模式识别受体PPT演示课件

1、1innate immune recognition2threats to the individual3protection from microbial invasion45nobel prize 2011 innate immunity6nobel prize 2011njules a. hoffmann: in 1996, found “toll” gene has a role in the flys immunity to fungal infections. nbruce a. beutler: in 1998, bruce a. beutler and colleagues d

2、iscovered that the toll-like receptors (tlrs) act as the principal sensors of infection in mammals. nralph m. steinman 1973，ralph steinman isolate dentritic cell)。 dc can activate t cell. dc is the birdge between innate immunity and adaptive immunity.7toll pathwaydrosophila8they all deserve the nobe

3、l prizeruslan medzhitovcharles janeway 19432003 takashi fujita, shizuo akira prrtlrrlryale univ.yale univ.kyoto univ., osaka univ. 9pathogen associated molecular patterns, pampsconserved pattern found only in pathogens, not in host cells。 (charles jenaway 1989，at cold spring harbor meeting)typical p

4、amps：1、glycans：g- bacteria (lipopolysaccharide, lps）; g+ bacteria (peptidoglycan)； bacterial flagellin2、nucleotide: virus dna/rna.10pampsglucanpeptidoglycanlps flagellin。11pattern recognition receptors, prr：receptors, on the surface or inside the cells, for those pathogen associated molecule pattern

5、s. types of prrs：toll-like receptors; tlrsrna sensor（rig-i, mda5）dna sensor（aim2，dai）nod-like receptors； nlrsc-lectin receptorsother prrs 12prr-pamps engagement activates phagocytes13toll like receptor （tlr）nnature. 1997 jul 24;388(6640):394-7.na human homologue of the drosophila toll protein signal

6、s activation of adaptive immunity.nmedzhitov r, preston-hurlburt p, janeway ca jr.nsourcensection of immunobiology, yale university school of medicine, new haven, connecticut 06520-8011, usa.nabstractnwe report here the cloning and characterization of a human homologue of the drosophila toll protein

7、 (toll) which has been shown to induce the innate immune response in adult drosophila. like drosophila toll, human toll is a type i transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (lrr) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of th

8、e human interleukin (il)-1 receptor. both drosophila toll and the il-1 receptor are known to signal through the nf-kappab pathway. we show that a constitutively active mutant of human toll transfected into human cell lines can induce the activation of nf-kappab and the expression of nf-kappab-contro

9、lled genes for the inflammatory cytokines il-1, il-6 and il-8, as well as the expression of the co-stimulatory molecule b7.1, which is required for the activation of naive t cells.pubmed search “toll like receptor” 24700 papers141-1) cellular distribution of tlrscell membraneendosome membrane15prrs

10、in pmn161-2) tlrs expression in cellsimmune cells and some epithelia cells express tlrs 17tlrs expressed in immune cells181-3) structure of tlrs* homo-or heterodimers, or together with other molecules 191-4) tlrs signaling pathway：myd88 dependent pathway: all tlrs except 3 myd88 independent pathway:

11、tlr3; part of tlr4effector genes20tlrs signaling pathway：21tlrs signaling pathway：221.5) negative regulation of tlrs signaling231-6) role of tlrs in immune responseninnate immunity:activate phagocytosis and killing: regulated expression of genes of phagocytosis promoting secretion of cytokines/ chem

12、okines : il1, il6, tnfa, ifns, cxcls, ccls (recruit other immune cells)promote secretion of anti-peptide: eg: defensins241-6) role of tlrs in immune responsenadaptive immunity:tlrs induce dc maturation: cytokine secretion; costimulatory molecules - dc activation - present antigen to activate t cells

13、tlrs signaling influences th cell differentiation: to influence the differentiation of t cells: th1, th2, th17tlrs induce treg activation: regulatory t cells treg express tlr4/5/7/8, tlr signal directly involved in the biological function of tregb cell activation (eg: cpg dna tlr9 ligands may be use

14、d as adjuvant)252-1）rna sensors（tlrs and rlrs）rig-i like receptors（rlr）：rig-imda-5lgp2。fujita tnat immunol. 2004 j immunol 2005262-2） structure of rig-irig-i 结合 5-ppp dsrna27mavs： adapter for rig-inseth, r.b., sun, l., ea, c., and chen, z.j., identification and characterization of mavs: a mitochondr

15、ial antiviral signaling protein that activates nf-b and irf3. cell, 122:669-682, 2005 prion-like protein fight off viruses: mavs, cell 2011university of texas southwesternhhmi282-3）rig-1/mda-5 signaling pathway292-4） regulator of rig-i/mda-5 30ubiquitin (泛素）对泛素）对prr信号的调节信号的调节泛素由泛素由76个氨基酸残基组成，其中包括个氨基

16、酸残基组成，其中包括7个赖氨酸残基个赖氨酸残基(k), 其其c末端可与末端可与底物的赖氨酸残基形成异肽键，从而引起底物的赖氨酸残基形成异肽键，从而引起底物泛素化底物泛素化。泛素的。泛素的k11、k29、k48和和k63均能参与形成泛素与泛素间的异肽键均能参与形成泛素与泛素间的异肽键 (isopeptide bond)。3031ubiquitination for rig-i signalingk63泛素化：激活k48泛素化：降解back323-1） dna sensor dna sensor： tlr9； pol iii； dai； aim2334-1） nod like receptors（

17、nlrs）nlrs： c端：亮氨酸重复序列 （lrr）中间：nacht： 寡聚体化，活化n端：card，pyd：相互作用344-2）nlrs activtes inflammasomepamp通过nlrs激活炎症反应35nlrc4 inflammasome 邵峰北京生命科学研究所shao f. (2011) nature, 477, 596600. 365-1）c-lectin receptor familyndectin-1， mannose receptors （mrs）375-2） the fungal pattern receptor： dectin-1one such subfami

18、ly is the dectin-1 clusterwhich is primarily, but not exclusively, expressed by myeloidcells macrophages, dendritic cells (dc) and neutrophils。385-2） the fungal pattern receptor： dectin-1back39dectin signaling pathway葡聚糖甘露聚糖甘露聚糖406-2）other prrsn清道夫受体（scavenger receptors）: 结合脂类，lps等n甲酸基多肽受体（formyl pe

19、ptide receptor)：结合含甲酸基的特殊氨基酸结构n补体受体（complement receptor）：41cross talk of prr signaling42cross talk of prr signaling43pathogen evasion of prr signaling pathwayneg: hcv interact with prrsfig1: structure of hcv44hcv interact with prrs45paper discussion （1）： role of tlr7 in wnv infection (town t et al.,

20、 2009 immunity; if20)ssrna dsrna (during replication) 46fig 1: increased susceptibility of tlr7/ and myd88/ mice, but not tlr9/ mice, after west nile virus challengewt: 50%死亡tlr7-/-: 90%死亡tlr7 ：抗病毒作用47fig 2. tlr7- and myd88-dependent viral load and innate immune cytokine responses after west nile vi

21、rus challenge：viral load: cytokine： il23, il12 48fig 3：immune cell homing to wnv-infected cells in vivo depends on tlr7green： wnv （more in tlr7 -/-）red： immune cells (less in tlr6 -/-)49immune cell hominghoming的意义：1、淋巴细胞得以合理的再分布及补充；2、增加抗原和淋巴细胞的接触机会，产生有效的免疫应答。(免疫细胞有效的迁移到受感染的部位)。50tlr7 dependant macro

22、phage homingless cell infiltration51fig 4. macrophage homing to west nile virus is il-23 signaling dependentmacrophagevirushoming issuebrain section staining52summary: tlr7 mediated anti-wnv functionimmune cell homingvirus clearance53paper discussion (2): caspase-12 controls west nile virus infectio

23、n caspase-12 controls west nile virus infection via the viral rna receptor rig-i. via the viral rna receptor rig-i. (wang p. et al., nature immunology (wang p. et al., nature immunology 2010)2010)caspase 12 -/- :less survival;severe neurological symptoms541) viral load in caspase 12-/- mice55 2) inf

24、b production in caspase12 -/- mice563) caspase12 interacts with rig-i/trim2557 4) less ub-rig-i in caspase 12-/- miceub- rig-i total rig-itotal trim2558story summary: caspase12 is required for rig-i ub ifnb production （caspase 12 的抗病毒作用）casp12eg: ifn production59paper discussion （3）： toll-like recep

25、tor 3 mediates west nile virus entry into the brain causing lethal encephalitis （tlr3 helps the virus?）wang t. et al., 2004 nature medicinewt: 0% survivaltlr3-/-: 40% survivaltlr3的存在 增强了病毒感染602） tlr3-/- mice have viral load in blood; but tnfa, il6613) tlr3-/- have viral in brain （tlr3-/- 血液里virus多，但

26、virus不能有效进入大脑。）624) reduced brain tissue damage in tlr3-/- mice炎性细胞渗入减少635） bbb permeability increased in wt but in tlr3-/- mice after wnv infection 血脑屏障被打开血脑屏障相对完好virus 难以进入tlr3-/- 小鼠脑部。646） tnfa is important for bbb breakdown1） tnfa -/-鼠，wnv感染死亡率下降2） il6-/- 鼠，没差异3）tnfa-/- 鼠， bbb保持相对完好tnfa是破坏bbb的细胞

27、因子65summary： tlr3 helps wnv enter the brain via tnfa* 免疫分子往往是把双刃剑血液- 大脑66paper discussion 4: tlr and agingj immunol. 2010 mar 1;184(5):2518-27. panda a, et al， yale university school of medicine age-age-associated decrease in associated decrease in tlr function in primary human dendritic cells predi

28、cts influenza vaccine function in primary human dendritic cells predicts influenza vaccine response.response.fig1. tlr expression in dcs67fig 2. less cytokine production in old68fig 3. vaccine efficiency in young and old populationvaccine efficiencyyoungoldresponses to influenza vaccination in older

29、 adults and young adults.69paper 4 summaryn1. less tlr expression in oldn2. tlr signaling are less responsive in oldn3. defect of tlr signaling resulted in vaccine failure in old 70paper discussion 5:ddx24 negatively regulates cytosolic rna-mediatedinnate immune signaling7172 ddx24 interact with fad

30、d73ifn induce ddx24 expression74ddx24 inhibit ifn production75silence ddx24， ifn production increased76figure 3 sirna-mediated knockdown of ddx24 enhances dsrna induced rlr signaling.(g) gene array indicating most up-regulated genes in meftreated with poly i:c at 3 hours and 9 hours vs non treatment

31、. data from (a)(b)(c)(d)(e)(f) are presented as means6s.e. from three independentexperiments. * indicates p,0.05. * indicates p,0.01.doi:10.1371/journal.ppat.1003721.g00377figure 4. sirna-mediated knockdown of ddx24 inhibits vsv replication.78figure 4. sirna-mediated knockdown of ddx24 inhibits vsv replication.(f) loss