W+天然免疫

Innate Immunity,秦志海, M.D.Lab phone: 64888435E-mail: ,How do organisms defend themselves against disease?,PAMPs: Pathogen-associated molecular patternsPRRs: Pattern-Recognition Receptors,Progression of Immunity,Innate Immunity,General features of Innate ImmunityMajor cell players Macrophage Neutrophil Natural Killer (NK) cells Mast cellPattern-Recognition Receptors (PRRs)Complement,Russian embryologist and immunologist; founder of comparative immunology whose influential phagocytosis theory was the starting point of Innate Immunology.,lie Metchnikoff (1845-1916),Immunologist at Yale University whose research has had a profound effect on the understanding of the immune system, who studied innate immunity (the bodys first natural defenses against infection) and how T-cells react with pathogens, and who wrote the textbook “Immunobiology: The Immune System in Health and Disease”,Charles A Janeway(1943-2003),Components of Innate Immunity,Components Principle FunctionsBarriersEpithelial layers Prevent entryDefensins and Cryptdins Microbial killingCirculating and Tissue Effector CellsMacrophages Efficient phagocytosis and killing of microbes: cytokinesNeutrophils Early phagocytosis and killing of microbesMast Cells Release of inflammatory granulesEosinophils Nasty toxic cells designed to kill helminths (worms)Natural killer cells Lysis of infected cells, activation of macrophagesCirculating ProteinsComplement (C) Killing of microbes, opsonization of microbes, activation leukocytesMannose binding protein Opsonization of microbes and activation of CC-reactive protein Opsonization of microbes and activation of CLysozyme Bacterial cell wall lysisCytokinesTNF, IL-1, 6, 18 InflammationIFN, Resistance to viral infectionIFN Macrophage activationIL-12 IFN production by NK cellsIL-15 Proliferation of NK cells, memory T cellsIL-10, TGF Control of Inflammation,Neutrophils,Macrophages,B Cells,T Cells,Humoral Immunity,Cell-Mediated Immunity,Innate Immunity,Adaptive Immunity,Microbial Pattern Molecules Specific Antigens + Co-stimulationRapid Response Delayed ResponseNo Memory Memory,Innate vs Adaptive Immunity,CD4+,CD8+,Dendritic cells,Nature Killer cells,天然免疫与特异性免疫的识别特点 识别特点 天然免疫 特异性免疫 识别抗原种类 仅识别微生物 既可识别微生物分子抗原 和靶分子结构 及其产物的组分（PAMP） 也可识别非微生物抗原识别的特异性 泛特异性 高度特异性 识别不同种类的微生物 微生物的不同抗原表位 识别受体基因 在胚系中编码 在个体发育过程中重排 （BCR体细胞基因突变） 识别受体分布 非克隆化 克隆化,The front line of host defense,Example: Complement (C),Example: Interferon,“Great Wall” of Host Defense,Phagocytes are the Most Important Cells,Phagocytes: Macrophage,Phagocytosis, Intracellular and extracellular killing, Tissue repair, Antigen presentation for specific immune response,Secreting cytokines.,The macrophage is the large, yellowish cell with projections; the bacterial cells are small, rod-like, blue cells.,Macrophages are important first responders to infection and tissue damage,Alveolar macrophages (lung) Histiocytes (connective tissue) Kupffer cells (liver) Mesangial cells (kidney) Microglial cells (brain)Tissue macrophage,Different names,Macrophages phagocytose and degrade foreign particles,bacteria and dead (and dying) host cells.,Receptors on Macrophages:LPS receptor-CD14Toll-like receptorsFc receptorsMannose receptorComplement receptorsIFNg receptorChemokine receptors,Recruitment and activation of phagocytes,Inflammation,Figure 2-9,Recruitment,Phagocytosis,Microbicidal mechanisms of phagocytes,Cytokine production,Macrophages: friends or foes?,Current Opinion in Immunology 2010, 22:231237,Orchestration of TAM in cancer promoting inflammation,Macrophages, innate immunity and cancer,Current Opinion in Immunology 2010, 22:231237,MDSC在体内的积聚需要TNF受体的激活,Zhao X, Qin ZH et al., 2012, J Clin Invest,Phagocytes: Neutrophils,Function:phagocytosis, intracellular killing, inflammation/tissue damage Characteristic: nucleus, cytoplasm,granules,CD66 marker,Express some of the same receptors found on macrophages. These cells are specialized in killing and swallowing microbes.,LPS receptor:CD14toll-like receptor-4CR3,4:Complement (C) receptors (C3b)Scavenger receptor:sialic acid-bearing proteinMannose receptor:Binds mannose on bacteria, activates CGlycan receptor:PolysaccharidesIN ADDITION: TLRs,Phagolysosome formation,Neutrophil 30 minutes after ingestion of C. albicans. The cytoplasm is already partly degranulated and two lysosomal granules (arrowed) are fusing with the phagocytic vacuole.,Mast cells induce an inflammatory cascade,Mast cells can also secrete:Cytokines to induce inflammationChemokines to induce infiltration by monocytes, and neutrophilsLeukotrienes to induce muscle contraction and increase vascular permeability,NK cells are large granular lymphocytes (LGL),Kill infected and malignant cellsIdentified by the presence of CD56 & CD16Absence of CD3Activated by IL2 and IFN- to become LAK cells,Regulation of NK Cell Function,The mononuclear phagocyte system,Transcriptional regulation of macrophage polarization: enabling diversity with identity. - Focus on: Monocytes and macrophages. Nature Rev. Immunol. 2011,Myoloid colony-forming units,Pattern recognition in the innate immune system,Pathogen associated molecular pattern, PAMP,一类或一群特定的微生物病原体（及其产物）共有的某些非特异性、高度保守的分子结构，其可被特异性免疫细胞所识别。病原微生物所特有微生物生存和致病性所必需宿主泛特异性识别的分子基础,Pattern-Recognition receptor，PRR,是一类表达于天然免疫细胞表面、非克隆性分布、可识别一种或多种PAMP的识别分子。调理作用吞噬作用启动细胞活化和炎症信号转导诱导凋亡,循环在体液中的体液成分：急性期反应蛋白或补体细胞表面表达的胞吞受体：清道夫受体、凝集素受体调理吞噬细胞的受体：Fc、补体受体信号转导受体：TLR、NLR、RLR,PRR分类,Mannose-binding lectin （MBL）,Mannose-binding lectin recognizes bacterial surfaces by their particular spacing of carbohydrate.,甘露糖结合凝集素,PRR,Toll mutant lacks defense against fungal infections18 Wheeler lacks defense against bacteriaThis led to the discovery of a family of receptors known as the Toll-related receptors (TLR) present in vertebrates,Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product.Anderson KV, Jrgens G, Nsslein-Volhard C.Cell. 1985 Oct;42(3):779-89.,Christiane Nsslein-Volhard (born October 20, 1942 in Magdeburg) is a German biologist who won the Albert Lasker Award for Basic Medical Research in 1991 and the Nobel Prize in Physiology or Medicine in 1995, together with Eric Wieschaus and Edward B. Lewis, for their research on the genetic control of embryonic development.,Immunity in Drosophila (Innate),1980，Nusslein-Volhard， Nature在研究果蝇胚胎发育过程中发现有一个基因决定着果蝇的背腹侧分化，将其命名为Toll基因。1988年，Hashimoto， Cell，Toll基因编码一种跨膜蛋白质，并阐明了Toll蛋白的结构。1991，Gay，NatureToll蛋白在结构上与哺乳动物中一种天然免疫功能分子白细胞介素受体1 （IL-1）具有同源性：二者的细胞质部分相似。1994，Nomura，DNA Res首先报道了人中的Toll样受体。1996，Jules A. Hoffmann，Cell发现Toll在果蝇对真菌感染的免疫中起着重要作用，从而确立了Toll的免疫学意义。1997年，Charles Janeway和Ruslan Medzhitov， Nature阐明了一种Toll样受体（后来被命名为TLR4）能够激活与适应性免疫有关的基因。1998，Bruce A. Beutle，ScienceTLR4能够探测LPS的存在。小鼠中的TLR4突变而丧失功能，小鼠不会对LPS起反应。,TLR的发现,Toll receptors in Drosophila were discovered first, and shown to confer resistance to bacteria and fungi by regulating the expression of anti-microbial peptides.,Toll family of receptors is evolutionarily ancient,10,The toll like receptors in humans,Non-specialized cells can detect and respond to infection by recognizing conserved motifs of microbes using TLRs,The effects of bacterial LPS on macrophages are mediated by CD14 binding to TLR-4,TLRs transmit signals about microbial constituents detected to the nucleus, thus regulating the type of genes expressed, and the subsequent response,Contributions of innate immunity to adaptive immune responses,Enhance Antigen Presentation,UpregulateCo-stimulatoryMolecules,IncreaseCytokineproductions,ActivatePhagocytosis,PRR ligands shape adaptive T cell immunity through direct and indirect effects on DCs,Immunity 33, October 29, 2010,Activation of Toll-like receptors triggers the production of pro-Inflammatory cytokines and chemokines, and the expression of co-stimulatory molecules,Nature 442, 39-44, 2006,NLR: nucleotide binding and oligomerization domain (NOD)-like receptor,Nature Reviews Immunology 6, 9-20, 2006,Cellular location of TLRs and NOD1 and NOD2,most Gram-negativespecific Gram-positive bacteria,all types of PGN,Immunity, 27,549-559, 2007,Model for PGN Recognition by NOD1 and NOD2,Role of NOD1 and NOD2 in Host Defense,Mice with a targeted deletion of the Nod1 gene display an increased susceptibility to Helicobacter pylori (Nat. Immunol. 2004).Activation of NOD1 stimulates the production of chemokines and the recruitment of neutrophils in vivo (J.Exp. Med. 2006).NOD1 has been implicated in priming antigen-specific T cell responses, thereby contributing to the onset of adaptive immunity (Immunity. 2007).Increased bacterial burdens were observed in Nod2-/- mice infected orally, but not through the intravenous and intraperitoneal routes, with Listeria monocytogenes (Science, 2005).NOD1 and NOD2 may perform unique and critical antibacterial functions in intestinal cells such as regulation of antimicrobial peptides (Science, 2005; Nat.Genet 2006).,52,RIG-I样受体： RIG-I-like receptors, RLRs,识别细胞质中的病毒RNARIG-IMDA-5LGP-2,The Nobel Prize in Physiology or Medicine 2011,Bruce A. Beutler and Jules A. Hoffmann for their discoveries concerning the activation of innate immunity Ralph M. Steinman for his discovery of the dendritic cell and its role in adaptive immunity,Complement System,History,Discovered in 1894 byJules Bordet It represents lytic activity of fresh serumThe activity of blood serum thatcompletes the action of antibody Its lytic activity destroyedwhen heated at 56 for 30 min,Complement functions,Host benefit:Opsonization to enhance phagocytosisPhagocyte attraction and activationLysis of bacteria and infected cellsRegulation of antibody responsesClearance of immune complexesClearance of apoptic cellsHost detriment:Inflammation, anaphylaxis,Activated component are usually over-lined: e.g. C1qrsWhen enzymatically cleaved, the larger moiety, binds to the activation complex or membrane and the smaller peptide is released in the microenvironmentLetter “b” is usually added to the larger, membrane-binding, peptide “a” to the smaller peptide (e.g., C3b/C3a, C4b/C4a, C5b/C5a), EXCEPT C2 (the larger, membrane-binding moiety is C2a; the smaller one is C2b),Pathways of complement activation,CLASSICALPATHWAY,ALTERNATIVEPATHWAY,LECTINPATHWAY,Components of the Classical Pathway,C4,C2,C3,C1 complex,Figure 2-21,Binds to antibody:antigen complex,C1q binds to antibody:antigen complexes, thus it recruits complement to antigen tagged by antibody,Figure 7.30,Figure 2-22,For MB lectin MASP1/2cleave C4,The rest is the same,Complement activation is a proteolytic cascade, in which one protease activates by proteolysis the next protease,Zymogen= inactive enzyme that is activated by proteolysis,Components of mannose-binding lectin (MBL) pathway,C4,C2,MASP1,MASP2,MASP2: mannan-binding lectin serine peptidase 2,Figure 2-24,Mannose binding lectin is an innate recognition molecule that recruits complement,Mannose-binding lectin pathway,C4,C2,C4b2a is C3 convertase; it will lead to the generation of C5 convertase,MASP1,MASP2,Components of thealternative pathway,C3,B,D,P,Spontaneous C3 activation,C3,H2O,B,D,Generation of C3 convertase,C3iBb complex has a very short half life,C3,Complement activation includes feed forward amplification steps,Macrophages, neutrophils and other white blood cells carry C3b receptors that they use to rapidly phagocytose and destroy microbes.,C3b regulation on self and activator surfaces,C3b,C3b,C3b,C5-convertase of the two pathways,C3b,Bb,C3b,C5-convertase of the Alternative Pathway,C5-convertase of the Classical and lectin Pathways,Generation of C5 convertase leads to the activation of the Lytic pathway,Lytic pathway,Biological effects of C5a,Opsonization and phagocytosis,三条激活途径的主要不同点,补体的生物学作用,溶菌及溶靶细胞作用： G(-)菌、RBC、粒细胞、血小板和病毒感染的细胞等调理作用：C3b、C4b以及 iC3b 氨基端与靶细胞结合，羧基端与相应受体结合清除免疫复合物：粘附到带有C3b受体的细胞表面（主要是 红细胞），最终达到清除免疫复合物的作用炎症介质作用： 激肽样作用：C2a、C3a、C4a,增加血管通透性 过敏毒素作用： C3a、C5a 趋化作用： C3a、C5a以及C567可吸引吞噬细胞定向移动免疫调