医学免疫学课件：3 固有免疫系统-补体

1、固有免疫系统-补体DEPARTMENT OF IMMUNOLOGYJules Bordet (1870-1961), discoverer of complementBelgian bacteriologist and immunologist who received the Nobel Prize for Physiology or Medicine in 1919 for his discovery of immunity factors in blood serum; this was a development vital to the diagnosis and treatment

2、 of many dangerous contagious diseases.1. 补体概 述补体，存在于新鲜血清中，能够裂解抗体包被的细胞（antibody (Ab)-coated cells） 。 这种活性可以经加热56度，30分钟而灭活 (失活)对热不敏感的特异性抗体热敏感的成分这种热敏感的成分被命名为补体 （ complement）, 即补充抗体活性的血清成分.1. 补体概 述补体调理、中和B细胞激活形成裂解复合物趋化和炎症反应补体系统凝血系统纤溶系统缓激肽系统是一组由生物大分子组成的连续而分级的激活反应系统。一旦激活，可介导一系列的对宿主重要的生物反应。1. 补体概 述1）固有成分：

3、C19，MBL、SP、Bf、Df2）调节蛋白：Properdin、C1INH、C4bBp、Hf、 If、CR1、Sp3）补体受体：CR1CR5、 C2aR、 C3aR、C4aR1. 补体概 述补体系统的组成1. “C” - 补体的11种蛋白 (C1, C2, etc.)2. Factor - 一些旁路途径的成分 (factor B)3. Overbar - 表示具有酶活性的蛋白活复 合物 （C4b2a） 4. Lower case letters - 表示蛋白酶裂解的 片段 (C3a or C5a)5. “R” - 补体的受体 (CR1 or C5aR)1. 补体概 述补体的命名 CLASSI

4、CAL MBL/Ficolin ALTERNATIVE经典途径 MBL途径 旁路途径C3a C3 C3bC5a C5 C5b + C6-C9TERMINAL终末途径2. 补 体 激 活 COMPLEMENT PATHWAYSThe binding of antibody to its antigen often triggers the complement system through the so-called classical pathway. It can occur in solution or when the antibodies have bound to antigens

5、on a cell surface. 2. 补 体 激 活VHCH1CH2CH3CH4VLCLHinge regionCOONH3+Complement Binding Site（Fc） AntigenBinding Site（Fab）2. 补 体 激 活 (The Classical Pathway)Before binding antigenFabFcC1q binding side closed CH1 CH2IgM CH3 region ，IgG CH2 region After binding antigenC1q binding side exposed The changes o

6、f structure of IgG molecule before and after binds antigen2. 补 体 激 活 (The Classical Pathway) C1sC1q C1rC1qr2s2 40nm AgAbAg the structure and function of C1C1:C1q C1r2 C1s2 Each C1q molecule must bind to at least two Fc sites for a stable C1-antibody interaction to occur. C1r and C1s are activated ，a

7、nd initiate the complement activation. C12. 补 体 激 活 (The Classical Pathway)C1 Activation by Ag-Ab Complexes2. 补 体 激 活 (The Classical Pathway)C1 Cleavage of C4 antibodyC1qr2s2 40nmantigen antigenC4C4bC4aC1s2. 补 体 激 活 (The Classical Pathway)C3 Convertase FormationC4bC2bC2C1sC4bC2a2. 补 体 激 活 (The Class

8、ical Pathway)C3 CleavageC3C3aC3bC3 ConvertaseC4bC2b2. 补 体 激 活 (The Classical Pathway)C5 ConvertaseC5C5bC5aC4bC2aC3b2. 补 体 激 活 (The Classical Pathway)IgM/IgG complex C1q : r : sC4C4b + C2C4aC2bC4b2aC3C3bC3a Ca+Mg+ Ca+（C3 convertase）（C5 convertase）C4b2a3b2. 补 体 激 活 (The Classical Pathway)There is a sp

9、ontaneous conversion of C3 to C3b. Ordinarily the C3b is quickly inactivated: the C3b binds to inhibitory proteins and sialic acid (唾液酸） present on the surface of bodys own cells, and the process is aborted. 2. 补 体 激 活 ( The Alternative Pathway) B C3 spontaneous hydrolysis C3 C3a C3bFactor DC3LPSC3b

10、Factor DFactor B* 参与C5转化酶形成的蛋白2. 补 体 激 活 ( The Alternative Pathway)Factor BLPSC3bC3bBbBaC3 Convertase FormationFactor D2. 补 体 激 活 ( The Alternative Pathway)LPSC3bBbC3aC3 convertaseC3C3b2. 补 体 激 活 ( The Alternative Pathway)C3 CleavageLPSC3bBbC3 convertaseC3bC5C5bC5aC3C5 Convertase Formation2. 补 体 激 活

11、 ( The Alternative Pathway)The surface on it the complement activation B C3b Factor D C3b B C3b Bb B C3b Generation of C3bBb二、补 体 激 活 ( The Alternative Pathway)2. 补 体 激 活 ( The Alternative Pathway)C3Factor D C3bBbB因子 C3b C3bB2. 补 体 激 活 ( The Alternative Pathway) Positive feedback of C3 and C3b旁路和凝集素

12、途径激活补体的关键步骤是C3b依赖性正反馈环路的形成。C3裂解产物C3b与B因子结合为C3bB复和物，在D因子的作用下成为C3与C5转化酶C3bBb。C3bBb作用于C3，产生大量的C3b，C3b的生成又导致更多的C3bBb出现，形成迅速放大的正反馈环路。 C3 C3b Bb C5 C3b C3 C3b C5 C5a C3a C3b C3b C5bC3bBbPC3bnBb2. 补 体 激 活 ( The Alternative Pathway) The di-functions of the C3bBb 补体活化表面的C3bBbP作用于C3，产生大量的C3b。C3bnBb还能将与C3b结合的C

13、5裂解为C5a和C5b两个分段。所产生的C3b5b复和物启动补体活化的终末途径。.P (properdin备解素 ): binds to and stabilizes C3bBb*Independent on the antibody*the mechanism is more like that of the classical pathway?甘露糖结合凝集素MBL （mannose-binding lectin （Protein）, 与微生物表面的糖蛋白的甘露糖残基或糖结合，则激活补体的MBL途径。2. 补 体 激 活 (MBL pathway) C1sMBLC1qThe functio

14、n and structure of MBL are similar to the that of C1q in the complement pathway.Cleavage and activation of C4.2. 补 体 激 活 (MBL pathway) mannoseMBLC4C4a + C4bC2C2b + C2aC4b2a（C3 convertase） + MASP2MASP2MBL mannoseMASP：MBL-associated serine protease2. 补 体 激 活 (MBL pathway)MASP1MBL mannoseC3C3b旁路激活途径 2.

15、 补 体 激 活 (MBL pathway)CLASSICAL MBL/Ficolin ALTERNATIVEC3a C3 C3bC5a C5 C5b + C6-C9TERMINAL2. 补 体 激 活 Three pathwayC5 convertaseC5C5a+C5bFormation of Membrane-Attack Complex（MAC） Terminal pathway C5bC9多聚体C5b+C6+C7+C8+C9 = MACsThe structure of MACs C7C6C810-17MACs-induced lesion on the membrane Termi

16、nal pathway Terminal pathwayMACs effect: complement Kill the Parasite Terminal pathway参与MAC形成的蛋白C5C5aC5b趋化因子和炎症介质 (过敏反应)与 C6结合启动 MAC的形成C8C7C6C9C6C7C8C9 形成C5b6，与 C7结合形成C5b67, 导致复合物、插入细胞的磷脂双层C5b678 与多个 C9 分子结合, 启动C9分子聚合聚合完成MAC的形成活性蛋白/裂解产物免疫学作用成分 Terminal pathway三种补体激活途径的比较经典途径MBL途径旁路途径激活物质抗原抗体复合物含有N氨基

17、半乳糖或甘露糖残基的病原微生物细菌细胞壁成分（脂多糖、肽聚糖、磷壁酸）、酵母多糖，以及聚合的IgA和IgG4等识别分子C1qMBL无参与补体成分C1C9C2C9C3、C5C9，B因子、D因子、P因子所需离子Ca2、Mg2Ca2、Mg2Mg2C3转化酶 C4b2aC4b2aC3bBbC5转化酶C4b2a3bC4b2a3bC3bBb3b作用参与适应性免疫效应阶段参与固有免疫参与固有免疫意义在抗感染的中晚期发挥作用，或参与抵御相同病原体的二次感染在感染早期或初次感染发挥作用在感染早期或初次感染发挥作用三条补体激活途径的比较补体系统爆发性的潜能需要机体严密的控制，已知有至少12种蛋白参与调节系统。补体系统的调节Factor H （H因子）removes Bb from the alternative pathway C3 convertase（C3 转化酶） breaking the positive feedback loop.Factor I （I因子）inactivates C3b and C4b. C1 inhibitor (C1INH， C1抑制剂) binds to sites on activated C1r and C1s shutting down （关闭） their proteolytic activity. 补体的生物学意义1、溶菌、溶解病毒和细胞的细胞毒作用补体