炎症与免疫研究进展 中科院感染免疫重点实验室 唐 宏.

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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 炎症通常可按其病程分为急性炎症和慢性炎症
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。

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
对损伤性因子/因素所产生的反应

5 PAMP vs DAMP

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

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

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

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

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

12 Both naïve and Treg cells efficiently suppress the inflammatory cytokine storm
TNF- 100 200 pg/ml NT PanT Non Treg Treg Poly I:C  NT+GFP-T F TNF- NT NT+T 100 200 Poly I:C pg/ml  IFN- 50 150 IFN- 50 100 150  100 200 pg/ml (CD4 T/NT ratio) +Poly I:C IL10-/- T Wild T

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

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

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

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

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

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

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

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

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

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

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

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25 谢 谢