Immunoregulation

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ImmunoregulationImmunoregulation

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Immunoregulation:homostasisImmunoregulation:homostasis

• Normal

anti-infection

anti-tumour

• Abnormal

Auto-immune disease

Tumour

Persisitent infection

Allergy

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SARS patient healthy subject

severeinflammation

reactionin lung

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Regulation of innate immunityImmunoregulation mediated by Inhibitory ReceptorRegulation by TregIdiotype networkImmunoregulation by other mechanism

ImmunoregulationImmunoregulation

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A. Regulation of innate immunity1.Feedback Regulation of secretion of inflammatory factor

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PAMP PAMP • PAMPs (Pathogen associated molecular

patterns) are conserved structures among many pathogens. PAMPs are generated by microbes and not by the host, suggesting that PAMPs are good targets for innate immunity to discriminate between self- and nonself. Furthermore, PAMPs are essential for microbial survival.

• LPS, CpG DNA ， ssRNA ， dsRNA, PGN, LTA, HSP, et al.

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PRR PRR

• Pattern Recognition Receptors (PRRs)• charateristic Few diversity Non clonal ditribution Immediate immune response

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PRR: classificationPRR: classification• Mambrane PRR:TLR1,2,4,6;MR ； SR ；• Secretory PRR:MBL;CRP;LPB ；• Cytoplasm RR:TLR3,TLR7/8,TLR9; NLR;RIG-Ⅰ,MDA-5;

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固有免疫中针对 TLR 信号转导的负向调节TIR: Toll/IL-1 receptor; ASK1: 凋亡信号调节激酶 1; IRAK: IL-1 受体相关激酶 ; MAPK: 丝裂原激活

蛋白激酶 ; MyD88: 髓样分化因子 88; NF-B: 核因子 B; PI 3K: 磷酸肌醇 3 激酶 ; PIP2 ： 2 磷酸磷脂酰肌醇 ; PIP3: 3 磷酸磷脂酰肌醇； PKB: 蛋白激酶 B; Rac: 小 G 蛋白 ; SIGIRR: 单一 Ig IL-1R 相关分子 ;

TIRAP: TIR (Toll/IL-1 受体 ) 相关蛋白 ; TRAF6: TNF 受体相关因子 6 。

炎症细胞因子基因转录

TLR4 CD14ST2SIGIRR

MD2

MyD88

TIRAP

TRAF6

SOCS1 IRAK1IRAK4

NF-B

MAPKPKB

PI 3K

MyD88s

IRAK-M

受体衔接蛋白信号分子激酶转录因子抑制因子基因转录激活抑制

Rac1

PIP2 PIP3

ASK1

TIR TIR

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A. Regulation of innate immunity1.Regulation by SOCS (suppressor of cytokine signaling)

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C

蛋白质泛素化降解

Jak

Stat

CIS

SOCS1

SOCS3

Jak

A

Jak

Stat

Stat

胞核

DNA

细胞因子受体细胞因子

SOCS 家族部分成员 D

N 端区 SH2 结构域 SOCS 框

胞核

B

基因 X,Y,Z

SOCS 基因

生物学效应

Yp

Stat

其它信号途径

基因转录

Stat

细胞因子细胞因子受体

磷酸化

胞核

Jak

Y

CISSOCS1SOCS2SOCS3

pY

SOCS 蛋白以负向反馈环路阻抑细胞因子的信号转导

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补体成分 C3裂介后产生的相关分子

C3

C3b

C3d

C3c

C3f

C3 转化酶

I factor

I factor+ H

Factor

C3dg

C3a

iC3b

C3g

C3 转化酶 C3 转化酶

Complement regulatory Protein

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蛋白磷酸化和脱磷酸化分别由蛋白激酶和蛋白磷酸酶促成

蛋白质 ATP -OH+ ADP + 蛋白质 O ‖-O-P-O-

| O-

蛋白质 O ‖-O-P-O-

| O-

蛋白质 -OH ++

O ‖HO-O-P-O-

| O-

H2O

蛋白激酶

蛋白磷酸酶

蛋白磷酸化

蛋白脱磷酸化

PTK and PTP

Inhibitory receptor mediated regulation

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免疫细胞激活性受体和抑制性受体及其作用特点

基因转录

激活抑制

Zap-70, Syk SHP-1, SHP-2

ITAM ITIM

Src PTK

PTK PTP

磷酸化

激活性受体

抑制性受体

磷酸化脱磷酸化

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24 h

B7

CD28

Ag

TCR

B7

CTLA-4

激活信号

I T I MI TAM

抑制信号 T 细胞

CTLA-4 对 T 细胞激活的反馈调节

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抑制性受体 FcRII-B 对抗体产生的反馈性调节

干扰 B 细胞激活的信号转导

BCR (mIgM)抗 BCR 抗体 Ag-Ab 复合物

FcRII-B FcRII-B

ITIM ITIM

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BCR (mIgM)

抗 BCR 抗体 (Ab2)

FcRII-B

ITIM

B 细胞激活信号转导受阻

抑制性受体 FcRII-B 对抗体产生的反馈性调节

1919人 NK 细胞主要的抑制性受体和激活性受体

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T Cell

B cell

T cell

Mast cell

NK cell

TCR-CD3

BCR-Ig/Ig

V9V2 TCR

FcRI

KIR-S + DAP12CD94/NKG2C + DAP12

NKG2D + DAP10NCR + /FcR1CD16 + /FcR1

CTLA-4, PDL-1, BTLA

FcRII-B, CD22

CD94/NKG2A

FcRII-B

KIR-LCD94/NKG2A

ILT2

Cell Activating receptor Inhibitory receptor

Activating receptor and Inhibitory receptor of Immune cells

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C. Regulation by Treg C. Regulation by Treg lymphocyteslymphocytes

characteristic Nature Treg adaptive Treg

Induction location Thymus (periphery), periphery

Foxp3 +++ +

IL-2 dependence + +

CD25 +++ -/+

Antigen specificity Auto-antigen Tissue-specific Ag and exogenous Ag

mechanism Cell-contact, CK independence

Cell-contact, CK dependence

Function Inhibit ART mediated Response

Inhibit pathological response

Example CD4+CD25+T CD4+ Tr1,Th3

Naturally Treg and adaptive TregNaturally Treg and adaptive Treg

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Differing immunosuppressive mechanisms used by TReg cells in lymphoid and non-lymphoid tissues. Nature Reviews Immunology 11, 119-130

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共刺激

IFN-TNF-

CCR5CXCR3

IL-4IL-5IL-13

CCR3,4,8

Th1

Th2

IL-4

pMHC

Th 0初始 T

IL-4RStat6

IL4

Gata3

IFNG

IFN-R

IL-12IL-12R

pMHC

TCRStat4 Stat1

IFNG

T-bet

IL4

IL-23IL-23R

Stat3

IL17

IFNG, IL4

IL-17IL-17F

Th17

IL-23

IL-12

IL-4

IFN

细胞免疫

体液免疫

炎症反应

IL-17

RORt

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发挥调节作用的 Th1 和 Th2 亚群在功能上的相互拮抗Th1 和 Th2 亚群各自藉助分泌的细胞因子和激活的亚群专一性转录因子以调

节性 T 细胞的形式抑制另一亚群的分化

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IFN- 逆转 Th2 极化格局通过激活 Th1 诱导抗胞内菌免疫

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Th2

肥大细胞

嗜酸粒细胞

IgE

发展中国家

发达国家

蠕虫感染

过敏体质

Th2系统的双刃剑效应和自然选择

自然选择

世界人口1/32

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D. Regulation by idiotypes and anti-idiotypic antibodies Antibodies formed against Ag-binding sites of an Ab are called anti-idiotypic antibodies, and are capable of influencing the outcome of an immune response. Id and AId interactions may enhance or suppress Ab responses.

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(1) Isotype The genes for isotype variants are

present in all healthy member of a species.

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(2) Allotype This refers to genetic variation

between individuals within a species.

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(3) Idiotype Variation in the V domain ,particularly in

CDR, produces idiotype.

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Idiotype network and antigen internal image

Ag

Ag Ab1 (Id) Ab2 (AId) Ab3 Ab

epitope

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利用独特型网络进行免疫干预的两种主要途径

Ag

Ab2

增强 Ab1

Ab1

Ab2

B

AAb3 / Ab1

Ab1

Ab2

Ab2

削弱 Ab1

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E. Regulation by apoptosisE. Regulation by apoptosis

1. Activation-induced cell death (AICD) Fas (CD95) and FasL• Fas membrane protein is expressed on lymphoid and other

cells but is increased in expression with cellular activation. FasL is expressed on activated T cells. Thus, activation of T cells results in the expression of both Fas and FasL.

• The intracellular portion of the Fas receptor molecule contains ‘ death domains’, which recruit proteins that lead to the activation of a cascade of proteases which induce apoptosis.

• Fas-FasL interaction is a major means of mediating AICD in CD4+ T cell.

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(1) Fas/FasL and death signal transd(1) Fas/FasL and death signal transduuction ction evoevokkeded by Fas molecules by Fas molecules

DD:death domain

70aa

80aa

150 aa

FasL Fas (receptor)

Fas (CD95), a type Imembrane protein with325 aa (48 kD)

FasL (Fas ligand), a type II membrane proteinwith 235 aa

sFasL

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Fas-FasL pathwayFas-FasL pathway

Caspase: 胱天蛋白酶

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• Major advances have recently been made in mapping the loci which govern susceptibility to the autoimmune disease.

• When the lymphoproliferative (lpr) gene is present in mouse strains, it causes the development of a characteristic clinical syndrome. The mice develop anti-DNA antibodies, rheumatoid factor, circulating IC and glomerulonephritis.

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WT TTT GAG GAA TCT AAG ACC TTT TTC GGC TTG TAT AAGgld TTT GAG GAA TCT AAG ACC CTT TTC GGC TTG TAT AAG

CYT TM EXTgld

Phe

Leu

lprAsn

死亡结构域Ile Fas

FasL

A

B

自身免疫性淋巴细胞增生综合征

自身抗原

自身抗原驱动下的淋巴细胞克隆扩增

克隆收缩受阻

克隆收缩

无疾病

AICD

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F. Regulation by neuroendocrine F. Regulation by neuroendocrine system system Lymphocytes express receptors for

many hormones, neurotransmitters and

neuropeptides.

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G. Genetic control of immune response

1. Control of immune response by MHC• Immune response genes (Ir) control all

immune responses• Most of the polymorphic residues in MHC

molecules reside in the peptide-binding groove

• MHC restriction APC-Th, Th-B MHC II CTL-Target MHC I

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2. Non-MHC-linked genes affect immune

response 1)Polymorphisms in the genes encoding

cytokine receptors have been shown to correlate with an increased susceptibility to infection, SCID or inflammatory conditions.

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2) 2) Genetic control of specificity of an Genetic control of specificity of an immune response immune response

• Antigen is recognized by the lymphocyte that express specific antigen receptor (TCR/BCR) for that antigen.

• TCR and BCR are encoded by corresponding genes, thereby specificity of an immune response is genetically controlled.

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3) Other non-MHC genes also 3) Other non-MHC genes also modulate immume responsesmodulate immume responses

• Deficiency in C1q,C1r,C1s SLE and lupus

nephritis• Deficiency in C3 bacterial infections• ‘atopy gene’ on human allergy (high IgE

chromosome 11q production)

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QuestionQuestion

• The inhibitory receptors of immune The inhibitory receptors of immune system and its biological significancesystem and its biological significance

• Difference between nature Treg and Difference between nature Treg and inducible Treginducible Treg

Immunoregulation

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