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Immune response and regulation 免疫应答(immune response, Ir) Body receive stimulation from Ag , Specific lymphocytes recognize Ag,they activate, proliferate and differentiate or become a state of anergy and apoptosis, exert biological effect. Immunological functions Functions Normal abnormal Defense clear pathogen ↑hypersensitivity、 (anti-infection)↓immune deficiency ( chronic infection ) homeostasis tolerant to auto-tissue ↑Autoimmune disease (clear damaged and aged cells) surveillance clear mutate cell ↓ ontogenesis (Anti-tumor) (persistent viral infection ) Classification • Innate immunity (non-specific) • Acquired immunity (specific) - Humoral immunity - Cellular immunity Classification • Physiological IR(Immune protection) Non-self reject Self tolerant • Pathological IR(Immune damage) IR too high hypersensitivity IR too weak Immune defect Tolerance terminate Autoimmune disease Classification of specific immunity (一)体液免疫(humoral immunity) –To exogenous Ag or soluble outside of cell Ag (二)细胞免疫(cell-mediated immunity) –To endogenous pathogen , cellular Ag (tumor Ag、grafted Ag). Place of Ir Peripheral immune organ (lymph node、 spleen and so on). Process of Ir 3 stages: Presenting and recognizing Ag: Activation、proliferation and differentiation Effect Basic process of Ir Cellular immune response T recognize Ag and activation Effect of T cell mediated IR and mechanism Biological effect of cellular immunity 3 stages: ①Recognition phase ②Activation,proliferation,differentiation ③Production of effector cells APC presenting Ag to T cell Ag +APC peptide-MH Complex T cell Interaction between APC and T cell • TCR peptide-MHC • LFA-1 change conformational structure • CD4 MHC CD8 MHC • Co-stimulatory molecule 一、Requirement for T recognizing Ag and activation (一)T cell recognize Ag * MHC restriction TCRαβchainre cognize MHC on APC surface (MHC restriction) Peptide on APC (Epitope of T cell ) TCR的MHC限制性识别示意图 Molecules involved in T cell recognition Recognition phase 1. Take in Ag: 2. Process and present Ag: 3. Interaction between APC and T cell • Recognition of Ag: Double recognition: TCR-peptide, TCR-MHC Co-receptor:CD4-MHCII, CD8-MHCI • Binding of co-stimulatory molecules on APC and T cells:B7-CD28 第二节 Activation,proliferation, differentiation Depend on 2 signals and CK T cell activation for signal requirement 1、2 signals for Th activation (1)Active signal 1 (Ag) TCR specifically recognize peptide/MHC (2) Active signal 2 (binding of costimulatory molecule) B7-CD28 Adhesion molecules-their ligands 2、CK(IL-2、4、12…) Signal 1(Ag):TCR recognize peptide-MHC Signal 2(Co-stimulator):binding of ADs CD4+T activation T cell activate signal 1(Ag recognition signal) T cell activate signal 2(costimulator signal) Flash * T acquire signal ,but lack signal 2, anergy and apoptosis occur. * Block or enhance active signal 2, can reduce or increase Ir。 The first signal for T cell activation TCR Specifically recognize MHC-peptide Second signal for T cell activation AD on APC + signal AD on T cell co-stimulatory CD28/B7:involve in T cell activation CTLA4/B7:suppress T cell activation CK:Promote T cell activation Proliferation and differentiation of T cell Th effector T CTL • Active T memory T 2. Proliferation and differentiation of CD4+T Active T Express variety of CKs and IL-2+IL-2R T IL-12,IFN-g Th1 cell grow Th0 IL-4 Th2 receptors Th divide into Th1 and Th2 Proliferation and differentiation of CD8+T •Th independent(direct activation) •Th independent(indirect activation) IL-2 IL-2 IL-2 Where will Active T go? • go to effector T; • go to memory T; • go to apoptosis. 二、Effect and mechanism of T cell mediated IR (一) CD4+Th1 mediate effect (inflammation) (二) CD8+TC mediate effect (lyses of cell) Cytotoxicity of CD8+CTL(TC) MHC restriction recognition of Tc * TCR recognize peptide/MHC-I on target cell; requirement for Tc activation Active signal 1: TCR recognize Ag; Active signal 2: Co-stimulatory molecule bind its ligand CK: APC→ active Th →CKs(IL-2,IL-6…) Double signals for TC activation A A:lack active signal 1,TC leave target cell B B:TC recognize infected cell,With signal 1 and 2, TC grow ,kill target cell and leave The killing mechanism for Tc cell • The specific recognizing and binding phase • The killing phase (1)active CTL de-granule release perforin →lysis of target cells release granzyme→ apoptosis of target cells (2)Fas-FasL pathway → apoptosis of target cells (3)Release cytotoxic CKs(IFN-γ,TNFα/β) CTL release perforin and granzyme to cause necrosis and apoptosis of target cell CTL release perforin and form a channel in target cell membrene (G=T细胞颗粒,Go=高尔基体,M=线粒体,N=核) TC express FasL to induce apoptosis of target cell FasL Viral infected targeted cell Actuve TC express FasL AAAAAA Interaction of FasFasL to induce apoptosis of target cell CTL killing possess high Ag-specificity and MHC restriction CTL kill one more target cells Property: Specificity、MHC restriction、high efficacy CD8+TC mediated Ir T/Target cell TCR recognize peptide-MHC-I Interaction of ADs signal signal 1 2 CD4+Th activate Secret CKs Resting Tc transform to active Tc Release perforin and granzyme Fas、FasL Death of target cell The effect caused by CD4+Th1 Release many kinds of lymphokines,lead to inflammation 1、Function on M —secret CK – Activate M :IFN-γ、CD40L – Induce and attract M: IL-3 、 GM-CSF 、 TNF、MCP-1 迟 发 型 超 敏 反 应 (delayed type hypersensitivity, DTH) : caused by lymphocytes 、 lymphocytes and monocytes are main cells found in inflammation site. Activation 、 proliferation 、 differentiation and migration of immune cells take too long time, inflammation occur too late and maintain longer, referred to DTH. Active M activated by Th1 Gathering of lymphocytes and monocytes/M 2、to T cells promote proliferation of Th1、 CTL,enlarge immune effect 3、to B cells promote the production of Ab 4、To neutrophill activate CD4+TDTH mediated cellular Ir TDAg Th1 contact APC APC take in、process、present Ag CD4+Th1 recognize peptide-MHC-II complex Active signal 1 Active signal 2 Th1 activation proliferation CKs Resting M Activated M Secret inflammatory Cks DTH Effect of active T (一) CD8+CTL mediate cytotoxicity (二) CD4+Th1 mediate DTH (三)CD4+Th2 assist B to produce Ab The process of Immune response 三、Biological effect of cellular immunity (一) Killing endogenous microorganism → antiinfection immunity; (二) Killing tumor cell → anti-tumor immunity; (三) Immune damage killing grafted cells → graft rejection reaction killing auto cells and tissue → AID。 DTH Review Questions • Describe the process of IR mediated by CD8+T.简述CD8+T细胞介导的免疫应答过 程。 • Describe the process of CD4+T activation简 述CD4+T细胞的活化过程。 • Describe the interaction of APC and Th简 述APC-Th细胞是如何相互作用的。