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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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slide1

炎症与免疫研究进展

中科院感染免疫重点实验室

唐 宏

slide2
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
slide3
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。
slide4

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

slide7

Adaptive immune system prevents overreactive innate immunity in the initial phase of infections

Dong et al, Nat Med (2007)

slide8

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

slide9

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

slide10

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-/-

slide11

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

slide12

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

slide13

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

slide14

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: -+ -+ - +

slide16

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

slide17

+ 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

slide18

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

slide19

**

*

*

**

*

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

slide20

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

slide21

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

slide22

effect

T

memory

T

IL1β,IL18

TNF

T CELLS MAINTAIN THE HOMEOSTASIS OF INNATE INFLAMMATION

PNAS (2008)

Trends Immunol (2009)

slide23

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

Adaptive immunity