医学免疫学英文版课件：Chapter 6 Complement system

1、MEDICAL IMMUNOLOGYChapter 6 Complement SystemContentsIntroduction of the complement systemActivation pathways of complement system Regulation of complement activationBiological functions of complement Jules Bordet (1870-1961), 1919 Noble PrizeDefinition of complement system： A system of serum and ce

2、ll surface proteins （including more than 30 proteins ) that interact with one another and with other molecules of the immune system to generate important effectors of innate and adaptive immune response. Part Components and properties of complement system(I) The components of complement system1. Com

3、ponents participating complement activation Classical pathway: C1 (C1q,C1r,C1s)，C2， C3， C4MBL（mannose-binding lectin) pathway: MBL, MASP( MBL-associated serine protease) Alternative pathway: factor B, factor DCommon terminal pathway：C5，C6，C7，C8，C92. Regulatory componentsfactor I, factor H, properdin

4、 (factor P) S protein, SP40/40C1 inhibitor (C1 INH)C4-binding protein (C4BP)membrane cofactor protein (MCP) decay accelerating factor (DAF)homologous restriction factor (HRF)membrane inhibitor of reactive lysis (MIRL)3.Complement receptors (CR) CR1CR5, C3aR, C2aR, C4aR() Physical and chemical featur

5、es of complement system 1. Synthesized sites: liver, macrophage, small intestine epithelium 2. The concentration of complement in serum is stable (4 g/L) , C3 is the highest in all of complement components:12 g/L 3. Heatlabile feature: 56 30mininactivation 010 for 35 days() Nomenclature of the compl

6、ement systemIntrinsic components in classical pathway: C1C9Intrinsic components in alternative pathway: factor B, factor DRegulatory proteins: C1 INH, C4BPCleaved fragments: C3a, C3b; C2a, C2bActivated components: C1; C4b2aInactivated components: iC3bComplement receptor: CRPart Activation of the com

7、plement system () The Classical pathway1. Components: C1(C1q,C1r,C1s),C4,C2,C3,5,6,7,8,92. Activating substances: Ag-Ab complex or immune complex IgG1-3, IgM3. Process of the classical pathway 1) Initiation step: activation of C12) Activation step: activating unit ( C4,C2,C3), formation of C3 conver

8、tase and C5 convertase3) Effector step: formation of membrane-attack complex (MAC), C59 recognizing unit (C1qrs) - activated C1IgG13 and IgM can activate complement by classical pathwayThe complement component C1 binds to the Fc part of the antibodies (CH2 of IgG or CH3 of IgM), and then is turned i

9、nto activated C1 (C1)1) Initiation step6C1q+ 2C1r+2C1s = C1C1qC1rC1sThe first protein in the classical pathway is C1Structure of C1After antibody binds to antigen on the surface of a pathogen，complement-binding sites are exposed.C1 binds to at least two IgG molecules or one IgM molecule to be activa

10、ted. C1s C4、C2 C4b2a（C3 convertase） C3 C4b2a3b （C5 convertase） 2) Activation stepFormation of C3 convertase and C5 convertaseC4aC4bThe C4b fragment binds to the surface of the pathogen Activated C1 cleaves C4 into C4b and C4a.C2bC2aC4bActivated C1 then cleaves C2 into C2b and C2a.C4b and C2a togethe

11、r form the C3 convertase (C4bC2a)C3 convertaseC2aC4bStructure and cleavage fragment of C3 Heterodimer: chain (120 kDa) and chain (70 kDa)C3a: anaphylatoxinC3b: C3 convertase (C3bBb) and C5 convertase (C4b2a3b)C3 convertaseC3C3bC3C3 convertase cleaves C3 into C3a and C3b.C3aC3bThe C3b covalently bind

12、s to C4b2a to form C4b2a3b complex, C5 convertaseC3bC3aC3aC5 convertase（C5 convertase）Classical pathwayIgM/IgG Ag complexC1q : r : sC4C4b + C2C4aC2bC4b2aC3C3bC3a Ca+Mg+ Ca+（C3 convertase）C4b2a3b Formation of the Membrane Attack Complex (MAC) MAC: a lytic complex of the terminal components of the com

13、plement cascade, including C5,6,7,8 and multiple copies of C9, that forms in the membrane of target cells. The MAC causes lethal ionic and osmotic changes in cells. 3) Effector step: Common terminal pathwayC5 convertase cleaves C5 into C5a and C5b.C5 convertaseC5bC5aC5bC5b binds to the surface and C

14、6 binds to C5b and stabilizes C5b.C6C5bC6C7Then C7 binds and inserts into the phospholipid bilayer of the plasma membrane.C5bC6C7Then C8 binds to the complex and also inserts into the bilayer.C8C5bC6C7Finally, C9 molecules bind to the complex and polymerize. C8C9C5bC6C7Twelve to fifteen C9 molecules

15、 form a pore in the membrane.C8C5bC6C7The membrane attack complex is a pore in the plasma membrane.C8Effect of MACOn the surface of cell: lyse the cellIn the serum: SC5b7, SC5b8, SC5b9() Alternative pathway 1. The initiating substances: some components of microbial cell surface, aggregated IgA or Ig

16、G4-providing a surface for binding of complement molecules 2. Components and process: factor D, factor B, C3,5,6,7,8,93. The process of complement activation 1) Initiation step: C3b binds to microbial surface, binds factor B, and forms C3 convertase.2) Activation step: formation of C5 convertase3) E

17、ffector step: formation of membrane-attack complex (MAC), C5-9 Normally, C3 in plasma is being continuously cleaved at a low rate to generate C3b in a process.A large amount of the C3b in the fluid phase is unstable and inactive. C3b may become covalently attached to the surfaces of cells, including

18、 microbes.Important characteristics In alternative pathway, complement can recognize self from nonself-complement regulatory protein.Alternative pathway is the important enlarge mechanism of complement activation.C3bC3bBC3positive feedback loop of C3D factor C3bBbB factor() MBL Pathway 1. Initiating

19、 substances: MBL combine with mannose on the surface of microbe.2. Components: Mannose-binding lectin (MBL), MBL-associated serine protease (MASP), C4,C2,C3,5,6,7,8,93. The process of complement activation1) Initiation step: MBL binding to mannose on the surface of microbe, activation of MASP.2) Act

20、ivation step: form C3 and C5 convertase3) Effector step: formation of membrane-attack complex (MAC), C5-9 The MBL and c-reactive protein were produced by liver after microbe infection.MBL binds to mannose residues of microbe.The MBL, structurally similar to C1q. Mannose-binding lectinMBL is Structur

21、ally similar to C1qMBL binds to mannose on glycoproteins on the surface of microorganisms. Then MASPs bind to it.MASP-1MASP-1MASP-2MASP-2MASP = MBL-associated serine protease (similar to C1r and C1s) mannoseMBL mannose MASPC4C4a + C4bC2C2a + C2bC4b2a(C3 convertase)+ MASP三种途径的比较 经典途径 MBL途径 旁路途径参与的 C1

22、C9 C2C9 C3,C5C9,B因子,补体部分 D因子, P因子 C3转化酶 C4b2b C4b2b C3bBb作用 参与特异性体液免疫的应答阶段参与非特异性免疫在感染早期发挥作用参与非特异性免疫在感染早期发挥作用激活物质 Ag-Ab复合物 MBL,CRP LPS, 凝集素,抗体C5转化酶 C4b2b3b C4b2b3b C3bnBb激活蛋白酶 C1s MASP D因子Part Regulation of complement system The explosive potential of the complement system requires that it is kept un

23、der tight control.There are at least 12 proteins known that do this.Mechanism of complement regulation Regulation of self-inactive: decay Spontaneous decay of complement: Cleaved components C3b,C4b,C5b C3 convertase (C4b2a,C3bBb) C5 convertase (C4b2a3b,C3bnBb) Action of regulatory factors 1.Regulati

24、on of C1 activation: C1 inhibitor (C1INH) binds to sites on activated C1r and C1s, shutting down their proteolytic activity. Action of regulatory factorsC1 inhibitor2. Regulation of C3 convertaseFactor H removes Bb from the alternative pathway C3 convertase, breaking the positive feedback loop.C4 bi

25、nding protein (C4bp) binds to C4b, blocking formation of C3 convertaseDecay-accelerating factor (DAF) -binds to Bb or C4b, breaking formation of C3convertase Factor I inactivates C3b and C2b Factor P binds to C3bBb and stabilizes C3 convertase.factor HC4-binding protein (C4BP)Decay-accelerating fact

26、or (DAF)3. Regulation of MACHomologous restriction factor (HRF): HRF (C8bp )-interferes with binding of C9 to C8, prevents formation of MAC Membrane inhibitor of reactive lysis (MIRL): MIRL(CD59)-interferes with binding of C5b6 complex and C7,C8, and prevents formation of MAC Homologous restriction

27、factor (HRF)Part Biological functions of complement system 1. Lyse bacteria and cells C3b and C4b in the surface of microorganisms attach to complement receptor (CR) on phagocytes and promote phagocytosis. 2. Opsonization1) CR1(CD35,C3b/C4bR):Mainly express on blood cellsCombine with C3b and C4b wit

28、h high affinityParticipate in opsonization, immune adhesion2) CR2(CD21) ：Mainly express on B cellCombine with C3dg,C3d and iC3bPromote B cell to be activated Act as the receptor of EBV (epstein-barr virus)3) CR3 ：Combine with iC3bNeutrophil, phagocyte, B cell, NK4) CR4(CD11c/CD18), CR5 ：Combine with iC3b and C3dgNeutrophil, phagocyte3. Elimination of immune