医学免疫学英文版课件：Chapter4 Complement system

1、Chapter 4 Complement system Complement(C): a group of globulins that exist in the serum of normal human or animal ,relate to immune response and bear of enzyme activity after being activated. Jules Bodet (1870-1961),Discoverer of complementPart I Introduction Component of Complement and definition1.

2、Connatural components of the complements: components which take part in the activation of complements classical pathway: C1-C9, C1-C1q,C1r,C1s-11 components . C5,C6,C7,C8,C9- terminal pathwayalternative pathway: B, D, factorMBL pathway: mannan-binding lectin(甘露糖结合凝集素 ,MBL), serine proteinase. 2. reg

3、ulatory factors existed on cells or in humour: properdin(备解素), C1 inhibitor （ C1抑制物，ClINH） , I factor, C4 binding protein (C4结合蛋白,C4BP), S-protein、SP40/40、 membrane cofactor protein（膜辅助因子蛋白，MCP）、 decay accelerating factor（衰变加速因子，DAF）、 homologous restriction factor（同源限制因子，HRF）, membrane inhibtor of r

4、eactive lysis（膜反应性溶解抑制物，MIRL) 3.The complement receptor : CR1, CR2, CR3, CR4, CR5 II. Denomination of complents1.classical pathway components: according to the finding time :C1C92. Other connatural components : D factor ,B factor, etc.3. Regulatory proteins: according to its function4. Fragments: “a

5、” small fragments and “b” for big fragments5.activated components:C16.inactivated components: iC1III. The physical and chemical features of complementsThe concentration of C in serum is stable , C3 is highest in all of complement components:1.20-1.60g/LThe liver is an important organ producing compl

6、enment. Sensitive to heat : inactivated by heating in 56 for 30 minPart II The activation of complement system 1.Three pathway : classical pathway :from C1 By Ag-Abalternative pathway: from C3 By the surface of microbe MBL(lectin )pathway: from C4 and C2 by MBL 2.Terminal pathway : same in the 3 pat

7、hwayI. classical pathwayActivator: The C1 molecule binds to the antibody attached to the surface of antigen to trigger the classical pathway Components: C1-C9Process: C1-C4,C2C3,4,5,6,7,8,9 phase of recognition: recognizing unit (C1qrs) Phase of activation: activating unit( C4,C2,C3) Phase of attack

8、: membrane-attack complex (MAC)Founction: participate in HI1. Phase of recognition: C1 C1q binds to complement-binding site of Ab The C1q molecule has six globular heads joined to a common stem by long filamentous domains . Each globular head can bind to one Fc domain and binding of two or more glob

9、ulin heads activates the C1q molecule Fab fragmentFc fragmentExplored C1q combing siteConformation of Ig C1q combing site was coveredBefore combining with AgAfter combining with Ag CH1 CH2C1qC1qr2s2 C1r C1s 40nmAgAbAgPhase of recognition in classical pathway 1、phase of activationEach of C1should bin

10、d to more than 2 com-plement binding sites of Ig before activation Only the immuno-complex formed by IgG1-3 and IgM can active C1The free Ig cant activate C1Phase of recognitionC1 activate C4 and C2Formation of C3 convertaseC3 convertase2. Phase of activation: generate C3 convertase and C5 convertas

11、e Phase of activation -1: formation of C3 convertaseC3 convertase and C3Opsonization of ComplementPhase of activation 2: formation of C5 convertaseC5 convertasePhase of activation 2: formation of C5 convertase3.phase of attack(terminal pathway) :formation of MACmembrane-attack complex(MAC) generate

12、the MAC-C56789 cytolysisClassical pathwayIgM/IgG Ag complexC1q : r : sC4C4b + C2C4aC2aC4b2bC3C3bC3a Ca+Mg+ Ca+（C3 convertase）C4b2b3b（C5 convertase）II. alternative pathway : The initiating substances: some components of bacteria wall Aggregated IgA or IgG4 -providing a surface for Complement binding

13、Components and process: C3,4,5,6,7,8,9Function: spontaneous reaction towards microbeThere is a spontaneous conversion of C3 to C3b. Ordinarily the C3b is quickly inactivated: the C3b binds to inhibitory proteins, and the process is aborted.I(Inhibitory) factor BFactor D Spontaneous conversion of C3

14、C3 C3a C3bC3bBbP C3转化酶（C3 convertase）C3bnBb C5转化酶（C5 convertase）Spontaneous conversion or from classical pathwayC3bB factorD factorC3bBbC3bBbC3 convertaseC3C3bC3bnBbC5 convertaseenlargeC3bC3bBC3positive feedback loop of C3Dfactor C3bBbBfactorIn alternative pathway, Complement can recognize self from

15、 nonselfalternative pathway is the important enlarge mechanism of Complement III. MBL pathwayManose-binding lectin(MBL)Manose-binding protein(MBP): acute phase protein produced by liverCombine with manose on the surface of microbeInitiating substances: MBL combine with manose on the surface of micro

16、be ,then operate with MASP(MBL-associated serine protease)Process: MBL-manose-MASP-C4,2-C3,5,6,7,8,9 mannanMBP mannanMBPMASPC4C4a + C4bC2C2a + C2bC4b2b（C3 convertase）+ MASPIV. Terminal pathwaygenerate MAC C5b+C6+C7+C8+C9 = MACs MAC MACs 造成的细胞膜损伤 C7C6C8 C5bC9多聚体补 体 杀 伤 寄 生 虫Effect of MACV. comparatio

17、n of there pathways MBL-manoseMASPPart III. regulation of Complement system The explosive potential of the complement system requires that it be kept under tight control. At least 12 proteins are known that do this.Mechanism of C regulationregulation of self-inactive :decayactivation of regulatory f

18、actors Factor H removes Bb from the alternative pathway C3 convertase breaking the positive feedback loop. Factor I inactivates C3b and C4b. C1 inhibitor (C1INH) binds to sites on activated C1r and C1s shutting down their proteolytic activity.Regulation of classical and alternative pathwayPart IV. Biological action of complement 1.lyses the target cells :by MACNeutralizing and lysing virus 2. Biologic action of complement fragments:1) opsonization:C3b,C4b -CR12) Inflammantory mediators:Kinin-like action: C2aAnaphylatoxins:C3a,C5aChemokine-like action: C3a,C5a,C567 3)