11
ImmunoregulationImmunoregulation
22
Immunoregulation:homostasisImmunoregulation:homostasis
• Normal
anti-infection
anti-tumour
• Abnormal
Auto-immune disease
Tumour
Persisitent infection
Allergy
33
SARS patient healthy subject
severeinflammation
reactionin lung
44
Regulation of innate immunityImmunoregulation mediated by Inhibitory ReceptorRegulation by TregIdiotype networkImmunoregulation by other mechanism
ImmunoregulationImmunoregulation
55
A. Regulation of innate immunity1.Feedback Regulation of secretion of inflammatory factor
66
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.
77
PRR PRR
• Pattern Recognition Receptors (PRRs)• charateristic Few diversity Non clonal ditribution Immediate immune response
88
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;
9
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
1010
A. Regulation of innate immunity1.Regulation by SOCS (suppressor of cytokine signaling)
11
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
12
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
13
14
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
15
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
16
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
17
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
18
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
20
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
2121
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
2222
Differing immunosuppressive mechanisms used by TReg cells in lymphoid and non-lymphoid tissues. Nature Reviews Immunology 11, 119-130
2323
24
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
2525
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
2626
27
IFN- 逆转 Th2 极化格局通过激活 Th1 诱导抗胞内菌免疫
28
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
2929
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.
3030
(1) Isotype The genes for isotype variants are
present in all healthy member of a species.
3131
(2) Allotype This refers to genetic variation
between individuals within a species.
3232
(3) Idiotype Variation in the V domain ,particularly in
CDR, produces idiotype.
3333
34
Idiotype network and antigen internal image
Ag
Ag Ab1 (Id) Ab2 (AId) Ab3 Ab
epitope
35
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
3636
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.
3737
(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
3838
Fas-FasL pathwayFas-FasL pathway
Caspase: 胱天蛋白酶
3939
4040
• 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.
41
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
4242
F. Regulation by neuroendocrine F. Regulation by neuroendocrine system system Lymphocytes express receptors for
many hormones, neurotransmitters and
neuropeptides.
4343
4444
4545
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
4646
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.
4747
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.
4848
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)
4949
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