complement system 补体系统 immunology qingqing wang institute of immunology zhejiang university...
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complement system补体系统
IMMUNOLOGY
Qingqing WangInstitute of Immunology
Zhejiang University School of Medicine
Complement
1. Introduction
2. Activation of the Complement System
3. Regulation of complement activation
4. Biological function of complement system
Jules Bodet (1870-1961),
Discoverer of Complement
1894 Bordet 发现绵羊抗霍乱血清能够溶解霍乱弧菌,加热 56 30 min ℃ 阻止其活性;加入新鲜非免疫血清可恢复其活性。
1919 Nobel Prize
百日咳杆菌
Complement
IntroductionComplement (C) A group of serum proteins involved in
the control of inflammation, the activation of phagocytes and the lytic attack on cell membranes.
This activity is destroyed (inactivated) by heating serum at 56C for 30 minutes .
Complement System consists of a large number of
proteins which become enzymes after being activated.
Complement
1. Activation proteins
2. Regulatory proteins
3. Complement receptor
Complement
I. Proteins of the Complement
System
b 是大片段, a 是小片段
Abul K. Abbas, Adrew H. Lichtman, Shiv Pillai. Cellular and Molecular Immunology. Saunders ELSEVIER, 6th edition
医学免疫学,人民卫生出版社,第四版
第五版… C2 特殊, C2a 是大片段
Activation ProteinsClassical pathway: C1q, C1r, C1s, C4, C2
MBL pathway: MBL, MASP
Alternative pathway: factor B, D
Terminal pathway: C3, C5, C6,
C7, C8, C9
Complement
Regulatory ProteinsC1INH, C4bp, factor I, factor HS protein, membrane cofactor proteindecay-accelerating factor (DAF) …
Complement receptorCR1~CR5, C3aR, C2aR, C4aR…
Complement
II. Complement producing cells
Liver hepatocytes Monocytes/Macrophages Epithelial cells
Complement
Notation C-----complement C1, C2,
C3, C5 a-----small fragment C2a, C3a b-----large fragment C2b, C3b,
C5b ¯-----activated (enzyme) C1 i-----inactivated iC3b
Complement
Activation of the complement system
1. Classical pathway 2. MBL pathway MBL: mannan-binding lectin
3. Alternative pathway
Complement
Classical pathway A suitable Ab bound to Ag, Ag-Ab complex C1, C4, C2 and C3, Ca++ and Mg++ cations 1. C1 activation 2. C4 and C2 activation (generation of C3 convertase) 3. C3 activation (generation of C5 convertase) 4. Generation of C5 convertase marks the end of the classical pathway
Complement
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ActivatorsActivation of this pathway may occur via Ag-Ab complex (immune complex, IC) or by aggregated Ig.IgG (IgG1,IgG3) and IgM are most efficient in reacting with complement. Only one molecule of IgM is required, whereas at least two molecules of IgG are needed.
Soluble antibody can’t activate complement
Complement
Three steps1. Recognition ( C1 activation ) The components involved : C1q, C1r, C1s Ag + Ab→ IC→bind C1q→C1r→ C1s → C12. Activation The components involved: C4, C2 and C3 (1) C4 and C2 activation, generation of C3 convertase (2) generation of C5 convertase3. Attack (terminal pathway) The components involved: C5, C6, C7, C8, C9 the membrane attack complex (MAC): C5b6789
Classical pathway
Complement
C1 molecule
Ca++
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Classical pathway
Complement
Ca++
Complement
Classical pathway
Ag-Ab complex
C3 convertase
C5 convertase
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Alternative pathwayActivators : bacterial lipopolysaccharides (endotoxin), certain complex polysaccharidesnormal: Circulating plasma C3 undergoes spontaneous hydrolysis of its thioester bond to form a conformationally altered species called C3(H2O). Once the thioester group has opened, C3(H2O) acts like C3b.
C3→ C3a ↓ D C3b+B→ C3bB→ C3bBb (C3 convertase) → be dissociated ↑- ↑- I I/H
abnormal: no factor I and H on the surface of bacterial C5 convertase :C3bBb3b or C3bnBb
Alternative pathway 1.It is rather different from the MBL and classical pathway. 2. no C1,C4 and C2 involved factor B and factor D involved 3. the presence of suitable activator surfaces,such
as bacterial and fungal cell walls. 4. C3b: from the classical pathway; spontaneous produced C3b
Complement
Alternative pathway
Complement
alternative pathway
characters 1. It can recognize “self” and “non-self”
2. The amplification loop
MBL pathwayActivators : MBL (like C1q)MBL recognizes certain carbohydrates expressed on the surface of microorganisms.
↓ MBL activate two MBL-associated serine proteases ------- MASP-1 and MASP-2.
↓ ↓cleaves C3 cleaves C4 and C2 to activate the alternative generate the C3 convertase
(C4b2b )pathway directly
Activation of the Complement System
MBL pathway
When MBL binds to terminal mannose groups on bacterial carbohydrates, it activates MASP-1 and MASP-2, which go on to activate the classical pathway in an antibody-independent fashion.
complement
MBL pathway
Complement
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The Complement Pathways
Lectin Pathway
Classical Pathway
Alternative Pathway
C1q C4 C2 C3 C5 to C9 Lysis
MBL
C3 (H2O), C3b Factors D, B, Properdin
MASP 1,2,3
C1r,C1s
Activation of the Complement System
Terminal pathway:MAC(membrane attack complex)
complement
Activation of the Complement System
complement
Terminal pathway
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不同途径补体系统激活的比较经典途径 MBL 途径 旁路途径
免疫复合物 病原体甘露糖残基
C1 、 C4 、 C2
MASP 、 C4 、C2
病原体表面
C3 、 B 、 D
C3 转化酶
C5 转化酶
攻膜复合体
Regulation of complement activation
1.Self-regulation C4b2b C3bBb C4b C3b C5b2.Control proteins classical pathway:C1INH C4bp I MCP
DAF alternative pathway: H I CR1 DAF P formation of MAC: C8bp CD59
complement
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Regulation of complement activation
complement
C1IHN 缺陷引起血管神经性水肿
Regulation of complement activation
complement
Regulation of complement activation
complement
Regulation of complement activation
complement
Regulation of complement activation
complement
Biological function of complement system
1. complement mediates anti-infection immunity
(1) Lysis of cell or microorganisms (2) opsonization (3) inflammation
complement
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(1)complement mediated lysis of cells
溶菌 溶细胞
补体的溶细胞作用
肥大细胞 过敏介质
C5aC3a
补体的过敏毒素作用
C567C5a
C3a
补体的趋化作用
中性粒细胞
单核 - 巨噬细胞血管
组织
免疫复合物
C3b 受体
红细胞
补体的免疫黏附作用
清除免疫复合物
细菌
C3b 受体
吞噬细胞
补体的调理作用
补体调理杀菌作用
C1q—— 识别免疫复合物、识别病毒膜蛋白
C4a—— 过敏毒素
C4b—— 组成 C3 、 C5 转化酶、参与免疫粘附
C2b—— 组成 C3 、 C5 转化酶
C3a—— 过敏毒素、趋化因子
C3b—— 组成 C3 、 C5 转化酶、参与免疫粘附、调理作用
C5a—— 过敏毒素、趋化因子
C5b 、 C6 、 C7—— 趋化因子、组成攻膜复合体
C8 、 C9—— 组成攻膜复合体
Ba—— 参与免疫调节
Bb—— 组成 C3 、 C5 转化酶
补体系统各成分的生物学作
用
(2) opsonization opsonin: C3b, C4b, iC3b cell: phagocyte receptor: CR1, CR3, CR4 function: enhance
phagocytosis
complement
(3) inflammatory response symptoms: redness, swelling,
heat and pain inflammation mediators anaphylatoxins: C5a, C3a, C4a chemoattractant: C5a
complement
2. Complement maintains
homeostasis(1) clearance of IC (immune complex): C3b
(2) elimination of apoptotic cells: C1q, C3b,
iC3b
3. Complement mediates adaptive immunity(1) Participates in the induction of immune
response (CD19/CD21/CD81on B cells)(2) Participates in the proliferation and differentiation of immune cells (B cells)(3) Participates in the effector function of
immune response (complement fixing Ab)(4) Participates in immune memory (through
FDC)4. Complement interacts with other enzyme systems
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