炎症与免疫研究进展唐宏培训课件

1、炎症与免疫研究进展唐宏炎症与免疫研究进展唐宏炎症的病理特征与进程炎症的局部临床特征是红、热、肿、痛和组织/器官功能衰竭红热: 炎症局部血管扩张、血流加快所致。肿胀: 局部炎症性充血、血液成分渗出引起。疼痛: 渗出物压迫和炎症介质直接作用于神经末梢而引起疼痛。功能衰竭：基于炎症的部位、性质和严重程度将引起不同的功能障碍，如肺炎影响气血交换从而引起缺氧和呼吸困难/窘迫等。炎症通常可按其病程分为急性炎症和慢性炎症急性炎症：启动急骤，持续几天至一个月。有害刺激一旦去除，炎症也就随之消失。以血浆渗出和中性粒细胞浸润为主要特征。慢性炎症：持续数月至数年，以淋巴细胞和单核-巨噬细胞浸润以及微/小血管和结缔组

2、织增生为主要病理学特征。炎症与免疫研究进展唐宏2炎症的病理特征与进程炎症的局部临床特征是红、热、肿、痛和组织炎症的细胞反应1、吞噬细胞是启动炎症反应的重要效应细胞，包括巨噬细胞和中性粒细胞。吞噬细胞通过其表面表达的多种受体 (甘露糖受体，葡聚糖受体，Toll样受体等)，迅速识别并摄入外源微生物，形成吞噬体，继而与溶酶体结合形成吞噬溶酶体，微生物通过氧依赖或氧非依赖途径被杀伤。被激活的吞噬细胞同时分泌大量的促炎症因子和趋化因子（IL-1，TNF，IL-6和KC/CXCL8等)，发挥多种非特异性效应，包括致炎，致热，趋化炎症细胞，激活免疫细胞，抑制病毒复制，胞毒作用等。中性粒细胞存在于外周血，寿命

3、短，数量多；巨噬细胞是从血液中的单核细胞分化而来分布于不同组织中，寿命长，形体大，富含细胞器。2、NK细胞也是参与炎症反应的重要细胞，在多种细胞因子刺激下，杀伤感染细胞内的微生物并产生细胞因子，进一步促进炎症细胞发挥作用而产生级联放大效应。3、此外，DC 、T 、B1、肥大细胞、NKT 、上皮细胞等在一定范围内参与炎症反应。炎症与免疫研究进展唐宏3炎症的细胞反应1、吞噬细胞是启动炎症反应的重要效应细胞，包括炎症是所有具有血管系统的个体，其组织与细胞对损伤性因子/因素所产生的反应炎症与免疫研究进展唐宏4炎症是所有具有血管系统的个体，其组织与细胞炎症与免疫研究进展PAMP vs DAMP炎症与免疫

4、研究进展唐宏5PAMP vs DAMP炎症与免疫研究进展唐宏5炎症与免疫研究进展唐宏6炎症与免疫研究进展唐宏6Dong et al, Nat Med (2007)Adaptive immune system prevents overreactive innate immunity in the initial phase of infections炎症与免疫研究进展唐宏7Dong et al, Nat Med (2007)Adap炎症与免疫研究进展唐宏培训课件CHours after Poly I:C injection020406080100012243648WtNude% Surviva

5、lBAHours after Poly I:C injection020406080100012243648WtRag-/-% SurvivalD 2 h6 h0123ng/ml 2 h6 h051015BL6Rag-/-ng/ml2h6hTNF-Balb/cNude030060090012001500pg/mlIFN-0300600900120015002h6hpg/mlThe susceptibility to TLR stimulation is independent of infectious agents 2 h6 h050100150 BALB/cNude030609012015

6、02 h6 h0153045602 h6 hMCP-1 (ng/ml)IL-6 (ng/ml)2 h6 h0255075100125BL6Rag-/-炎症与免疫研究进展唐宏9CHours after Poly I:C injectioETNF-2 h6 h051015Control-CD4/8 ng/ml IFN-2 h6 h0200400600800pg/ml IFN-012ng/mlTNF-02468ControlTransferng/mlF 2h 6h 2h 6hConventional T cells are necessary and sufficient to suppress t

7、he early inflammatory responses to pICRag1-/-Balb/C炎症与免疫研究进展唐宏10ETNF-2 h6 h051015Control-CD4CTNF-NTNTPan-TOTII CD4OTI CD80100200300 + NT+ Poly I-Cpg/mlIFN-05001000pg/ml0 0 0.3 1.0 Wild NT025050075010001250IFN- (pg/ml)+ Poly I:C MHC Class II KO NT050100150IFN- (pg/ml) (CD4T/NT ratio)0 0 0.3 1.0 + Pol

8、y I:C DNTNTNT+TNT+T0200400600800Transwell+ Poly I-Cpg/ml TNF-IFN-0255075100125pg/mlBT cells tempering the innate cytokine surge is cell-cell contact dependent(TCR engagement-independent, but MHC-dependent)炎症与免疫研究进展唐宏11CTNF-NTNTPan-TOTII CD4OTI CDNT+GFP-TFTNF-NTNTNT+T0100200 Poly I:Cpg/mlIFN-05010015

9、0pg/mlBoth nave and Treg cells efficiently suppress the inflammatory cytokine stormETNF-0100200pg/mlpg/ml NT PanTNon Treg Treg Poly I:C- - + - - - - + - - - - +- + + + + + + + +IFN-050100150 - - + - - - - + - - - - +- + + + + + + + +0100200pg/ml(CD4 T/NT ratio)+Poly I:C 0 0 0.3 1.0 0.3 1.0 IL10-/- T

10、Wild T炎症与免疫研究进展唐宏12NT+GFP-TFTNF-NTNTNT+T0100200 020406080100012243648Rag-/-NK-depletedRag-/-Hours after Poly I:C injection% SurvivalFTNF-2 h6 h01234Rag-/-NK-/- Rag-/-ng/mlIFN-2 h6 h0.00.51.0GNK cells play essential roles in pIC-induced sudden death of Rag-1 KO mice.炎症与免疫研究进展唐宏13020406080100012243648

11、Rag-/-NK-CD11bTNF-CD11cNK1.1IFN-NT+ Poly I:CNT+ Poly I:C+ Pan-T cell11.333.7428.085.760.525.34T cells primarily inhibit APCs to block NK activation CD11b+: + + + + - - TNF-050100150200250pg/mlNK : - - + + + +T cell: - + - + - +IFN-01020pg/ml 炎症与免疫研究进展唐宏14CD11bTNF-CD11cNK1.1IFN-NT+ PT CELLS MAINTAIN

12、THE HOMEOSTASIS OF INNATE INFLAMMATIONTrends Immunol （2009）炎症与免疫研究进展唐宏15T CELLS MAINTAIN THE HOMEOSTASNeonateAdult*02468TNF- (ng/ml)B *060120180240MCP-1 (ng/ml)NeonateAdult*0100200300400IL-6 (ng/ml)NeonateAdult*05101520IL-6 (ng/ml)NeonateAdult*0246810MCP-1 (ng/ml)NeonateAdult*00.40.81.2TNF- (ng/ml)N

13、eonateAdultNeonates are susceptible to higher proinflammatory responsesMHVLPS*02004006008001000AdultNeonateTNF- (pg/ml)*0123IL-6 (ng/ml)AdultNeonatepIC炎症与免疫研究进展唐宏16NeonateAdult*02468TNF- (ng/m Adult Neonate Adult Neonate Adult Neonate Adult Neonate Adult Neonate Adult Neonate02468 Untreated Poly(I:C

14、) MHV-A59 LPSAdultNeonate*TNF- (ng/ml)0246 Untreated Poly(I:C) MHV-A59 LPSAdultNeonate*IL-6 (ng/ml)Neonatal mice (Day 1)Adult mice1x106 or 2x10 6 Splenocytes+ LPS+poly I:C+MHV-A59Culture for 20hDetect TNF in supernatantsNeonatal splenocytes produced more inflammatory cytokines than adults 炎症与免疫研究进展唐

15、宏17 Adult Neonate Adult BDays020406080100120012345678Survival Rate (%)day 1day 72 wk10 wk024day 1 day 7 2 wk10wkTNF- (ng/ml)*050100150200day 1 day 7 2 wk10wkMCP-1 (ng/ml)*0100200300IL-6 (ng/ml)day 1 day 7 2 wk10wk*0204060801001200122436486072Hours Post InjectionSurvival (%)Day 1 AdultDay 7LPSpICT ce

16、lls counts reversely correlate with the levels of inflammatory cytokines T cell(%)40-4515-77-1002040608010012002468Days After InfectionSurvival (%)Neonate 6x103pfu/gNeonate 2x103pfu/gAdult 6x103pfu/gAdult 2x103pfu/gMHV炎症与免疫研究进展唐宏18BDays020406080100120012345678SB05101520ControlAnti-CD4/8TNF- (ng/ml)

17、*0153045ControlAnti-CD4/8IL-6 (ng/ml) *C04812ControlTransferTNF- (ng/ml)0510MCP-1 (ng/ml)ControlTransfer02.55.0IL-6 (ng/ml)ControlTransfer * * *Adoptive transfer of T cells renders efficient control of inflammation in neonates炎症与免疫研究进展唐宏19B05101520ControlAnti-CD4/8TNF-B*0100200300TNF- (pg/ml)Neonata

18、l NT-+-+-+LPSNeonatal TAdult T+0123IL-6 (ng/ml)*Neonatal NT-+-+-+LPSNeonatal TAdult T+Adult or neonatal T cells are functionally the same1x106 neonatal non-T cellsCulture for 20h2x106 neonatal T cells2x106 adult T cellsor+LPSdetection ofTNF/IL6 in supernatants炎症与免疫研究进展唐宏20B*0100200300TNF- (pg/ml)Neon01224364860720255075100WildTNFRI/II KOT