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炎症与免疫研究进展

炎症与免疫研究进展. 中科院感染免疫重点实验室. 唐 宏. 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。

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炎症与免疫研究进展

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  1. 炎症与免疫研究进展 中科院感染免疫重点实验室 唐 宏

  2. 炎症的局部临床特征是红、热、肿、痛和组织/器官功能衰竭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/小血管和结缔组织增生为主要病理学特征。 炎症的病理特征与进程

  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 、γδT 、B1、肥大细胞、NKT 、上皮细胞等在一定范围内参与炎症反应。

  4. 炎症是所有具有血管系统的个体，其组织与细胞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

  5. PAMP vs DAMP

  6. Adaptive immune system prevents overreactive innate immunity in the initial phase of infections Dong et al, Nat Med (2007)

  7. 100 80 IL-6 MCP-1 60 Balb/c 600 80 % survival 8000 4000 Nude Balb/c Balb/c   40 P=0.7 Nude Nude 500 P=0.06 20 60 6000 3000 400 0 pg/ml pg/ml ALT (U/L) AST (U/L) 0 2 4 6 8 10 12 14 40 300 4000 2000 Days after injection 200 P=0.05 20 2000 1000 P=0.02 100 6 Balb/c IFN- 0 0 0 0 TNF- Nude 5   Day 2 Day 4 Balb/c Nude 250 Day 2 Day 4 Balb/c Nude 100 Log PFU/gm Liver 200 4 80 150 60 pg/ml pg/ml 3 100 40 2 50 20 Day 2 Day 4 0 0 Balb/c Nude Balb/c Nude Acute infection in immunocompromised mice results in stronger innate immune responses Hepatitis virus induced lethality in nude mice A B C

  8. 100 80 IFN- TNF- 1500 Wt 60 1500  % Survival Balb/c MCP-1 (ng/ml)  IL-6 (ng/ml) pg/ml Nude 1200 Nude 1200  40 60  150 BALB/c 900 900 pg/ml Nude 20 600 120 600  45   300 300 90 0  30 0 0 12 24 36 48 0 2h 6h 60 2h 6h Hours after Poly I:C injection 15 15 30  0 0 10 2 h 6 h 2 h 6 h ng/ml  5 100 BL6 BL6 80  0 125  150 3  2 h 6 h Rag-/- Rag-/- % Survival Wt 60  100 Rag-/- 2 100  40 75 50 20 1 50  25 0 0 12 24 36 48 0 0 0 2 h 6 h 2 h 6 h 2 h 6 h Hours after Poly I:C injection The susceptibility to TLR stimulation is independent of infectious agents A B D C ng/ml

  9. IFN- TNF- 2 8 Control Transfer 6 ng/ml ng/ml 1 4 2 0 0 F IFN- 800 E 600 TNF-  pg/ml  15 400 Control -CD4/8 200 10 ng/ml 0 2h 6h 2h 6h 2 h 6 h 5 0 2 h 6 h Conventional T cells are necessary and sufficient to suppress the early inflammatory responses to pIC Balb/C Rag1-/-

  10. TNF- IFN- IFN- TNF-       125 800 300 1000 100 600 200 75 pg/ml pg/ml 400 pg/ml pg/ml 500 50 Wild NT MHC Class II KO NT 100 200 25 150 1250 0 0 0 0 1000 NT NT NT NT NT+T 100 NT+T Pan-T 750 OTI CD8 OTII CD4 IFN- (pg/ml) IFN- (pg/ml) Transwell 500 + Poly I-C 50 + NT 250 + Poly I-C 0 0 (CD4T/NT ratio) 0 0 0.3 1.0 0 0 0.3 1.0 + Poly I:C + Poly I:C T cells tempering the innate cytokine surge is cell-cell contact dependent (TCR engagement-independent, but MHC-dependent) B D C

  11. E IFN-   150 100 pg/ml TNF- IFN-   200 F 50 150 100 0 + + + + + + + + + + pg/ml pg/ml 100 TNF- 50 200 200 0 0 NT+T NT NT pg/ml 100 pg/ml 100 Poly I:C NT+GFP-T 0 NT PanT Non Treg Treg Poly I:C - - + - - - - + - - 0 - - - + - - - - + - - - - - + - - - - + Wild T - + + + + - + + + + IL10-/- T (CD4T/NT ratio) 0 0 0.3 1.0 0.3 1.0 +Poly I:C Both naïve and Treg cells efficiently suppress the inflammatory cytokine storm

  12. 100 80 60 Rag-/- % Survival NK-depleted 40 Rag-/- 20 0 0 12 24 36 48 Hours after Poly I:C injection TNF- IFN-   Rag-/- 4 1.0 NK-/- Rag-/-  3 ng/ml 2 0.5 1 0 0.0 2 h 6 h 2 h 6 h NK cells play essential roles in pIC-induced sudden death of Rag-1 KO mice. F G

  13. 11.33 3.74 28.08 NT+ Poly I:C 5.76 0.52 5.34 NT+ Poly I:C + Pan-T cell IFN- TNF- NK1.1 CD11b CD11c IFN-  20 pg/ml 10 0 T cells primarily inhibit APCs to block NK activation TNF- 250  200  150 pg/ml 100 50 0 CD11b+: + + + + - - NK :- - + + + + T cell: -+ -+ - +

  14. T CELLS MAINTAIN THE HOMEOSTASIS OF INNATE INFLAMMATION Trends Immunol （2009）

  15. 240 400 8 180 300 6 MCP-1 (ng/ml) TNF- (ng/ml) IL-6 (ng/ml) 120 4 200 ** 1000 60 3 2 100 800 0 0 0 Neonate Neonate Neonate Adult Adult Adult 2 600 IL-6 (ng/ml) TNF- (pg/ml) 400 1 200 ** ** ** ** ** ** 0 0 Adult Neonate Adult Neonate 1.2 20 10 8 15 0.8 6 MCP-1 (ng/ml) TNF- (ng/ml) IL-6 (ng/ml) 10 ** 4 0.4 5 2 0 0 0 Neonate Neonate Adult Adult Neonate Adult Neonates are susceptible to higher proinflammatory responses pIC B LPS MHV

  16. + LPS +poly I:C +MHV-A59 Detect TNF in supernatants Culture for 20h Neonatal mice (Day 1) 1x106 or 2x10 6 Splenocytes Adult mice Neonatal splenocytes produced more inflammatory cytokines than adults 6 8 ** ** 6 ** 4 ** ** 4 ** IL-6 (ng/ml) TNF- (ng/ml) ** 2 ** 2 ** ** ** ** 0 0 Adult Adult Neonate Neonate Adult Neonate Adult Neonate Adult Neonate Adult Neonate Adult Neonate Adult Neonate Untreated Poly(I:C) MHV-A59 LPS Untreated Poly(I:C) MHV-A59 LPS

  17. 120 100 80 Survival Rate (%) day 1 120 day 7 60 120 100 2 wk 40 10 wk 100 80 Survival (%) 60 20 Day 1 80 Survival (%) Day 7 40 0 60 Adult 20 0 1 2 3 4 5 6 7 8 40 0 0 2 4 6 8 Days After Infection 20 ** ** 0 ** 200 300 4 0 12 24 36 48 60 72 Hours Post Injection 150 200 TNF- (ng/ml) MCP-1 (ng/ml) IL-6 (ng/ml) 2 100 100 50 0 0 0 day 1 day 1 day 1 day 7 2 wk day 7 2 wk day 7 2 wk 10wk 10wk 10wk T cells counts reversely correlate with the levels of inflammatory cytokines LPS pIC MHV Neonate 6x10^3pfu/g Neonate 2x10^3pfu/g Adult 6x10^3pfu/g Adult 2x10^3pfu/g Days B T cell(%) <1 5-7 7-10 40-45

  18. ** * * ** * B 45 20 15 30 IL-6 (ng/ml) TNF- (ng/ml) 10 15 5 0 0 Control Anti-CD4/8 Control Anti-CD4/8 5.0 10 C 12 IL-6 (ng/ml) 2.5 5 MCP-1 (ng/ml) 8 TNF- (ng/ml) 4 0 0 Control Transfer Control Transfer 0 Control Transfer Adoptive transfer of T cells renders efficient control of inflammation in neonates

  19. B ** 300 ** 3 Culture for 20h 2x106 neonatal T cells 2x106 adult T cells detection of TNF/IL6 in supernatants 200 2 LPS + + TNF- (pg/ml) or IL-6 (ng/ml) 1x106 neonatal non-T cells 100 1 0 0 + + + + + + + + Neonatal NT Neonatal NT - - + + + + + + LPS LPS - - - - - - + + Neonatal T Neonatal T - - - - - - + + Adult T Adult T Adult or neonatal T cells are functionally the same

  20. 100 100 75 80 Wild Control Ig 50 60 % survival TNFRI/II KO Anti-IFN- Ab Percent survival 40 TNFRI KO 25 20 0 0 0 12 24 36 48 60 72 0 12 24 36 48 Hours after poly(I:C) injection time (h) TNF is the mortality factor of neonatal death Zhao J et al, PNAS, 2008

  21. effect T memory T IL1β，IL18 TNF T CELLS MAINTAIN THE HOMEOSTASIS OF INNATE INFLAMMATION PNAS (2008) Trends Immunol （2009）

  22. T cells are part of the innate immunity and negatively regulate the early innate inflammatory response Adaptive immunity

  23. 谢 谢

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