第四讲 补体The complement system补体补体complementcomplement，C C）：）： 一组一组 蛋白质蛋白质 激活后具有活性激活后具有活性Complement is a group of proteins that form the Complement is a group of proteins that form the principal effector arm of humoral immune principal effector arm of humoral immune system. By a series of specific activation system. By a series of specific activation steps, complement proteins mediate a set of steps, complement proteins mediate a set of activities ranging from the initiation of activities ranging from the initiation of inflammation, neutralization of pathogens, inflammation, neutralization of pathogens, clearance of immune complexes, disruption of clearance of immune complexes, disruption of cell membranes, and regulation of the immune cell membranes, and regulation of the immune response. response. 抗微生物防御反应抗微生物防御反应 免疫调节免疫调节 免疫病理损伤免疫病理损伤一一. 补体系统的组成补体系统的组成补体的固有成分：补体激活级联反应的补体成分补体的固有成分：补体激活级联反应的补体成分经典途径经典途径MBL途径途径旁路途径旁路途径共同末端成分共同末端成分C1q、C1r、C1s、C4、C2、C3MBL、丝氨酸蛋白酶、丝氨酸蛋白酶B因子、因子、D因子因子C5、C6、C7、C8、C9补体调节蛋白：包括备解素、补体调节蛋白：包括备解素、I因子、因子、C1抑制物等抑制物等补体受体：包括补体受体：包括CR1CR5、C3aR等等共包含共包含 30 余种余种命名原则命名原则 nomenclatureC：静止状态如：静止状态如 C1 C9）C：激活状态如：激活状态如 C4b2b） iC：灭活状态如：灭活状态如 iC3b） inactivateda：某成分裂解后产生的小片段如：某成分裂解后产生的小片段如3a）b：某成分裂解后产生的大片段如：某成分裂解后产生的大片段如3b）A bar placed over the symbol of the component to indicate active enzymatic activity. The smaller fragment resulting from cleavage of a component is designated “a” and larger fragment designated “b”. But C2 is an exception.二二. 补体的激活补体的激活识别阶段识别阶段 recognize and initiate 活化阶段活化阶段 cascade of activation效应阶段效应阶段 effect三条途径、三个阶段、三个酶、一个三条途径、三个阶段、三个酶、一个MACMAC3 pathways, 3 steps, 3 enzymes, a membrane 3 pathways, 3 steps, 3 enzymes, a membrane attack complex attack complex （一经典途径（一经典途径 (classical (classical pathway)pathway)1.1.激活物及激活条件激活物及激活条件 AbAg AbAg复合物复合物ICIC）（IgMIgM、IgG1IgG1、2 2、3 3）构象改变构象改变 暴露暴露 补体结合部位补体结合部位2 2个以上补体结合位点个以上补体结合位点与与C1qC1q球型头部结合球型头部结合The classical pathway is initiated by binding of antibody to an antigen. Binding of C1q to Fc portion of antibody results in activation of the proteolytic enzyme activities of C1r and, subsequently C1s.2. 2. 激活顺序激活顺序 (complement activation cascade) (complement activation cascade)C1C1AbAgAbAgC1C1(C1(C1脂酶脂酶) )C4C4C4a C4a C4bC4bC2C2C2a C2a C2bC2bC4b2aC4b2a （C3C3转化酶）转化酶） C3 C3 convertaseconvertase( (与细胞膜或与细胞膜或AbAgAbAg结合结合) )C3C3C3bC3bC3aC3aC4b2a3bC4b2a3bC5 convertase (C5转化酶转化酶)C5C5C5aC5aC5bC5bC6C6、C7C7C5b67C5b67C8C8C5b678C5b678多个多个C9C9C5b6789C5b6789n n( (攻膜复合体攻膜复合体) ) MAC MACMembrane attack complex经典激活途径之识别、活化阶段经典激活途径之识别、活化阶段关键酶：关键酶：C4b2b 和和 C4b2b3b补体激活的共同末端效应阶段补体激活的共同末端效应阶段（二）（二） MBL MBL途径途径 (MBL pathway) (MBL pathway)病原体病原体急性期反应急性期反应机体机体MBLMBL（甘露聚糖结合凝集素）（甘露聚糖结合凝集素）Mannose binding lectinMannose binding lectin甘露糖残基甘露糖残基 MASP MASP(MBL(MBL相关的丝氨酸蛋白酶相关的丝氨酸蛋白酶) )MBL associated serine MBL associated serine proteinaseproteinaseMASP + MBL C1MASP + MBL C1以后过程同经典途径以后过程同经典途径MASPMASP（三旁路途径（三旁路途径 (alternative pathway)自发产生自发产生C3C3b灭活灭活B因子因子C3bBD因子因子BaC3bBb(C3转化酶转化酶)降解降解细菌、内毒素、酵母多糖、细菌、内毒素、酵母多糖、葡聚糖、凝聚的葡聚糖、凝聚的IgAIgG4、结合在结合在外表外表C3bnBb(C5转化酶转化酶)以后同经典以后同经典补体激活的共同末端效应阶段补体激活的共同末端效应阶段三条激活途径的主要不同点三三. 补体的生物学作用补体的生物学作用（一裂解靶细胞（一裂解靶细胞 (cell lysis)MAC在细胞膜上形成小孔在细胞膜上形成小孔溶菌、细胞毒溶菌、细胞毒（二补体活性片段介导的生物学效应（二补体活性片段介导的生物学效应1. 调理作用调理作用(opsonization)：2. 清除免疫复合物清除免疫复合物(clearance of immune complex)：C3b、C4b以及以及 iC3b氨基端与抗原结合，氨基端与抗原结合， 羧基端与吞噬细胞的羧基端与吞噬细胞的CR结合结合C3b与与Ig及血细胞表面及血细胞表面CR结合可促进结合可促进IC清除清除3. 引起炎症反应引起炎症反应 (inflammation)C3a、C4a、C5a过敏毒素过敏毒素趋化作用趋化作用 (a) Photomicrograph of poly-C9 complex formed by in vitro polymerization of C9. (b) Photomicrograph of complementinduced lesions on the membrane of a red blood cell. These lesions result from formation of membrane-attack complexes. Scanning electron micrographs of E. coli showing (a) intact cells and (b, c) cells killed by complement-mediated lysis.Note membrane blebbing on lysed cells.