1、Complement system Xiaojian Wang Institute of immunology, ZJU http:/ of the Complement System Regulation of complement activationBiologic function of complement system,Jules Bodet (1870-1961),Discoverer of complementNobel prize in 1919,complement,Introduction,complement,Complement (C) 补体(complement，C
2、)是存在于正常人和动物血清与组织液中的一组经活化后具有酶活性的蛋白质。 是一种不耐热的成分，可辅助和补充特异性抗体，介导免疫溶菌、溶血作用，故称为补体。Complement System补体是由30余种补体固有成分、补体受体和细胞膜补体调节蛋白的多分子系统，故称为补体系统（complement system）。,Introduction,Components of C system 1. Innate C components 2. Regulatory Proteins 3. Complement receptor,complement,Introduction,Components of
3、C system 1. innate components classical pathway:C1q,C1r,C1s,C4, C3,C2 Alternative pathway:B,D,P,C3 MBL pathway:MBL,MASP terminal pathway:C5,C6,C7,C8,C9,complement,Introduction,2. regulatory proteins C1-INH, C4-BP, I factor, H factor S protein,Sp40/40, decay-accelerating factor (DAF) 3. complement re
4、ceptor CR1CR5,C3aR,C4aR,C5aR,complement,Introduction,nomenclature : C-complement C1,C2,C3,C5 B,D,H,I,P factor C4B,DAF a-small fragment C2a,C3a b-large fragment C2b,C3b,C5b -activated(enzyme) C1 i-inactivated iC3b,complement,The properties of Complementglycoprotein: globulinLabile to heat: The activi
5、ty of C is destroyed (inactivated) by heating serum at 56 for 30 minutes .C produced cells: Hepatocytes and MacrophagesBelongs acute phase protein zymogen to protease: number of complement proteins are zymogens that can be activated by proteolytic cleavage,complement,Activation of the C System,Pathw
6、ays of complement activation: triggered-enzyme cascade 1. Classical pathway 2. Alternative pathway 3. MBL pathway MBL:mannose-binding lectin,complement,Classical pathway 1. C1 activation by Ag-Ab complex 2. C4 and C2 activation generation C3 convertase 3. C3 activation (generation of C5 convertase)
7、4. Generation of C5 convertase marks the end of the classical pathway,complement,Three steps：Classical pathway,1. Recognition ( C1 activation ) involved：C1q, C1r, C1s Ag + AbICbind C1qC1rC1sC1 2. Activation involved：C4, C2 and C3 (1) C4 and C2 activation, generation of C3 convertase (2) C3 activatio
8、n (generation of C5 convertase)3. Attack (terminal pathway) involved：C5,C6,C7,C8,C9 the membrane attack complex(MAC):C5b6789 the MAC causes lysis of cells,Activator: Ag-Ab complex /IC Combinding CH2 of IgG or CH3 of IgM One of IgM molecule or two molecules of IgG are needed. IgMIgG3IgG1IgG2 Soluble
9、antibody cant activate complement,complement,Recognition ( C1 activation ),classical pathway,complement,C1 molecule,Activation The components involved: C4,C2 and C3 (1)C4 and C2 C3 convertase (2)C4,C2,C3 C5 convertase,C4,Classical Pathway Generation of C3-convertase,C4b,Mg+,C4a,C2,Classical Pathway
10、Generation of C3-convertase,C4b,Mg+,C4a,C2b,C3,Classical Pathway Generation of C3-convertase,complement,complement,Attack (terminal pathway) involved：C5,C6,C7,C8,C9 the membrane attack complex(MAC):C5b6789 the MAC causes lysis of cells,complement,Terminal pathway(MAC),Terminal pathway,complement,Alt
11、ernative pathway,Activators： LPS(endotoxin), certain complex polysaccharides, IgA and IgG4,Alternative pathway It is rather different from the MBL and classical pathway. 1. no C1,C4 and C2 involved factor B and factor D involved 2. the presence of suitable activator surfaces,such as bacterial and fu
12、ngal cell walls. 3. C3b: from the classical pathway; spontaneous produced C3b,complement,Characters of alternative pathway 1. it can recognize “self” and “non-self” 2. the amplification loop,Mannan-binding lectin pathway,Activators：MBL (similar to C1q, hexamer)MBL recognizes certain carbohydrates ex
13、pressed on the surface of microorganisms MBL activate two MBL-associated serine proteases - MASP-1 and MASP-2 cleaves C3 cleaves C4,C2 to generate activate the alternative the C3 convertase (C4b2a)pathway directly,Regulation of complement activation,1.Self-regulation C4b2b C3bBb C4b C3b C5b2.Control
14、 proteins Classical pathway: C1INH C4bp I MCP DAF (C3b和Bb) Alternative pathway:H I CR1 DAF MCP Properdin Formation of MAC: C8bp CD59(MIRL),complement,Regulation of complement activation,complement,Regulation of complement activation,complement,Regulation of complement activation,complement,A,Regulat
15、ion of complement activation,complement,Biologic function of complement system,1. mediates anti-infection immunity (1) Lysis of cell or microorganisms (2) opsonization (3) inflammation,complement,complement mediated the lysis of cells,complement,opsonization opsonin:C3b,C4b,iC3b cell:phagocyte recep
16、tor:CR1,CR3,CR4 function:enhance phagocytosis,complement,(3) inflammatory response symptoms: redness, swelling, heat and pain inflammation mediators: C5a,C3a,C4a ( anaphylatoxins) C5a (chemotaxis),complement,Biologic function of complement system,complement,2. Complement maintains homeostasis 1) cle
17、arance of IC C3b 2) elimination of apoptosis cells C1q,C3b,iC3b,3. Complement mediates adaptive immunity 1) Induction of immune response 2) Proliferation and differentiation of immune cells c3d 3) Effective stage of immune response 4) Immune memory,4. Interaction with other enzyme system,Summary,Review the differences between the three pathways of complement in terms of how they are activated. Why the complement do not attack autologous cells?,Thanks!,
