complement system补体系统

IMMUNOLOGY

Qingqing WangInstitute of Immunology

Zhejiang University School of Medicine

wqq@zju.edu.cn

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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