1、补 体系统,Discoverer of Complement Jules Bodet (1870-1961), 1894 发现绵羊抗霍乱血清能够溶解霍乱弧菌，加热56 C 30 min 阻止其活性；加入新鲜非免疫血清可恢复其活性。 Ehrlich 在同时独立发现了类似现象，将其命名为补体Complement Complement存在于血清中的一组蛋白质，活化后具有酶活性，辅助抗体发挥溶细胞作用。,第一节 概 述,补体系统是由存在于人或脊椎动物血清与组织液中的一组可溶性蛋白;存在于血细胞与其它细胞表面的一组膜结合蛋白;补体受体所组成。 在机体的免疫系统中担负抗感染和免疫调节作用, 并参与免疫病理
2、反应。 补体是天然免疫（Innate immunity）的重要组成部分,补体的分类：补体固有成份 补体调节蛋白 补体受体,C1C9, B、D、P因子,C1INH、C4BP、H、I、S蛋白和血清羧肽酶等, MCP, DAF, HRP,C1qR、C3b/C4bR (CRI)、3dR(CRII)、H因子受体、C3a和C5a受体等,第二节 补体的激活,一、补体固有成份的组成、命名、生成部位和理化特征1 参与经典途径活化的补体固有成份按其发现的先后分别命名为C1、C2、C3、C4、C5、C6、C7、C8和C9，其中C1由C1q、C1r和C1s三个亚基组成。 2 参与旁路途径活化的补体固有成份由B、D、P
3、因子和C3、C5C9组成。 3 MBL途径成份：MBL(mannose-binding lectin, MBL)，MASP（MBL-Associated serum proteinase), C4,C2,C3,C5-C9,4 补体固有成份是由肝细胞、巨噬细胞、 肠粘膜上皮细胞和脾细胞等合成的糖蛋白，含量约占血清球蛋白总量的10%，其中C3含量最高、D因子含量最低。 5 对热不稳定，56、30min即被灭活，010 条件下活性只能保持34d。 6 多种理化因素如射线、机械振荡、酒精、胆汁和某些添加剂等均可破坏补体,二、补体系统的命名： 固有成分：C1-C9,C1q r s 其他成分：B、D、P、
4、H 调节成分：功能命名C1INH,C4BP,DAP. 活化成分具有酶活性：C1qrs 裂解片断：大C4b 小C4a 灭活片断：iC3b,三、补体的活化,补体的活化途径,经典途径,MBL途径,旁路途径,（一）补体的经典激活途径,参与成分：C1qrs-C4-C2-C3-C5-C6-C7-C8-C9,C1由 一个C1q、两个C1r 和两个C1s分子的共同组成。一个C1q分子如果同时与两个以上的Fc段结合将造成其构象的变化，继之使C1r和C1s活化，启动补体活化的经典途径。,（一）补体的经典激活途径,参与成分：C1qrs-C4-C2-C3-C5-C6-C7-C8-C9 激活物：免疫复合物（抗原抗体特异
5、结合） 激活条件： a.抗原抗体结合，Ig的Fc段空间构型改变，易与补体C1q结合 b.抗体类型：C1与IgM的CH3区或IgG（ IgG 1/ IgG 2 /IgG 3）的CH2区结合 c. 1个C1分子同时与两个或以上Fc段结合,IgM CH3区，IgG CH2区,T,Y,C1q分子的C端球形结构是与Ig上的补体结合位点相结合的部位，它的启动可使C1r构型改变，成为具有活性的C1r并诱导C1s的活化，成为具有酯酶活性的C1s,在 Mg+存在下可启动补体活化的经典途径。,补 体 活 化 的 经 典 途 径,IgM/IgG -Ag复合物,1. 激活物：炎症急性期蛋白（MBL,CRP）与病原体的
6、结合2. 特点：（1）细菌多糖经MBL（Mannose binding lectin）激活MASP（MBL associated serum protease）进而裂解C4和C2（2）之后的步骤与“经典途径”同（3）无C1的参与,(二),MBL途径,1. 激活物：炎症急性期蛋白（MBL,CRP）与病原体的结合2. 特点：（1）细菌多糖经MBL（Mannose binding lectin）激活MASP（MBL associated serum protease）进而裂解C4和C2（2）之后的步骤与“经典途径”同（3）无C1的参与,(二),MBL途径,（三）旁路途径1. 不经过C1, C4 和C
7、2，而是有B因子、D因子、P因子参与2. 激活物（反应平台）：某些细菌、细菌肽聚糖、酵母多糖成分和凝聚的IgG4/IgA等,C3C3b+B因子C3bBb(P) C3bnBb(P),D,C3a,Ba,C5b-C6,7,8,9 C5,C5a,正反馈调节环路,LPS，多糖，凝聚Ig等,活化,旁路活化途径,P因子,细胞溶解,（C3转化酶）,（C5转化酶）,（三）旁路途径的几个特点：1. C1, C4 和C2不参与，B因子、D因子、P因子参与天然活化，LPS等多糖类物质可促进其活化。2. 不需抗体及免疫复合物参与：发生较早，在机体早期抗感染免疫中发挥重要作用。3. 含有一个C3活化的正反馈调节环路。4.
8、 产生的C3转化酶和C5转化酶不同于“经典途径”和“MBL途径”，但终末的膜攻击阶段是相同的。,C5b+C6+C7+C8+C9 = MACs,终末途径,经典和旁路途径的主要区别,比较项目,经典途径,旁路途径,激活物,补体固有成份,所需离子,C3转化酶,C5转化酶,生物学作用,IgM/IgG13与抗原形成的免疫复合物,细菌脂多糖、肽聚糖、酵母多糖和凝聚的IgG4/IgA等,C1C9,C3、B、D、P因子和C5C9,Ca+、Mg+,Mg+,C4b2b,C3bBb(P),C4b2b3b,C3bnBb(P),在特异性体液免疫的效应阶段起作用,参与非特异性免疫，在感染早期起作用,Components o
9、f the Classical Pathway,C1 complex,C2,C3,C4,C4,Classical Pathway Generation of C3-convertase,27,Classical Pathway Generation of C3-convertase,C4b,Mg+,C4a,C2,C4b2a is C3 convertase,Classical Pathway Generation of C5-convertase,C4b,Mg+,C4a,C2b,C3,C4b2b3b is C5 convertase; it leads into the Membrane At
10、tack Pathway,Components of mannose-binding lectin pathway,C4,MASP2,C2,MASP,2.MBL 途经,Mannose-binding lectin pathway,C4,C2,C4b2a is C3 convertase; it will lead to the generation of C5 convertase,MASP,MASP2,Components of the alternative pathway,C3,B,D,P,Spontaneous C3 activation,C3,H2O,B,D,C3,Generatio
11、n of C3 convertase,This C3b molecule has a very short half life,Degradation of spontaneously produced C3b,C3b stabilization and C5 activation,C3,C5,B,D,P,This leads to membrane attack pathway,B,D,If spontaneously-generated C3b is not degraded,C3-activation the amplification loop,C3,C3a,B,D,C3,C3-act
12、ivation the amplification loop,C3a,C3a,C3,B,D,C3-activation the amplification loop,C3a,C3a,C3a,C3-activation the amplification loop,C3a,C3a,C3a,C3-activation the amplification loop,C5- convertase of the two pathways,C3b,Bb,C3b,C5-convertase of the Alternative Pathway,C5-convertase of the Classical a
13、nd lectin Pathways,Generation of C5 convertase leads to the activation of theLytic pathway,Lytic pathway,Components of the lytic pathway,C6,C 9,C5,Lytic pathway C5-activation,C5,Lytic pathway assembly of the lytic complex,C6,Lytic pathway: insertion of lytic complex into cell membrane,C 9,C 9,C 9,C
14、9,C 9,C 9,C 9,C 9,C 9,Target cell,四、补体激活过程的调节,补体系统的激活必需在适度调节的情况下进行，才能发挥正常的生理学作用。补体激活失控，则大量补体无益消耗，导致机体感染能力下降，而且会使机体发生剧烈炎症反应或造成自身组织细胞的损伤。 补体活化途径的调节主要包括 （一） 补体自身衰变的调节 （二） 可溶性补体调节因子的作用 （三）膜补体调节蛋白和补体受体的作用,Control of spontaneous C3 activation via DAF,DAF prevents the binding of factor B to C3b,B,Control o
15、f spontaneous C3 activation via DAF,DAF dislodges C3b-bound factor Bb,Autologous cell membrane,H,I,Control of spontaneous C3 activation via CR1,I,DAF,C3b regulation on self and activator surfaces,C3b,C1Inh,C1qrs breakdown,Biological Consequence of Complement Activation,Cell lysis Inflammatory respon
16、se Opsonization of particulate antigens Viral neutralization Solublization and clearance of immune complexes,Cell lysis,most gram-negative bacteria are susceptible to complement mediated lysis.,Most gram-negative bacteria are susceptible to complement mediated lysis. Some gram-negative bacteria, Esc
17、herichia coli and Salmonella e g., are resistant to complement for the increased lipopolysaccharide (LPS) component which may prevent insertion of the MAC into thebacterial membrane. Gram-positive bacteria are generally resistant to complement-mediated lysis because the thick peptidoglycan layer in
18、their cell wall prevents insertion of the MAC into the inner membrane.,Alive or Killed by Complement,Microbial evasion of complement-mediated damage,Inflammatory response,2. C3a, C5a, and C5b67 can each induce monocytes and neutrophils to adhere to vascular endothelial cells, extravasate through the
19、 endothelial lining of the capillary, and migrate toward the site of complement activation in the tissues.C5a is most potent.,1. C3a, C4a, and C5a, calledanaphylatoxins, bind to receptors on mast cells and blood basophils and induce degranulation, with release of histamine and other pharmacologicall
20、y active mediators. The anaphylatoxins also induce smooth-muscle contraction and increased vascular permeability.,Opsonization- To make (bacteria or other cells) more susceptible to the action of phagocytes.,C3b is the major opsonin of the complement system, although C4b and iC3b also have opsonizin
21、g activity. Binding of C3b to its receptor CR1 on macrophage boosts the phagocytosis of bacterial.,Ab or C-mediated opsonization,Viral neutralization,Enveloped virus are susceptible to complement mediated lysis. herpesviruses orthomyxovirusesparamyxoviruses retroviruses.,virus,Env,MAC,C3b,Virus neut
22、ralization,control,antibody,Ab+Complement,clearance of immune complexes,C1-inhibitor deficiency: angioedema,C1INH缺陷引起血管神经性水肿,Complement functions,Host benefit: lysis of bacteria and infected cells opsonization to enhance phagocytosis phagocyte attraction and activation clearance of immune complexes Host detriment: Inflammation, anaphylaxis,五、补体系统的异常与疾病,1.补体缺陷2.补体与炎症性疾病3.补体与病毒感染4.补体与器官移植的超急性排斥反应5. 补体含量的增高和降低,本章小结,补体系统的概念与组成 3条激活途径 几个调节因子: C1INH, C4BP, H,I,C8BP,CR1 补体的生物学作用,
