最新炎症与免疫研究进展唐宏课件.ppt

1、 炎症的局部临床特征是红、炎症的局部临床特征是红、热、肿、痛和组织热、肿、痛和组织/器官功器官功能衰竭能衰竭 红热红热:炎症局部血管扩张、炎症局部血管扩张、血流加快所致。血流加快所致。肿胀肿胀:局部炎症性充血、血局部炎症性充血、血液成分渗出引起。液成分渗出引起。疼痛疼痛:渗出物压迫和炎症介渗出物压迫和炎症介质直接作用于神经末梢而引质直接作用于神经末梢而引起疼痛。起疼痛。功能衰竭：基于炎症的部位、功能衰竭：基于炎症的部位、性质和严重程度将引起不同性质和严重程度将引起不同的功能障碍，如肺炎影响气的功能障碍，如肺炎影响气血交换从而引起缺氧和呼吸血交换从而引起缺氧和呼吸困难困难/窘迫等。窘迫等。炎症通

2、常可按其病程分为炎症通常可按其病程分为急性炎症和慢性炎症急性炎症和慢性炎症 急性炎症：启动急骤，持急性炎症：启动急骤，持续几天至一个月。有害刺续几天至一个月。有害刺激一旦去除，炎症也就随激一旦去除，炎症也就随之消失。以血浆渗出和中之消失。以血浆渗出和中性粒细胞浸润为主要特征。性粒细胞浸润为主要特征。慢性炎症：持续数月至数慢性炎症：持续数月至数年，以淋巴细胞和单核年，以淋巴细胞和单核-巨巨噬细胞浸润以及微噬细胞浸润以及微/小血管小血管和结缔组织增生为主要病和结缔组织增生为主要病理学特征。理学特征。炎症的细胞反应炎症的细胞反应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

3、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

4、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。Dong et al,Nat Med(2007)A02040608010002468101214Balb/cNude Days after injection%survivalBCBalb/cNude23456Day 2Day 4Log PFU/gm LiverTNF-020406080100Balb/cNudepg/mlIFN-050100150200250Balb/cNudepg/mlBalb/cNudeP=0.02P=0.0602000400060008000Day

5、 2Day 4ALT(U/L)Balb/cNudeP=0.7P=0.0501000200030004000Day 2Day 4AST(U/L)MCP-10100200300400500600Balb/cNudepg/mlIL-6020406080Balb/cNudepg/mlCHours after Poly I:C injection020406080100012243648WtNude%SurvivalBAHours after Poly I:C injection020406080100012243648WtRag-/-%SurvivalD 2 h6 h0123ng/ml 2 h6 h0

6、51015BL6Rag-/-ng/ml2h6hTNF-Balb/cNude030060090012001500pg/mlIFN-0300600900120015002h6hpg/ml 2 h6 h050100150 BALB/cNude03060901201502 h6 h0153045602 h6 hMCP-1(ng/ml)IL-6(ng/ml)2 h6 h0255075100125BL6Rag-/-ETNF-2 h6 h051015Control-CD4/8 ng/ml IFN-2 h6 h0200400600800pg/ml IFN-012ng/mlTNF-02468ControlTra

7、nsferng/mlF 2h 6h 2h 6hCTNF-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 +Poly I:C DNTNTNT+TNT+T0200400600800Transwell+Poly I-Cpg/ml TNF-IFN-025507510012

8、5pg/mlBNT+GFP-TFTNF-NTNTNT+T0100200 Poly I:Cpg/mlIFN-050100150pg/mlETNF-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-/-TWild T020406080100012243648Rag-/-NK-depletedRag-/-Hours after Poly I:C injection%Surv

9、ivalFTNF-2 h6 h01234Rag-/-NK-/-Rag-/-ng/mlIFN-2 h6 h0.00.51.0GCD11bTNF-CD11cNK1.1IFN-NT+Poly I:CNT+Poly I:C+Pan-T cell11.333.7428.085.760.525.34 CD11bCD11b+:+-:+-TNF-050100150200250pg/mlNK:-+T cell:-+-+-+IFN-01020pg/ml NeonateAdult*02468TNF-(ng/ml)B*060120180240MCP-1(ng/ml)NeonateAdult*0100200300400

10、IL-6(ng/ml)NeonateAdult*05101520IL-6(ng/ml)NeonateAdult*0246810MCP-1(ng/ml)NeonateAdult*00.40.81.2TNF-(ng/ml)NeonateAdultMHVLPS*02004006008001000AdultNeonateTNF-(pg/ml)*0123IL-6(ng/ml)AdultNeonatepIC Adult Neonate Adult Neonate Adult Neonate Adult Neonate Adult Neonate Adult Neonate02468 Untreated P

11、oly(I:C)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 supernatantsBDays020406080100120012345678Survival Rate(%)day 1day 72 wk10 wk024day 1 day 7

12、2 wk 10wkTNF-(ng/ml)*050100150200day 1 day 7 2 wk 10wkMCP-1(ng/ml)*0100200300IL-6(ng/ml)day 1 day 7 2 wk 10wk*0204060801001200122436486072Hours Post InjectionSurvival(%)Day 1 AdultDay 7LPSpIC02040608010012002468Days After InfectionSurvival(%)Neonate 6x103pfu/gNeonate 2x103pfu/gAdult 6x103pfu/gAdult

13、2x103pfu/gMHVB05101520Control Anti-CD4/8TNF-(ng/ml)*0153045Control Anti-CD4/8IL-6(ng/ml)*C04812Control TransferTNF-(ng/ml)0510MCP-1(ng/ml)Control Transfer02.55.0IL-6(ng/ml)Control Transfer *B*0100200300TNF-(pg/ml)Neonatal NT-+-+-+LPSNeonatal TAdult T+0123IL-6(ng/ml)*Neonatal NT-+-+-+LPSNeonatal TAdu

14、lt T+1x106 neonatal non-T cellsCulture for 20h2x106 neonatal T cells2x106 adult T cellsor+LPSdetection ofTNF/IL6 in supernatants01224364860720255075100WildTNFRI/II KOTNFRI KOtime(h)%survivalHours after poly(I:C)injection020406080100012243648Control IgAnti-IFN-AbPercent survivalZhao J et al,PNAS,2008effectTmemoryTIL1，IL18谢谢 谢谢