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第四讲 补 体 系 统 （ complement system)

第四讲 补 体 系 统 （ complement system). 上海交通大学医学院免疫学教研室 张 勇. 补体的发现. 感染霍乱豚鼠血清. 霍乱弧菌菌液. 凝集. 溶菌. 正常豚鼠血清. 感染霍乱豚鼠血清. 溶菌. 56℃ ， 30 分钟. 凝集. 溶菌.

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第四讲 补 体 系 统 （ complement system)

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  1. 第四讲 补 体 系 统 （complement system) 上海交通大学医学院免疫学教研室张 勇

  2. 补体的发现 感染霍乱豚鼠血清 霍乱弧菌菌液 凝集 溶菌 正常豚鼠血清 感染霍乱豚鼠血清 溶菌 56℃，30分钟 凝集 溶菌

  3. Belgian 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 of many dangerous contagious diseases. Jules Bordet(1870-1961), discoverer of complement

  4. Specific antibodies heat-insensitive heat-labile component Paul Ehrlichcoined the term complement, defining it as “the activity of blood serum that completes the action of antibody.” Complement refers, historically, to fresh serum capable of lysing antibody (Ab)-coated cells. This activity is destroyed (inactivated) by heating serum at 56 degrees C for 30 minutes.

  5. 基本概念 • 补体（complement,C）： • 是存在于人和脊椎动物血清中一组经激活后具有酶活性的蛋白质，参与抗微生物防御反应、免疫调节及免疫病理的损伤反应等。 • 补体大多是  球蛋白，少数是  及  球蛋白 • 自然条件下，以无活性酶原形式存在 • 对热不稳定，56℃、30 min可灭活 • 各成分中，C3含量最高 • 主要由肝细胞和巨噬细胞产生

  6. 补体系统的组成 补体的固有成分：存在于体液中，参与补体级联反应的补体成分，如C1,C2,C3…C9、B因子、D因子及MBL等 补体调节蛋白：包括备解素、I因子、C1抑制物等 补体受体：包括CR1~CR5、C3aR等 共包含 30 余种

  7. 命名原则 C：静止状态（如 C1 ~ C9） C：激活状态（如 C4b2b） iC：灭活状态（如 iC3b） a：代表某成分裂解后产生的小片段（如C3a） b：代表某成分裂解后产生的大片段（如C3b） R:补体的受体 (CR1 or C5aR)

  8. sequentiallyreacting I Ia Ib II IIb IIa III IIIa IIIb biological effects 补体的激活 • 激活后具有效应 • 级联反应 • 放大反应 • 三条途径

  9. 补体的激活 识别阶段 活化阶段 效应阶段

  10. C1r C1s C1q Ca++ Components of the Classical Pathway C4 C2 C3 C1 complex

  11. 经典激活途径之识别、活化阶段 激活物：抗原-抗体复合物 • 激活条件： • 抗体Fc段暴露出补体 结合位点 • C1q分子必须有两个 以上的球形亚蛋单位 与抗体结合 关键酶：C1s C4b2b C4b2b3b

  12. IgG分子结合抗原前后的构象变化 结合抗原之后 结合抗原之前 Fab段 CH1 暴露的C1q结合位点 C1q 结合位点被屏障 CH2 Fc段 IgM CH3区，IgG CH2区

  13. C4a C1r C1s C1q b Ca++ Classical Pathway Generation of C3-convertase C4

  14. C2a C1r C1s b C1q Ca++ C2 C4b2b is C3 convertase b Classical PathwayGeneration of C3-convertase C2 C4a Mg++ C4b

  15. C1r C3a C1s C1q Ca++ C4b2b3b is C5 convertase; it leads into the Membrane Attack Pathway C2 b b Classical PathwayGeneration of C5-convertase C2a C4a Mg++ C3 C4b

  16. MBL Components of mannose-binding lectin pathway C4 MASP-2 C2 MASP-1

  17. MBL激活途径之识别、活化阶段 激活物：细菌表面的甘露糖残基 关键酶：MASP-1、MASP-2 C4b2b C4b2b3b 过程： MBL + +丝氨酸蛋白酶 病原体甘露糖残基 MASP-1、2 裂解C4、C2 后续步骤同经典途径

  18. C2b C2b C2a C4a C4b2b is C3 convertase; it will lead to the generation of C5 convertase C4b C4b MBL Mannose-binding lectin pathway C4 C2 MASP-2 MASP-1

  19. Components of thealternative pathway D C3 B P

  20. 替代激活途径之识别、活化阶段 激活物：G(-)菌细胞壁成分--脂多糖、凝聚IgG4、IgA等 • 准备阶段： • 自发产生的 C3b • 经典途径产生的 C3b 关键酶：C3bBbC3bBb3b

  21. b b b C3a Spontaneous C3 activation Generation of C3 convertase（C3bBb) D B C3 H2O C3 This C3b molecule has a very short half life

  22. C3b b b C3a C3-activationthe amplification loop If spontaneously-generated C3b is not degraded D B C3

  23. C3b b b Bb C3b C3a C3-activationthe amplification loop D B C3 C3a

  24. Bb C3b C3b b b Bb C3b C3a C3-activationthe amplification loop D B C3 C3a C3a

  25. Bb Bb C3b C3b C3b Bb C3b C3-activationthe amplification loop C3a C3a C3a

  26. Bb Bb C3b C3b Bb C3b C3-activationthe amplification loop C3a C3a C3a

  27. Bb Bb C3b C3b Bb C3b C3-activationthe amplification loop C3a C3a C3a

  28. C5a C3a C3b finds an activator (protector) membrane C3b b b b C3b stabilization andC5 activation D P B C5 C3 This leads to formation of membrane attack complex

  29. 替代途径激活特点 • 体内C3自发水解成C3b，使替代途径处于准激活状态 • 替代途径能识别自己与非己 • 替代途径是补体系统重要放大机制

  30. C2b C3b C4b C5- convertase of the three pathways C5-convertase of the Classical and lectin Pathways C5-convertase of the Alternative Pathway Bb C3b C3b

  31. Terminal sequence Generation of C5 convertase leads to the formation of the membrane attack complex

  32. C8 C7 Components of the Terminal sequence C6 C5 C 9

  33. C5a b C3b C4b C2 b Terminal sequenceC5-activation C5

  34. C7 C5 b Terminal sequenceassembly of the lytic complex C6

  35. C8 C6 C7 C5 b Terminal sequence :insertion of lytic complex into cell membrane C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9 C 9

  36. MACs effect complement Kill the Parasite

  37. Pathways of complement activation ALTERNATINE PATHWAY CLASSICAL PATHWAY antibody dependent Mannose binding lectin dependent Activation of C3 and generation of C5 convertase activation of C5 LYTIC ATTACK PATHWAY

  38. C3 C3b 补体三条激活途径全过程示意图 抗原抗体复合物（IgG或IgM） 经典途径 C1qr2s2 C1qr2s2 C4+C2 C4b2b （C3转化酶） C4b2b3b （C5转化酶） MBL途径 MBL + 病原体甘露糖 C5b~9 MAC 丝氨酸蛋白酶 C5 C5b MASP C3bBb （C3转化酶） C3bBb3b （C5转化酶） C3 C3b C6 C7 C8 C9 B因子 D因子 替代途径

  39. 三条激活途径的主要不同点

  40. 补体活化的调控 • 自身衰变： • 体液中灭活物质的作用： • 经典途径中的灭活物质 • 替代途径中的灭活物质 • 膜攻击复合物形成的调节

  41. 调节蛋白 替代途径活化产物 调节蛋白对补体活化的调节作用 经典途径活化产物 C4b2b C4b2b3b C5b6789(MAC)    C1 INH DAF, I因子，C4bp S蛋白, CD59,HRF DAF, I因子，H因子 备解素    C3bBb C3bBb3b C5b6789(MAC)

  42. 补体激活过程中的调控蛋白

  43. C1r C1r C1s C1s C1q C1qrs breakdown C1INH

  44. C1-inhibitor deficiency:angioedema

  45. C3b regulation on self and activator surfaces C3b C3b C3b

  46. C3b DAF CR1 Autologous cell membrane Control of spontaneousC3 activation via DAF DAF prevents the binding of factor B to C3b B

  47. 超急排斥（HAR, hyper acute rejection） 移植受者 (人) 血流中的异种反应天然抗体(XNA) 识别供者 (猪) 器官血管内皮细胞膜上以半乳糖苷为抗原表位的糖蛋白，激活补体级联反应，引起内皮细胞裂解和激活，导致凝血和血管阻塞，移植物坏死。 排斥时间：40～120分钟。

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