细胞生物学免疫细胞与炎症信号20课件.ppt

1、Contents 1.Brief Introduction of Immunology2.Immune Cells*Development of Immune cells*Types of Immune cells (Innate and adaptive cells)*Unique characters and Functions of Innate Immune Cells:Phagocytosis/Inflamation/antigen process and presentation/What is Immunity?感染&免疫We are not alone!Originally f

2、ocused on protection from Infectious DiseasesCommensal flora (共生菌群)staph,strep,pneumonia(葡萄球菌，链球菌，肺炎)Opportunistic pathogens(条件致病菌)candida,Clostridium difficile(念珠菌，艰难梭状芽胞杆菌)True pathogens(致病菌)-InfluenzaEdward Jenner Portrait by John Raphael Smith.Reproduced courtesy of Yale University,Harvey Cushin

3、g/John Hay Whitney Medical Library.Used the knowledge gained to develop vaccines to stimulate the body to provide protection from infections明隆庆年间（1567-1572），鼻苗法预防天花 清海藏癍论萃英Some vaccines have almost eliminated certain highly dangerous contagious infectious diseasesSmallpox：天花；Diphtheria：白喉；Polio：脊髓灰质

4、炎；Measles：麻疹；SSPE:亚急性硬化性全脑炎Available Vaccines(白喉)(破伤风)(百日咳)(副伤寒)(斑疹伤寒)(霍乱)(结核)(伤寒)(脑膜炎)(细菌性肺炎)(脑膜炎)(黄热病)(麻疹)(流行性腮腺炎)(风疹)(脊髓灰质炎)(水痘)(流感)(狂犬病)(甲肝)(乙肝)(乳头状瘤病毒)(轮状病毒)(疟疾)(血吸虫病)(蠕虫病毒侵扰)(结核病)(腹泻病)(呼吸系统疾病)(麻疹)(丙肝)Particularly important in protecting newborns,infants and young children百日破脊髓灰质炎MMR疫苗肺炎球菌嗜血杆菌乙

5、乙肝水痘轮状病毒流感脑膜炎双球菌乳头状病毒An Example:Effies Immunization RecordCommon themes of the cellular and molecular basis for immunity from infection also apply to:Rejection of transplants:移植免疫Elimination of many tumors before they can become dangerous：肿瘤免疫Reproductive problems(miscarriages,impotency)：生殖免疫Allergi

6、c reactions：过敏症Autoimmune diseases(e.g.,lupus,multiple sclerosis,type 1 diabetes)：自身免疫病Immunodeficiency diseases(HIV/AIDS,SCID)：免疫缺陷There is not another scientific subject as closely and widely related to everybodys daily life.Back to our topic:Immune Cells:This makes“immunology”different from“immun

7、ity”Immune Cells：Structure pattern（H&E stain）Development of immune cellsFactors driving hematopoiesisThe name“colony-stimulating factors”comes from the method by which they were discovered.Hemopoietic stem cells were cultured in semi solid matrix which prevents cells from moving around,so that if a

8、single cell starts proliferating,all of the cells derived from it will remain clustered around the spot in the matrix where the first cell was originally located,and these are referred to as colonies.It was therefore possible to add various substances to cultures of hemopoietic stem cells and then e

9、xamine which kinds of colonies(if any)were stimulated by them.The substance which was found to stimulate formation of colonies of macrophages,for instance,was called macrophage colony-stimulating factor,for granulocytes,granulocyte colony-stimulating factor,and so on.Colony-stimulating factorsWell e

10、stablished protocols for in vitro differentiation of innate immune cellsM-CSF:macrophageGM-CSF:dendritic cellsIL3:mast cellsHematopoietic Lineage differentiation controlled by transcription factorsCell types and subtypes defined by surface markers(CDs)B cellT cellCD4+T cellTregs(CD4+CD25+)Type of ce

11、ll CD markers stem cells CD34+,CD31-all leukocyte groups CD45+Granulocyte CD45+,CD15+Monocyte CD45+,CD14+T lymphocyte CD45+,CD3+T helper cell CD45+,CD3+,CD4+Cytotoxic T cell CD45+,CD3+,CD8+B lymphocyte CD45+,CD19+or CD45+,CD20+Thrombocyte CD45+,CD61+Natural killer cell CD16+,CD56+,CD3-Immune cells g

12、rouped by Functional characteristicsPhagocytes:Neutrophils,Monocytes/Macrophages,dendritic cells etc.Lymphocytes:T cells,B cells.NK cellsPhagocytes include:Neutrophils,cells that circulate in the blood but move into tissues when they are needed.Monocytes,which circulate in the blood;Macrophages,whic

13、h are found in tissues throughout the body;Dendritic cells,which are more stationary,monitoring their environment such as the skinPhagocytes:are the white blood cells that protect the body by ingesting(phagocytosing)harmful foreign particles,bacteria,and dead or dying cells.Phagocytes are major inna

14、te immune cellsNeutrophils1.Polymorphonuclear leukocytes:nucleus segmented into three to five connected lobules.2.Most abundant population of circulating white blood cells3.An adult human produces more than 1 x 1011 neutrophils per day,each of which circulates in the blood for only about 6 hours.4.M

15、ediate the earliest phases of inflammatory responses.:the cytoplasm contains filled with enzymes such as lysozyme,collagenase，elastase,defensins and cathelicidins(溶菌酶，胶原酶，弹性蛋白酶，防御素和抗菌肽)5.Neutrophils may migrate to sites of infection within a few hours after the entry of microbes.If a circulating neu

16、trophil is not recruited into a site of inflammation within this period,it undergoes apoptosis and is usually phagocytosed by resident macrophages in the liver or spleen.Total Neutrophils counts in BAL fluid during lung airspace inflammationControlLPSThe cells of the mononuclear phagocyte system ori

17、ginate in the bone marrow,circulate in the blood,and mature and become activated in various tissues.The first cell type that enters the peripheral blood after leaving the marrow is incompletely differentiated and is called the monocyte.Monocytes have bean-shaped nuclei and finely granular cytoplasm

18、containing lysosomes,phagocytic vacuoles.Once they enter tissues,these cells mature and become macrophages.Macrophages may assume different morphologic forms after activation by external stimuli,such as microbes.Monocytes/MacrophagesMonocytes/MacrophagesMacrophages(M):white blood cells within tissue

19、s,produced by the division of monocytesGreek:big eaters,from makros large+phagein eat;They can be identified by specific expression of a number of proteins including CD14,CD11b,F4/80(mice)/EMR1(human),Lysozyme M,Mac1/Mac-3 and CD68.Functions:Phagocytose cellular debris and pathgens(innate immunity)S

20、timulate lymphocytes and other immune cells to respond to pathogen(adaptive immunity)Monocytes/MacrophagesMacrophagesName of cellLocationDust cells(尘细胞)Alveolar macrophages(肺泡巨噬细胞)pulmonary alveolus of lungsHistiocytes(组织细胞)connective tissueKupffer cells(库夫)liverMicroglia(小胶质)neural tissueEpithelioi

21、d(上皮)cellsGranulomas(肉芽肿)Osteoclasts(破骨细胞)boneA majority of macrophages are stationed at strategic points where microbial invasion or accumulation of dust is likely to occur.Each type of macrophage,determined by its location,has a specific name:MacrophagesDendritic cellsDendritic cells(DCs)are immun

22、e cells that form part of the mammalian immune system.Their main function is to process antigen material and present it on the surface to other cells of the immune system,thus functioning as antigen-presenting cells.They act as messengers between the innate and adaptive immunity.Surface Marker of DC

23、:MHC class I/II moleculesCD1a,CD11c,CD83(human)33D1,NLDC145(mouse)Co-stimulatory molecules:B7.1(CD80)/B7.2(CD86),CD40,CD44,CD54Classification of DCLymphoid tissue DC：follicular(滤泡样)DC(FDC),interdigitating(并指状)DC(IDC),thymic DCNon-lymphoid tissue DC Langerhans(朗格汗斯)cell(skin),interstitial(间质性)DCCircu

24、lating DC peripheral blood DC,veiled(隐蔽)cell(lymph fluid)Dendritic cells Dendritic Cell Maturation Basic Functions of Phagocytes1.Phagocytosis2.Mediate inflamation(Activation&Cytokine secretion)3.Antigen presentation and co-stimulation Adaptive Immunity4.Clear bacteria or virus-infected cells as ins

25、tructed by Adaptive immune cells.Phagocytosis is the process of taking in particles such as bacteria,parasites,dead host cells,and cellular and foreign debris by a cell.PhagocytosisSelf-cleaningPhagocytosis12345PhagocytosisPrimary granules:Antimicrobial peptidesSecondary granules:phagocyte oxidaseLy

26、sosomes:Digestive enzymesProteases(elastase,etc.)Inflammatory Response1.Activation by pattern recognition receptors2.Producing of CytokinesRecognition microbes by Phagocytes PAMPs(pathogen associated molecular patterns):Highly conserved and essential components of microbes(cell wall structures;nucle

27、ic acids)Pattern Recognition Receptors（PPRs）:Toll-like receptors(TLRs;transmembrane receptors)RIG-I-like receptors(RLRs;cytoplasmic RNA helicases)NOD-like receptors(NLRs;cytoplasmic sensors)C-type lectin receptors(CLRs;transmembrane receptors)PAMPsToll-like receptors(TLRs)are single membrane-spannin

28、g non-catalytic receptors that recognize structurally conserved molecules derived from microbes.Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa,they are recognized by TLRs which activates immune cell responses.They receive their name from their similar

29、ity to the protein coded by the Toll gene identified in Drosophila in 1985.Toll-like receptorFrom Wikipedia,the free encyclopediaToll-like receptors and recognition of pathogensK.Takeda&S.Akira,Cell.Microbiol.5:143-53,2003diacyl-triacyl-lipopeptide 酰基脂肽；flagellin:鞭毛蛋白;LPS:脂多糖(Lipopolysaccharides)TLR

30、s:StructureLigand RecognitionTLR3-dsRNALigand RecognitionTLR4/MD2 LPSMyD88-dependent and independent pathway Cytoplasmic tails of TLRs show similarities to IL-1 receptor(TIR)Common adaptor to TLRs is MyD88 Crucial proline residue in all TLR TIR domains,except TLR3 If mutated or deleted,no signaling

31、occurs All TLRs likely have a MyD88 pathway(TLR3 is an exception)TLR4 has a MyD88 independent pathway as wellCytoplasmicTIR domainTLRs and TIR Domain MyD88 knockout mice have no response to LPS MyD88 is essential to all inflammatory signaling pathways MyD88s,a splice variant of MyD88 down regulates

32、the inflammatory response MyD88 interacts with TIR domain of TLR and recruits IRAK-4,IRAK-1 and TRAF-6MyD88 AdaptorRakoff-Nahoum et al.,Recognition of commensal microflora by Toll-like receptors is required for intestinal homestasis.Cell 118:229-41,2004.4 IRAKs known,IRAK1,IRAK-2,IRAK-M and IRAK-4IR

33、AK are serine/threonine kinasesIRAK-4 phosphorylates IRAK-1IRAK-M plays an inhibitory role in TLR signaling TRAF6 is a member of the TNF receptor associated factor(TRAF)familyTRAF6 interacts with IRAK-1 and gets activatedRelease of TRAF6/IRAK-1 ensues subsequent signalingIRAK and TRAF6IL-1RI-associa

34、ted protein kinases(IRAKs)tumor necrosis factor receptor-associated factor 6(TRAF6).TRAF6/IRAK-1 complex associates with 3 proteins TAK1(TGF-B activated kinase)TAB1(TAK1 binding proteins)TAB2(TAK1 binding proteins)Large complex associates with membraneEventually IRAK-1 stays in membrane while TRAF6/

35、TAK1/TAB1/TAB2 move to cytosolE2 Ligases such as Ubc13 and Uev1A join further enlarging complexIRAK and TRAF6 ReleaseTAK-1 ActivationThe enlarged complex that includes TRAF6,TAK1,TAB1,TAB2,Ubc13,Uev1A activate TAK1Activated TAK1 phosphorylates IKK complex Activated TAK1 can also phosphorylate MAP Ki

36、nases IKK complex consists of IKK,and/NEMOIB phosphorylation results in NF-B translocation to nucleusOverview of MyD88-dependent pathwayStep by Step view of MyD88-mediated signalingMyD88 Independent Pathway MyD88 Knock out mice do not produce inflammatory cytokines such as TNF-However with TLR4 stim

37、ulation NF-B and JNK delayed activity occurs This strongly suggests the existence of 2 pathways in TLR signaling a MyD88 dependent pathway a MyD88 independent pathway TLR3 stimulation also exchibits a MyD88 independent pathwayTLR4Overview of TLR signalingGenes regulated by NF-BCellular location of T

38、LRsEndolysosomal compartments and lysosome-related organelles in immune cellsToll-like receptor signaling regulated by its location in different cellular compartmentsTLR4 signaling is regulated by membrane traffickingRab7b promote endocytosis and degradation Cao X Blood 2007Rab10 promote trafficking

39、 onto cell surface.Wang D et al in Lu lab PNAS 2010TLR4 signaling is regulated by membrane trafficking57 5）定义构件属性 在绘图之前，必须先定义构件属性。以墙构件为例，单击构件工具栏的“墙定义构件属性”按钮，进入“属性管理”窗口。选择“新建砖石墙”，默认墙编号=nq-1，墙厚=240，内/外墙=内，如图8.23所示。在“构件做法定义”窗口，双击“项目编号”，在弹出的“项目指引”窗口选择“定额”选项卡，选择砖墙定额子目354，确认后退出。所选定额返回到“构件做法定义”窗口中，同时，双击“换算

40、”栏可以对该项子目进行换算。重复步，定义“外墙”属性qi-3，墙厚=370，内/外墙=外。5859 单击“属性管理”窗口中的“确认”按钮，退出“属性管理”窗口，这样就完成了对墙构件的属性定义。其他构件的属性定义方法同上，一种构件有多个属性项目时，在“属性管理”窗口中一次性定义完成。比如柱构件，有不同截面尺寸的柱，则可定义多个柱属性：zu2，zu3，zu4，6）绘制构件属性定义好之后，就是画图了，利用软件提供的画图工具，将构件图元绘制到轴网上。对于不同类型的构件，软件提供了不同的画法及智能布置方法。如墙，可以通过画线的方式绘制，也可以选择按轴线自动生成，以下分别说明。60（1）画墙 画外墙，单击

41、墙构件工具栏右侧的属性下拉列表框，选择“qi-3外墙”，再单击“墙画”，光标定位到轴线上的（A，1）点，单击左键，这时墙的第一个端点确定；移动光标到（A，3）坐标点，再次单击左键，墙第二点确定，同时一堵墙也显示在绘图区中。其他墙依此继续画出。外墙画完转换到内墙时，从构件工具栏的属性列表中选择“内墙”，当前墙属性为内墙，按照刚才的方法，画出全部内墙。61（2）智能布置墙 智能布置是为了提高画图效率而提供的一种快速画墙的方法，系统提供了可按轴线生成、按梁线生成、按墙线生成3种方式，由于当前只有轴线，所以我们选择按轴线生成（见图8.24），选择“内墙”，单击构件工具栏“墙布”按钮，鼠标框选需要布置墙

42、的轴线，确认后轴线上自动生成墙。626364 1）新建工程 单击欢迎界面上的“新建工程”，进入新建工程界面，如图826所示。65 输入“工程名称”及工程的相关工程概况，如图827所示。66 单击图8.27中的“下一步”按钮，进入“计算规则”设定，如图8.28所示。67 单击图8.28中的“下一步”按钮，进入“楼层设置”设定，如图8.29所示。681.电路中不含互感和受控源的情况(相量法)SS()kkkkkUZ IIU 111S1S1SSSS00000000000000000000kkkkkbbbbbZUIIUZUIIUZUIIU 按定义写开 kUSkUkIekIZkkIS二、支路方程的矩阵形式

43、 2.电路中含有互感的情况 设第k条、j条支路有耦合关系，编号时把它们相邻的编在一起（设两个电流都为流入同名端）：eeSSSSeeSSSSj()j()jj()()kkkkjjkkkkkjjjkjjkkjjjjkkkjjjjUZ IM IUZIIMIIUUM IZ IUMIIZ IIU ()()()11e1S111S1S122e2S222S2S2eSSSbbbbbbbbUZ IUZIIUUZ IUZIIUUZ IUZIIU 其余支路电压、电流的关系为：111S1S1222S2S2SSS0000000000j000j00000kkjkkkkjjjjjbbbbZUIIUZUIIUZMUIIMZUII

44、ZUII SSSkjbUUUSS()UZ IIU 故回路电流方程不变，只是阻抗阵Z不再为对角阵，其非对角线元素的第k行、第j列和第j行、第k列的两个元 素是两条支路的互阻抗。互阻抗前的“”，电流流入同名 端的对应取“”，反之取“”。仍可统一写为 3.电路中含有受控源的情况 deS()kkjjkjjjUr IrIISdS()kkkkkkUZIIUU而 这时含有受控源的支路阻抗 Z 为非对角阵，非对角线上的元素是与受控电压源的控制系数有关的元素。因支路方程的右端加上受控电压源，故支路阻抗阵变为：kU ISkSkUkIekIZk+dkU12kkjbZZZZrZk j 取回路电流（连支电流）为未知变量

45、。0 SkSkkkkkUBIBZIBZUBSkkSklkIBZUBIBBZT SkSkkkkUIIZU)(回路方程矩阵形式 支路电压与支路电流的关系 代入上面方程，整理后得 SkU.Zk+-kU.kI.SkI.ekI.+-lSllUIZ 回路矩阵方程（回路电压源相量）Zl（回路阻抗阵）三、回路电流方程的矩阵形式 13.2列出图示电路矩阵形式回路电流方程的频域表达式。124356+-U2Z3Z6 IS6+-Z2Z5Z1+-U2US1TS6S00000II111000001101000011fB652321000000000000000000000000000000ZZZZZZZ 画出有向图，给支

46、路编号，选树(1,4,6)。TS1S00000UU 6523121121Tff000ZZZZZZZZZZZBBZlTS66S1S1SSSIZUUIBZUBUlS66S1S15326523121121000IZUUIIIZZZZZZZZZZSlU计算Zl 和 。矩阵形式回路电流方程的频域表达式为13-3列出图示电路矩阵形式回路电流方程的复频域表达式。R1C2L3L5uS4uS5*M12435 画出有向图，给支路编号，选树(1,4)。TS5S4)()(000(s)sUsUU0)(sI110000110100011fB532100000000000000100000)(sLsMsMsLsCRsZ 计

47、算Z(s)UlS(s)。5311121Tff001)()(sLsMsMsLRRRsCRBsZBsZlTS5S4S4fS)()()(0)()(sUsUsUsUBsUl)()()(0)()()(001S5S4S45325311121sUsUsUsIsIsIsLsMsMsLRRRsCR矩阵形式回路电流方程的复频域表达式为小结列写回路电流方程矩阵形式的步骤如下：(1)画有向图，给支路编号，选树。(2)写出支路阻抗矩阵Z(s)和回路矩阵Bf。按标准 复合支路的规定写出支路电压列向量)()()(sUsIsZlSll(4)写出矩阵形式回路电流方程的复频域表达式SlllUIZ或TlBZBZ(3)求出回路阻抗矩

48、阵。1.什么是复合支路？2.矩阵形式回路电流方程的列写中，若电路中含有无伴电流源，将会有何问题？13.4 节点电压方程的矩阵形式一、复合支路ekI 元件电流 支路电流 kI 受控电流 dkI 支路的复导纳（阻抗）)(kkZY 支路电压 kUSkU 独立电压源 SkI 独立电流源 按复合支路的规定，电路中不允许有受控电压源，也不允许存在“纯电压源支路”。复合支路规定了一条支路可以最多包含的元件数，可以缺少某些元件，但不能缺少阻抗。dkISk.UZk(Yk)+-k.Uk.ISk.Iek.I+-矩阵形式)(100111ddddStuLiuLCRCtituLCLC RuLCuS(t)+-uCiLiCu

49、R+-+-+-LiR(4)把状态方程整理成标准形式。对于简单的网络，用直观法比较容易，列写状态方程的步骤为：(1)选择独立的电容电压和电感电流作为状态变量；(2)对只接有一个电容的节点列写KCL方程；对只包含一个电感 的回路列KVL方程；(3)列写其他必要的方程，消去方程中的非状态变量；直观编写法的缺点：1)编写方程不系统，不利于计算机计算。2)对复杂网络的非状态变量的消除很麻烦。步骤：(1)选择一个树，也称为特有树，它包含电容和电压源，而不包含电容和电流源。(2)对包含电容的单树支割集列写KCL方程。(3)对包含电感的单连支割集列写KVL方程。(4)列写其他必要的方程，消去非状态变量。(5)

50、整理并写出矩阵形式。2.系统法：对于比较复杂的电路，仅靠观察法列写状态方程有时是很困难的，有必要寻求一种系统的编写方法。简单的说，系统编写法就是寻求一个适当的树，使其包含全部电容而不包含电感。对含电容的单树支割集用KCL可列写一组含有的方程。对于含电感的用KVL可列写出一组含有的方程。这些方程中含有一个导数项，若再加上其他约束方程，便可求得标准状态方程。dtduCdtdiL单连支回路运13.7 列写如下图所示电路的状态方程。+_1F+_+_uSiSuiLiC110dd1SiiituLC01SLiiu0dd1SuuutiCL01SCuui对图示的两个树支，按基本割集列写KCL方程 对图示的两个连