免疫学课件-1.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,Pattern recignition and Innate protection,Overview,Pattern recognition,Negative regulation of pattern recognition,Significance of patter recognition,PRR and human diseases,Dangerous signal,Innate Immunity:A(Very)Broad Overview,Pattern recignition and Innate protection,Overview,Pattern recognition,Negative regulation of pattern recognition,Significance of patter recognition,PRR and human diseases,Strategy of Host?,Microbes are heterogeneous and can mutate,FOCUS,-,On highly conserved structures present in large groups of microorganisms.,PAMPS,-,Pathogen-associated molecular patterns,Pattern recognition,机体接触致病微生物后即迅速进行识别并产生抵抗病原体入侵的反应。发挥这一功能主要是巨噬细胞、树突状细胞和中性粒细胞。这些天然免疫细胞表达模式识别受体,(pattern-recognition receptors/molecule,PRR/PRM),受体识别高度保守的病原体相关分子模式,(pathogen-associated molecular patterns,PAMP),。,Pattern recognition,Dangerous signal:,-Exogenous:,PAMP(pathogen associated molecular pattern),-Endogenous:alarmins(Damage associated molecular pattern,DAMP),PRR(pattern recognition receptor),Requirements for the recognition of targets by the innate immune,Molecular structures recognized by the immune system must be shared by large groups of pathogens,molecular patterns vs.particular structures(antigens),PAMPs must be conserved products of microbial metabolism not subject to antigenic variability,The recognized structures must be absolutely distinct from self antigens:discrimination of self vs.non-self,Common Features of PAMP,pathogen-associated molecular patterns are produced only by microbial pathogens,and not by their hosts.,the structures recognized by the innate immune system are usually essential for the survival or pathogenicity of microorganisms.,pathogen-associated molecular patterns are usually invariant structures shared by entire classes of pathogens.,PAMPs,PAMPs that trigger innate immune responses in,various vertebrate and non-vertebrate organisms,include lipopolysaccharides(,LPS,)from Gram-,negative bacteria,bacterial,flagellin,viral and,bacterial,nucleic acids,fungal cell wall-derived,glucans,chitins,mannans,or,proteins,and,peptidoglycans(,PGN,)from Gram-positive bacteria.,Structure of a Gram-Positive Cell Wall,Structure of a Gram-Negative Cell Wall,pathogen-associated molecular patterns,(PAMP),Fungi:Cell wall,:,mannan,glucans,Virus:,Double strands,RNA,Virion-,Composition,Parasite:modified sugar,parasite specified protein(GPI Anchor of,cytoplasm,),Bacterium:,Alarmins,They are rapidly released following non-programmed cell death but are not released by apoptotic cells.,Cells of the immune system also can be induced to produce and release alarmins without dying generally by using specialized secretion systems or by the ER-Golgi secretion pathway.,They recruit and activate receptor-expressing cells of the innate immune system,including DCs and thus directly or indirectly promote adaptive immunity response.,Alarmins should restore homeostasis by promoting the reconstruction of the tissue that was destroyed either because of the direct insult or the secondary effects of inflammation.,Pattern recognition,Dangerous signal:,-Exogenous:PAMP(pathogen associated molecular pattern),-Endogenous:Alarmins,PRR(pattern recognition receptor),Sensor systems,(PRR,PRM),humoral components:,acute phase proteins,complement,endocytic PRRs:,scavenger receptors,lectin receptors,opsonic phagocytic PRRs:,FcR and CR,Signaling PRR:,-TLRs(Toll-like receptors),-NLRs(NOD-like receptors),-RLHs(RIG-like helicases),吞噬细胞对病原体的识别和吞噬,Host receptors that sense the molecules of pathogens,(NLR),(RLH),1.,分泌型,PRR,甘露聚糖结合凝集素（,MBL,）,*属于肝脏合成的急性期反应蛋白,*识别并结合,G,-,/G,+,菌、酵母菌、某些病毒和寄生虫等表面的甘露糖,*激活,MBL,补体途径，发挥调理、致炎作用。,Acute Phase Proteins,2.Endocytic pattern-recognition receptors,甘露糖受体：特异性识别微生物细胞壁糖蛋白和糖脂末端的甘露糖和岩藻糖残基，介导吞噬细胞吞噬。,清道夫受体：识别并与细菌细胞壁某些组分,(,肽聚糖、磷壁酸）结合，有效地清除血循环中的细菌。,内吞型,PRR,Endocytic pattern-recognition receptors,Endocytic pattern-recognition receptors are,found on the surface of phagocytes,and promote the attachment of microorganisms to phagocytes and their subsequent engulfment and destruction,.They include:,mannose receptors,Mannose receptors bind to terminal mannose and fucose groups on microbial glycoproteins and glycolipids.(Human glycoproteins and glycolipids typically have terminal N-acetylglucosamine and sialic acid groups.),scavenger receptors,Scavenger receptors bind to bacterial cell wall components such as LPS,peptidoglyan and teichoic acids.There are also scavenger receptors for certain components of other types of microorganisms,3.,调 理 性 受 体,(FcR,和,CR),C3b,、,C4b,、,iC3b,与吞噬细胞表面,CR1,、,CR3,和,CR4,结合，促进吞噬,。,4.Signaling PRR,针对细胞外病原体,-TLRs(Toll-like receptors),针对细胞内病原体,-NLRs(NOD-like receptors),-RLHs(RIG-like helicases),Toll-like receptors(TLRs),ridge-abdominal pattern of fly foetus,TOLL,蛋白最早在果蝇中发现,是一种,I,型跨膜受体,可介导真菌和,G+,细菌对果蝇的感染免疫反应。,LRR domain:leucinerich repeats domain,TIR domain:TOLL/IL-1R,Toll-like receptors(TLRs),Means of detecting,invasion by microorganisms,Recognize,Specific pattern of microbial components conserved among pathogens,Patterns not found in mammals,到目前为止,在哺乳动物细胞中已发现,11,种与,TOLL,蛋白同源的蛋白,命名为,TOLL,样受体,(TLR),。,LRR,TIR,G+bacterialria,lipoteichoic acid,PG,TLR-Ligand,AP-1,NF-,k,B,IRF-3,IRF-7,Kinases,Zytokine,Kostimulatorische,Molekle,siRNA,Quantitative mRNA Expression of TLRs 1-10 in Human PBMC Subsets,TLR1,主要在单核细胞、中性粒细胞、,B,细胞、自然杀伤细胞,(NK,细胞,),上表达,;,TLR2,、,TLR4,和,TLR5,主要表达于除,T,、,B,、,NK,细胞以外的免疫细胞,;,TLR3,主要表达于幼稚的树突状细胞,(DC);,TLR6-9,广泛表达于多种细胞,;,TLR10,主要表达于淋巴样组织中和脾脏细胞。,Cellular expression of TLR,R&D systems,Release of LPS(Endotoxin)from the Gram-Negative Cell Wall,LPS,PGN,Peptidoglycan(PGN)is an essential and unique component of the bacterial envelope that provides rigidity and structure to the bacterial cell.,All bacteria contain a layer of PGN,but the amount,location and specific composition vary.,PGN is perceived in animals via various pattern recognition receptors(PRRs),including scavenger receptors,nucleotide-binding oligomerization domain-containing proteins(NODs),a family of peptidoglycan recognition proteins(PGRPs),PGN-lytic enzymes and Toll-like receptor TLR2,Flagellin,Flagellin consists of a conserved domain that is widespread in bacterial species and is dedicated to filament polymerization.,Mammalian hosts detect the conserved domain on flagellin monomers through Toll-like receptor(TLR)5,which triggers proinflammatory and adaptive immune responses,CpG-DNA,DNA from bacteria has stimulatory effects on mammalian immune cells,which depend on the presence of unmethylated CpG dinucleotides in the bacterial DNA.,In contrast,mammalian DNA has a low frequency of CpG dinucleotides,and these are mostly methylated;therefore,mammalian DNA does not have immuno-stimulatory activity.,CpG DNA induces a strong T-helper-1-like inflammatory response.,CpG DNA is recognized by Toll-like receptor 9.,Modified nucleic acid,Double-stranded RNA(dsRNA),Double-stranded RNA(dsRNA)arises in the cytoplasm during viral replication.,Besides the intracellular recognition,released dsRNA from dying,infected cells can function as a pathogen-associated molecular pattern(PAMP)for the innate immune system.,dsRNA is recognized by TLR3.,病原真菌,白色念珠菌表面的特征性糖磷脂甘露聚糖可被,TLR2,、,TLR4,识别,诱导促炎性细胞因子的释放,促进中性粒细胞的聚集。,新型隐球菌的多糖荚膜成分葡糖醛氧化甘露聚糖,GXM,可与,TLR2,、,TLR4,、,CD14,结合,在单核细胞、巨噬细胞对,GXM,的内化、吞噬中起重要作用。,酿酒酵母胞壁成分酵母多糖则可激活,TLR2,、,TLR6,异源二聚体。,4.Signaling PRR,针对细胞外病原体,-TLRs(Toll-like receptors),针对细胞内病原体,-NLRs(NOD-like receptors),-RLHs(RIG-like helicases),Intracellular sensors,NOD-like receptors,RIG-like helicases,LRR,NODs,NOD,(nucleotide-binding oligomerization domain)proteins,NOD1,recognizes peptidoglycan containing the muramyl dipeptide NAG-NAM-gamma-D-glutamyl-meso diaminopimelic acid(,mesodiaminopimelic acid,DAP,),part of the peptidoglycan monomer in common gram-negative bacteria and just a few gram-positive bacteria.,NOD2,recognizes peptidoglycan containing the muramyl dipeptide NAG-NAM-L-alanyl-isoglutamine(,muramyl dipeptide,MDP,)found in practically all bacteria.,As macrophages phagocytose either whole bacteria or peptidoglycan fragments released during bacterial growth,the peptidoglycan is broken down into muramyl dipeptides,.Binding of the muramyl dipetides to NOD1 or NOD2 leads to,the activation of genes coding for proinflammatory cytokines,in a manner similar to the cell surface toll-like receptors.,Effect of PAMP recognition,activation of innate effector mechanisms,phagocytosisantimicrobial peptide synthesisinduction of NO in macrophages,induction of inflammatory effector cytokines and chemokines,induction of co-stimulatory molecules on surface of APC (B7.1+B7.2),Pattern recignition and Innate protection,Overview,Pattern recognition,Negative regulation of pattern recognition,Significance of patter recognition,PRR and human diseases,Negative regulation of pattern recognition,Soluble TLRs:sTLR2,sTLR4,Intracellular negative regulators:MyD88s,IRAKM,SOCS1,NOD2,PI3K,TOLLIP and A20,Transmembrane protein regulators:ST2,SIGIRR and TRAILR,Reduction of TLR expression:,-promote the degradation of TLRs:TRIAD3A(TLR4 and TLR9),-inhibit TLR expression:IL-10,TGF-,b-1(,TLR4 expression,MyD88 degradation),Regulation of TLR effect by apoptosis:TLRs function as death receptors,Soluble TLRs,Intracellular TLR regulators,Transmembrane TLR regulators,ST2L:,interacts with MyD88 and MAL.,SIGIRR,(single immunoglobulin interleukin-1-related receptor)binds to TLR4 and IRAK.,TRAILR,suppresses NF-B activation.,Toll-like receptors induce apoptotic and anti-apoptotic pathways,Pattern recignition and Innate protection,Overview,Pattern recognition,Negative regulation of pattern recognition,Significance of patter recognition,PRR and human diseases,Significance of pattern recognition,clean up pathogens and maintain tolerance.,initiate innate immunity and induce inflammation,Control adaptive immunity,-trigger adaptive immunity,-determine types of immune response,-participate in effector reponse of adaptive immunity,Distinction of non-self from self,The recognized structures(PAMP)must be absolutely distinct from self antigens:discrimination of self vs.non-self.,Alarmins are produced and released by host who can be recognized and cleaned up by pattern recognition.,Maintain tolerance,induce PPAR,g,expression,Innate and adaptive immunity,Cytokines,Chemokines and Growth Factors,Production modulated by PRR,engagement,Important in recruitment of innate effector cells,May be paracrine and/or endocrine,Form basis for cellular communication,Inflammation,Activation of a B-lymphocyte by way of LPS Binding to Toll-like Receptors,TI-1 antigens are PAMPs which activate B-lymphocytes by binding to their specific TLRs rather than to B-cell receptors.Antibody molecules generated against TI-1 antigens are often called natural antibodies because they are always being made against bacteria present in the body.,Production of Co-stimulatory Molecules by Antgen-Presenting Cells(APCs),These co-stimulatory molecules are only synthesized when toll-like receptors on APCs bind to PAMPs of microbes.,Without innate immune responses there could be no adaptive immunity.,DCs Activated with Different TLR Ligands Elicit Distinct Th Responses,Participation in effector reponse of adaptive immunity,Pattern recignition and Innate protection,Overview,Pattern recognition,Negative regulation of pattern recognition,Significance of patter recognition,PRR and human diseases,Garbage in and garbage out.Put the good stuff in,and youll get the good stuff out.,OVER THE TOP,-Zig Ziglar,