醫(yī)學(xué)免疫學(xué)英文版教學(xué)課件：Chapter 10 Innate immunity

1、趙 偉教授，醫(yī)學(xué)博士醫(yī)學(xué)院免疫學(xué)系6540研究領(lǐng)域：固有免疫調(diào)控、抗病毒免疫E-mail: wzhao個人簡介學(xué)習(xí)、工作經(jīng)歷2004 固有免疫調(diào)控1996-2001 第二軍醫(yī)大學(xué)海醫(yī)系 學(xué)士2001-2004 第二軍醫(yī)大學(xué)長海醫(yī)院 碩士2004-2007 第二軍醫(yī)大學(xué)免疫所 博士2008-2011 山東大學(xué)醫(yī)學(xué)院 博士后2011-2013 山東大學(xué)醫(yī)學(xué)院 講師 2013.9至今 山東大學(xué)醫(yī)學(xué)院 教授 (破格)Pathogens（病原）Innate Immunity（固有免疫）(NK cells, DC, Neutrophils, Monocytes/Macrophages)Adaptive I

2、mmunity（適應(yīng)性免疫） (T and B Lymphocytes)機體如何檢測病原的存在，并在不傷害自身組織的前提下清除它們（識別自我和非我）？固有免疫真的是非特異的嗎？獲得性免疫由經(jīng)過克隆選擇的T&B淋巴細胞介導(dǎo)特點是特異性和記憶效應(yīng)固有免疫長期以來被認為是非特異性的免疫反應(yīng)現(xiàn)在研究發(fā)現(xiàn)固有免疫具有相當(dāng)?shù)奶禺愋钥梢宰R別自我和非我區(qū)別不同的病原固有免疫也被認為是獲得性免疫的始動環(huán)節(jié)CHALLENGE: How can the host discriminate large numbers of diverse pathogens from each other &/or from sel

3、f using a restricted number of receptors? 通過有限的受體迅速識別大量不同的病原體并作出應(yīng)答？SOLUTION模式識別理論及TLR4的發(fā)現(xiàn)Charles A. Janeway Jr（1943-2003）模式識別理論將固有免疫針對主要靶分子信號稱作病原相關(guān)的分子模式（Pathogen-associated molecular pattern, PAMP）；相對應(yīng)的識別受體稱為模式識別受體（pattern recognition receptor, PRR）。PAMP分子結(jié)構(gòu)在進化中高度保守，是病原體生存和產(chǎn)生致病性必需的，并且能被免疫細胞所識別。TLR4的

4、發(fā)現(xiàn)Bruce A. Beutler Jules A. HoffmannRuslan Metzhitov Nobel Prize 2011 EKF Immunology Award 20134,000,000Nobel Prize 2011模式識別受體(Pattern-recognition receptors, PRRs)Toll like receptors (TLRs)RIG-I-like receptors (RLRs) NOD-like receptors (NLRs)C-type lectin receptors (CLRs)DNA sensors研究領(lǐng)域：固有免疫調(diào)控我們發(fā)現(xiàn)的固

5、有免疫信號通路調(diào)控分子Selected Publications1. Huai W#, Zhao R#, Song H, Zhao J, Zhang L, Zhang L, Gao C, Han L*, Zhao W*. Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription. Nat.Commun. 2014; 5:4738.2. Song H#, Huai W, Yu Z, Wang W, Zhao J, Zhang L, Zha

6、o W*. MLN4924, a first-in-class NEDD8-activating enzyme inhibitor, attenuates IFN- production. J. Immunol. 2016; Feb.19. 3. Huai W#, Song H, Wang L, Li B, Zhao J, Han L, Gao C, Jiang G, Zhang L, Zhao W*. Phosphatase PTPN4 preferentially inhibits TRIF-dependent TLR4 pathway by dephosphorylating TRAM.

7、 J. Immunol. 2015;194(9):4458-65.4. Zhang M#, Wang L, Zhao X, Zhao K, Meng H, Zhao W*, Gao C*. TRAF-interacting protein (TRIP) negatively regulates IFN- production and antiviral response by promoting proteasomal degradation of TANK-binding kinase 1. J.Exp.Med. 2012; 209(10):1703-11. 5. Wang L#, Zhan

8、g L#, Zhao X, Zhang M, Zhao W*, Gao C*. Lithium attenuates IFN- production and antiviral response via inhibition of TANK-binding kinase 1 kinase activity. J. Immunol. 2013; 191(8):4392-4398.6. Zhao W#, Wang L, Zhang M, Yuan C, Gao C*. E3 Ubiquitin Ligase Tripartite motif 38 negatively regulates TLR-

9、mediated immune responses by proteasomal degradation of TNF receptor-associated factor 6 in macrophages. J. Immunol. 2012;188(6):2567-2574. 7. Zhao W#, Wang L#, Zhang M#, Wang P, Yuan C, Qi J, Meng H, Gao C*. Tripartite motif-Containing protein 38 negatively regulates TLR3/4- and RIG-Imediated IFN-

10、production and antiviral response by targeting NAP1. J. Immunol. 2012;188(11):5311-5318. 8. Zhao W#, Wang L, Zhang M, Wang P, Qi J, Zhang L, Gao C*. Nuclear to cytoplasmic translocation of heterogeneous nuclear ribonucleoprotein U enhances TLR-induced pro-inflammatory cytokines production by stabili

11、zing mRNAs in macrophages. J. Immunol. 2012;188(7):3179-3187. 9. Zhao W#, Wang L#, Zhang M, Wang P, Zhang L, Yuan C, Qi J, Qiao Y, Kuo PC, Gao C*. NF-B and AP-1 mediated DNA looping regulates osteopontin transcription in endotoxin-stimulated murine macrophages. J. Immunol. 2011;186(5):3173-3179. 10.

12、Zhao W*. Negative regulation of TBK1-mediated antiviral immunity. FEBS. Lett. 2013; 587(6):542-548. Chapter 10Innate immunity Pathogens（病原）Innate Immunity（固有免疫）(NK cells, DC, Neutrophils, Monocytes/Macrophages)Adaptive Immunity（適應(yīng)性免疫） (T and B Lymphocytes )Effector Functions啟動抗原特異性反應(yīng)抗原遞呈細胞(APC)以MHC抗

13、原肽復(fù)合物的形式遞呈給T細胞雙信號：即特異性抗原的刺激和來自APC的共刺激信號 Innate immunity Part overview of innate immunityPart innate immune cellsPart functions of innate immunityPart I overview of innate immunity1. definition of innate immunity Protection against infections that relies on the mechanisms that exist before infection

14、and are capable of rapid response to pathogens . Innate immunity is the first line of defence against infection 2.Characteristicsset up at birthnonspecifichereditable rapid response no immune memory 3.Composition Barriers: Skin and mucosal barriers Internal barriersHumoral components: Complement Lys

15、ozyme CytoinesCells: Phagocytes (neutrophils, macrophages) natural killer cells(NK)1).BarriersSkin and mucosal barriers Physical barriers Chemical barriers Biological barriers: normal flora Internal barrier /Anatomic barrier blood-brain barrier blood-placental barrier blood-thymus barrier2).Humoral

16、components Complement Lysozyme Cytokine 3).Cells of the innate immunity NK cellsPhagocytes: neutrophils monocytes/macrophagesOthers: DC, basophils, mast cells, eosinophils, T cells, B1 cells, NKT cells 4.Recognition features of the innate immune systemRecognitionPattern recognition receptors, PRRs-

17、pathogen associated molecular pattern, PAMP PAMP:distinct structures or components that are common for many pathogens e.g. LPS, proteoglycan, N-formylated peptides, double RNA of viruses et al.Pattern-recognition receptors, PRRsToll like receptors (TLRs): TLR4/TLR3/TLR2RIG-I-like receptors (RLRs): R

18、IG-I、MDA5NOD-like receptors (NLRs): NALP3 (NLRP3) 、NALP1 (NLRP1)C-type lectin receptors (CLRs)DNA sensors: AIM2、DAI 、IFI16 、DDX41Cellular locations and structure of PRRsTLR signalingRLR SignalingNLRP3 inflammasomePart Innate immune cells -Immunocytes participating in innate immunityNK cellsPhagocyte

19、s: neutrophils monocytes/macrophagesOthers: DC, basophils, mast cells, eosinophils, T cells, B1 cells, NKT cells 1. Natural killer( NK )cells in innate immunity Concept : large lymphocytes which can directly kill tumor cells and virus-infected cells without induction of antigensSource: Bone marrow,

20、exist mainly in peripheral blood, spleen and liver.Characteristics:contain cytotoxic substancesSurface marker: no specific marker CD16(Fc R III), CD56, CD57 Functions: 1) Fighting infection and cancer killing virus infected cells and tumor cells directly and nonspecifically 2) Immunoregulation secre

21、ting INF-Natural killer cells (NK) Functions: 1) Fighting infection and cancer killing virus infected cells and tumor cells directly and nonspecifically 2) Immunoregulation secreting INF-1). Recognition (1). Direct recognition receptors Recognizing tumor cell and virus-infected cell(2). FcR Recogniz

22、ing Ab-bound target cell(1). Direct recognition receptorsNK cell activating receptors recognize the ligands on virus-infected cells and some tumor cells-transduce active signals to kill target cells Natural cytotoxicity receptors,NCR NKp30,NKp44,NKp46 NKG2DNK cell inhibitory receptors recognize the

23、MHC-I molecules on normal cells in normal condition,transduce inhibitory signals to inhibit the killing effect of NK cellActivation mechanisms of NK cellsITAM and ITIMITAM, immunoreceptor tyrosine-based activation motif, is a conserved motif of two copies of sequence tyrosine-X-X-leucine found in th

24、e cytoplasmic tails of various membrane proteins in the immune system that are invovled in signal transduction. When these recptors bind their ligands, ITAMs become phosphorylated and transduce activation signals.ITIM, immunoreceptor tyrosine-based inhibition motif, sequence of six amino acids (isol

25、eucine-X-tyrosine-X-X-leucine) motif found in the cytoplasmic tails of various inhibitory receptors in the immune system. When these recptors bind their ligands, ITIMs become phosphorylated and transduce inhibitory signals.(2). FcR Recognizing Ab-bound target cellADCC2. The mechanisms of killingPerf

26、orin and GranuzymePerforin: creates pores in target cell membranesGranzymes : enzymes which enter through perforin pores and induce apoptosis of target cells.Fas-FasL pathwayNK cellTarget cell2.Monocyte/ macrophageThe cell type of that enters the peripheral blood after leaving the marrow is incomple

27、tely differentiated and is called monocyte. Once they enter tissues, these cells mature and become macrophages. Macrophages are 5- to 10-fold larger than monocytes and contain more organelles, especially lysosomesProcess of phagocytosis Recognization Endocytosis Killing and digestion 1) Recognition

28、(1) Pattern recognition receptors(2) Opsonic receptorFcR the receptor for Fc region of Ab CR the receptor for complement component,C3b/4bMechanisms of opsonization2) EndocytosisActivated macrophages kill phagocytosed microbes by producing microbicidal molecules in phagolysosomeOxygen-dependent syste

29、m.Oxygen-independent system: -Low pH(3.5-4) , Lysozyme 3) killing and digestionFunctions of monocytes/macrophagesPhagocytosisPresentation of antigenInduction of inflammation and immune regulation3. Dendritic cellsDendritic cells are bone marrow-derived cellsClassification By source Myeloid DCLymphoi

30、d DCBy matureImmature DCMature DCEndocytosisNobel Prize 2011 Ralph Marvin Steinman(1943-2011)DC: activates nave T cells and then initiates adaptive cellular immune responsesFunction of DC :1. Capturing and processing antigens2. Presenting antigens During the maturation of DC , its ability of Ag capt

31、ure and processing decreased while its ability of Ag presenting give a rise.4.NeutrophilsNeutrophils, also called polymorphonuclear leukocytes, are the most abundant population of circulating white blood cells and mediate the earliest phases of inflammatory responses. An adult human produces more th

32、an 11011 neutrophils per day, each of which circulates in the blood for only about 6 hours.Morphology of neutrophils. The light micrograph of a blood neutrophil shows the multilobed nucleus, because of which these cells are also called polymorphonuclear leukocytes, and the faint cytoplasmic granules

33、.5.Other innate immune cellsBasophils/mast cellsEosinophilsT cellsB1 cellsNKT cells M cells(1).Basophils/mast cellsConnective tissueMast cellsBasophilsBloodExpressing high affinity FcR I on cellA large amount of basophilic granule in cytoplasm(2). Eosinophils.Regulation of type I hypersensitivity.In

34、volved in the immune responses against helminthsClassification according to TCR T cells: T cells: (3).T cellsComparison of T and T -Characteristics T cells T cells-TCR more diversity less diversity peripherial blood 85-95% 5-15%tissue peripherial lymphoid mucosa epithelia tissueSurface marker CD4+/C

35、D8+ (SP) CD4-CD8- (DN) CD8+ (a small amount)- CD5Two B cell lineagesBB cell precursorBMature B cellB2 cellsPlasma cellYYYYYYYYYPCIgGBYYYYYYYYYYYYYYYYYYYYIgM - no other isotypesBDistinct B cellprecursor?B1 cellsPrimitive B cells found in pleura and peritoneum(4).B1 cells-Comparison of B1 and B2 cells

36、- B1 B2 CD5 + - location thorax, abdominal cavity lymph organs lamina propria of intestine Recognized Ag TI Ag and auto-Ag TD Ag-特 性B1細胞B2細胞分化來源骨髓外骨髓分化標(biāo)志CD5+CD5-主要分布黏膜腔（胸腔和腹腔）外周免疫器官更新方式自我更新骨髓Th細胞輔助不需要需要抗體首次產(chǎn)生時間胚胎期出生后分泌Ig類型IgM各類Ig免疫記憶無有識別的抗原TI-AgTD-Ag、TI-Ag主要功能固有免疫適應(yīng)性免疫B1細胞和B2細胞的主要區(qū)別Surface marker：TCR、CD3，hCD56/ mNK1.1; 2.5% in total spenic T cells, 30% in liver T cells 。Origin and maturation： NKT maturation in thymus CD4+CD8+ pre-T cells epress TCR and