophages,Mast cells,Promote inflammation by releasingHistamineLeukotriensProstaglandin,Cells,Inn
6、ate immunity:cytokines,细胞因子是免疫细胞遇到抗原刺激后分泌的小分子可溶性蛋白，是调节先天性和获得性免疫应答的化学信使。,调节先天性免疫应答的细胞因子：,Monocytes Macrophages Dendritic cells,TNF-a IL-1 Chemokines(ex:IL-8),Sequential steps of Pathogen elimination,Plasma,Normal capillary,Endothelial cells,No injury or infection,Mast cells,Neutrophils,Monocytes,T an
7、d B Lymphocytes,Eosinophils,Basophils,Resident Macrophages,Plasma,Normal capillary,Mast cells,Neutrophils,Monocytes,T and B Lymphocytes,Eosinophils,Basophils,Complement,Bacterial peptides fMet-Leu-Phe(fMLP),Plasma,Normal capillary,Neutrophils,Monocytes,T and B Lymphocytes,Eosinophils,Basophils,Chemo
8、taxisPathogen recognitionPhagocytosis and cytokinesInflammation,Plasma,Normal capillary,Neutrophils,Monocytes,T and B Lymphocytes,Eosinophils,Basophils,ChemotaxisPathogen recognitionPhagocytosis and cytokinesInflammation,Sequential steps of Pathogen elimination,Mediators of inflammation(Histamine,cy
9、tokines,chemokines),Dilating capillary during inflammation,Neutrophils,Monocytes,Lymphocytes,Eosinophils,ComplementClotting factorsAb,Killing mechanisms,MACMembrane attack complex,Phagocytosis,白细胞向血管腔外迁徙,Cell 2000,Inflammation:transmigration of neutrophils,E-selectinP-Selectin,ICAM-1,问题：先天性免疫系统如何识 别
10、病原微生物抗原？,先天性,快速（小时内）慢（3-5天）,细胞表面特异性识别受体,受体特异性识别抗原决定簇,吞噬细胞（中性粒细胞、巨噬细胞）炎症介质（噬碱性粒细胞、肥大细 胞、噬酸性粒细胞）NK细胞补体细胞因子,APC（巨噬细胞、DC）Ag特异性B细胞Ag特异性T细胞Ab、CTL、细胞因子,大多抗原决定簇来自病原体的多肽,BCR、TCR识别抗原,?,?,?,?,获得性,先天性免疫系统对病原体的识别系统Pathogen-associated molecular patterns(PAMPs，病原相关分子模式)Pattern recognition receptors(PRRs，模式识别受体)Tol
11、l-like receptors(TLR)NF-KB activationTLR signalingNod proteins,病原相关的分子模式：PAMP模式识别受体：PRR,Pathogen-Associated Molecular Patterns(PAMPS),Pathogen Recognition Receptor(PRR),Macrophage,PAMPs,主要特点：微生物(非机体细胞)产生，以确保先天免疫系统识别自身和非自身抗原。PAMP是微生物生存所必需的。PAMP是很稳定的，仅有限的PRR可以识别之。,PAMPS:,G-菌的LPSG+（少部分G-）菌细胞壁肽糖类抗原G+菌细胞
12、壁磷脂壁酸、微生物糖蛋白、糖脂质蛋白细菌鞭毛蛋白flagellin菌毛蛋白pilin细菌和病毒的核酸物质 细菌的N-甲酰蛋氨酸dsRNA 霉菌的糖脂蛋白微生物膜表面的磷脂酰胆碱,PAMP组成,PAMPS:,Pattern Recognition Receptors,Toll-like receptors(TLRs):,I型转膜蛋白首先在黑腹果蝇中发现后来在哺乳类动物、鱼、鸡、植物中发现，可能来自一个起源。命名来自黑腹果蝇的基因Toll。1996年，发现Toll是苍蝇识别真菌感染基因。1997年发现Toll表达在哺乳类细胞。,Leucine-rich repeats(LRRs),Toll/IL-
13、1 Rc domain(TIR domain),Pattern Recognition Receptors(PRRs)：TLR,2 classes of PRRs:-Endocytic PRRs-Signaling PRRs,PRRs,Endocytic PRRs:在吞噬细胞表面，促使细胞对病原微生物 的吞噬。,Signaling PRRs:与微生物结合，促使细胞因子分泌，引起 先天性和获得性免疫应答。,TLR识别微生物抗原成分,TLR分布,(Viral),Uracil-rich single-stranded viral RNA(ex:HIV),Unmethylated cytosine-g
14、uanine dinucleotide sequences(CpG DNA)found in bacterial and viral genomes,细胞膜,TLR信号传导,Pathogen-Associated Molecular Patterns(PAMPS),Pathogen Recognition Receptor(PRR),Macrophage,Up regulation of cytokine genes,Inflammation,Nucleus,TLR activation,Adaptor proteins,NF-KB activation(Transcription facto
15、r),Inflammation,TLR信号诱导NF-KB激活,Toll-like receptor,Leucine-rich repeats(LRRs),Toll/IL-1 Rc domain(TIR domain),Adaptor protein:MyD88,Toll/IL-1 Rc domain(TIR domain),Death domain,Death domain,IRAK:IL-1 associated kinase,Nucleus,NF-kB,TRAF6,IKKs,Pathogen recognitionTLR activation,TLR信号传导,TLR在免疫细胞表面表达,先天
16、性免疫与获得性免疫联系,表达TLR 通过TLR识别PAMP(除隐窝上皮)Nod蛋白,Commensal bacteria:,肠道营养必需菌 促使肠道发育 阻止肠道病原微生物的感染,Mucosal epithelium:,Intestine and commensal bacteria,Intestinal crypt,肠腔内抗原进入体内的途径,NF-KB,Nod,Shigella,InflammationDisruption of epithelium integrity,GM-CSFCXCL1CYR-61,IL-8ICAM-1,微生物抗原诱导上皮细胞Nod激活、促使炎症应答,Neutroph
17、ils,Nod蛋白:表达的IEC、Mf Nod1（Card4）、Nod2（Card15）细胞内识别细菌抗原,Nod分子,Caspase-activating and recruitment domain,Leucine-rich repeat,Nucleotide binding site,Nod1和Nod2识别细菌肽糖类抗原,Gram-,Gram+,Nod诱导NF-kB激活,Nod:Nucleotide-binding oligomerization domain,RICK:RIP-like CARD-containing domain,Inflammation,Russel RK.et a
18、l.,ADC online,2004;89;598-603,病原微生物识别异常导致炎症疾病发生,Nod and Crohns disease：Mutant Nod2 is a predisposing risk factor for CD,which is likely to act in synergy with other factors both genetic and environmental,in causing the disease.,克罗恩病,NOD2突变与Crohns disease,NBS,Region involved in peptidoglycan recognit
19、ion,Heterozygous carriers:2 to 4-fold increased riskHomozygous carriers:15 to 40-fold increased risk,Loss of functionFailure in NF-KB activation,Crohns disease,?,肠道菌群改变导致的免疫激活异常 使细胞凋亡机制失常 导致CD慢性炎症和组织破坏 与CD临床类型有关（纤维化、狭窄）,NOD2突变与Crohns disease,Peptidoglycan,Muramyl dipeptide=MDP,Normal NOD2,NOD2 variant,CD患者NOD2突变,IFNg,Eckmann L.et al,Immunity 2005；22;661,总结,先天性免疫应答是机体本身固有的，识别病原微生物的侵袭，清除感染。肠道黏膜上皮细TLR、Nod对PAMP的识别，引起肠道黏膜的免疫保护。先天性免疫应答异常（Nod基因突变），引起肠道炎症性疾病（Crohns disease)。,谢 谢,刘占举450014 郑州市经八路2号郑州大学第二附属医院消化内科Email:Cell phone:13598826127,
