醫(yī)學(xué)免疫學(xué)課件：3 固有免疫系統(tǒng)-補(bǔ)體

1、固有免疫系統(tǒng)-補(bǔ)體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. 補(bǔ)體概 述補(bǔ)體，存在于新鮮血清中，能夠裂解抗體包被的細(xì)胞（antibody (Ab)-coated cells） 。 這種活性可以經(jīng)加熱56度，30分鐘而滅活 (失活)對(duì)熱不敏感的特異性抗體熱敏感的成分這種熱敏感的成分被命名為補(bǔ)體 （ complement）, 即補(bǔ)充抗體活性的血清成分.1. 補(bǔ)體概 述補(bǔ)體調(diào)理、中和B細(xì)胞激活形成裂解復(fù)合物趨化和炎癥反應(yīng)補(bǔ)體系統(tǒng)凝血系統(tǒng)纖溶系統(tǒng)緩激肽系統(tǒng)是一組由生物大分子組成的連續(xù)而分級(jí)的激活反應(yīng)系統(tǒng)。一旦激活，可介導(dǎo)一系列的對(duì)宿主重要的生物反應(yīng)。1. 補(bǔ)體概 述1）固有成分：

3、C19，MBL、SP、Bf、Df2）調(diào)節(jié)蛋白：Properdin、C1INH、C4bBp、Hf、 If、CR1、Sp3）補(bǔ)體受體：CR1CR5、 C2aR、 C3aR、C4aR1. 補(bǔ)體概 述補(bǔ)體系統(tǒng)的組成1. “C” - 補(bǔ)體的11種蛋白 (C1, C2, etc.)2. Factor - 一些旁路途徑的成分 (factor B)3. Overbar - 表示具有酶活性的蛋白活復(fù) 合物 （C4b2a） 4. Lower case letters - 表示蛋白酶裂解的 片段 (C3a or C5a)5. “R” - 補(bǔ)體的受體 (CR1 or C5aR)1. 補(bǔ)體概 述補(bǔ)體的命名 CLASSI

4、CAL MBL/Ficolin ALTERNATIVE經(jīng)典途徑 MBL途徑 旁路途徑C3a C3 C3bC5a C5 C5b + C6-C9TERMINAL終末途徑2. 補(bǔ) 體 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. 補(bǔ) 體 激 活VHCH1CH2CH3CH4VLCLHinge regionCOONH3+Complement Binding Site（Fc） AntigenBinding Site（Fab）2. 補(bǔ) 體 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. 補(bǔ) 體 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. 補(bǔ) 體 激 活 (The Classical Pathway)C1 Activation by Ag-Ab Complexes2. 補(bǔ) 體 激 活 (The Classical Pathway)C1 Cleavage of C4 antibodyC1qr2s2 40nmantigen antigenC4C4bC4aC1s2. 補(bǔ) 體 激 活 (The Classical Pathway)C3 Convertase FormationC4bC2bC2C1sC4bC2a2. 補(bǔ) 體 激 活 (The Class

8、ical Pathway)C3 CleavageC3C3aC3bC3 ConvertaseC4bC2b2. 補(bǔ) 體 激 活 (The Classical Pathway)C5 ConvertaseC5C5bC5aC4bC2aC3b2. 補(bǔ) 體 激 活 (The Classical Pathway)IgM/IgG complex C1q : r : sC4C4b + C2C4aC2bC4b2aC3C3bC3a Ca+Mg+ Ca+（C3 convertase）（C5 convertase）C4b2a3b2. 補(bǔ) 體 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. 補(bǔ) 體 激 活 ( The Alternative Pathway) B C3 spontaneous hydrolysis C3 C3a C3bFactor DC3LPSC3b

10、Factor DFactor B* 參與C5轉(zhuǎn)化酶形成的蛋白2. 補(bǔ) 體 激 活 ( The Alternative Pathway)Factor BLPSC3bC3bBbBaC3 Convertase FormationFactor D2. 補(bǔ) 體 激 活 ( The Alternative Pathway)LPSC3bBbC3aC3 convertaseC3C3b2. 補(bǔ) 體 激 活 ( The Alternative Pathway)C3 CleavageLPSC3bBbC3 convertaseC3bC5C5bC5aC3C5 Convertase Formation2. 補(bǔ) 體 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、補(bǔ) 體 激 活 ( The Alternative Pathway)2. 補(bǔ) 體 激 活 ( The Alternative Pathway)C3Factor D C3bBbB因子 C3b C3bB2. 補(bǔ) 體 激 活 ( The Alternative Pathway) Positive feedback of C3 and C3b旁路和凝集素

12、途徑激活補(bǔ)體的關(guān)鍵步驟是C3b依賴性正反饋環(huán)路的形成。C3裂解產(chǎn)物C3b與B因子結(jié)合為C3bB復(fù)和物，在D因子的作用下成為C3與C5轉(zhuǎn)化酶C3bBb。C3bBb作用于C3，產(chǎn)生大量的C3b，C3b的生成又導(dǎo)致更多的C3bBb出現(xiàn)，形成迅速放大的正反饋環(huán)路。 C3 C3b Bb C5 C3b C3 C3b C5 C5a C3a C3b C3b C5bC3bBbPC3bnBb2. 補(bǔ) 體 激 活 ( The Alternative Pathway) The di-functions of the C3bBb 補(bǔ)體活化表面的C3bBbP作用于C3，產(chǎn)生大量的C3b。C3bnBb還能將與C3b結(jié)合的C

13、5裂解為C5a和C5b兩個(gè)分段。所產(chǎn)生的C3b5b復(fù)和物啟動(dòng)補(bǔ)體活化的終末途徑。.P (properdin備解素 ): binds to and stabilizes C3bBb*Independent on the antibody*the mechanism is more like that of the classical pathway?甘露糖結(jié)合凝集素MBL （mannose-binding lectin （Protein）, 與微生物表面的糖蛋白的甘露糖殘基或糖結(jié)合，則激活補(bǔ)體的MBL途徑。2. 補(bǔ) 體 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. 補(bǔ) 體 激 活 (MBL pathway) mannoseMBLC4C4a + C4bC2C2b + C2aC4b2a（C3 convertase） + MASP2MASP2MBL mannoseMASP：MBL-associated serine protease2. 補(bǔ) 體 激 活 (MBL pathway)MASP1MBL mannoseC3C3b旁路激活途徑 2.

15、 補(bǔ) 體 激 活 (MBL pathway)CLASSICAL MBL/Ficolin ALTERNATIVEC3a C3 C3bC5a C5 C5b + C6-C9TERMINAL2. 補(bǔ) 體 激 活 Three pathwayC5 convertaseC5C5a+C5bFormation of Membrane-Attack Complex（MAC） Terminal pathway C5bC9多聚體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參與MAC形成的蛋白C5C5aC5b趨化因子和炎癥介質(zhì) (過敏反應(yīng))與 C6結(jié)合啟動(dòng) MAC的形成C8C7C6C9C6C7C8C9 形成C5b6，與 C7結(jié)合形成C5b67, 導(dǎo)致復(fù)合物、插入細(xì)胞的磷脂雙層C5b678 與多個(gè) C9 分子結(jié)合, 啟動(dòng)C9分子聚合聚合完成MAC的形成活性蛋白/裂解產(chǎn)物免疫學(xué)作用成分 Terminal pathway三種補(bǔ)體激活途徑的比較經(jīng)典途徑MBL途徑旁路途徑激活物質(zhì)抗原抗體復(fù)合物含有N氨基

17、半乳糖或甘露糖殘基的病原微生物細(xì)菌細(xì)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等識(shí)別分子C1qMBL無參與補(bǔ)體成分C1C9C2C9C3、C5C9，B因子、D因子、P因子所需離子Ca2、Mg2Ca2、Mg2Mg2C3轉(zhuǎn)化酶 C4b2aC4b2aC3bBbC5轉(zhuǎn)化酶C4b2a3bC4b2a3bC3bBb3b作用參與適應(yīng)性免疫效應(yīng)階段參與固有免疫參與固有免疫意義在抗感染的中晚期發(fā)揮作用，或參與抵御相同病原體的二次感染在感染早期或初次感染發(fā)揮作用在感染早期或初次感染發(fā)揮作用三條補(bǔ)體激活途徑的比較補(bǔ)體系統(tǒng)爆發(fā)性的潛能需要機(jī)體嚴(yán)密的控制，已知有至少12種蛋白參與調(diào)節(jié)系統(tǒng)。補(bǔ)體系統(tǒng)的調(diào)節(jié)Factor H （H因子）removes Bb from the alternative pathway C3 convertase（C3 轉(zhuǎn)化酶） breaking the positive feedback loop.Factor I （I因子）inactivates C3b and C4b. C1 inhibitor (C1INH， C1抑制劑) binds to sites on activated C1r and C1s shutting down （關(guān)閉） their proteolytic activity. 補(bǔ)體的生物學(xué)意義1、溶菌、溶解病毒和細(xì)胞的細(xì)胞毒作用補(bǔ)體