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Complement system Xiaojian Wang IMMUNOLOGY
Institute of immunology, ZJU
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Complement Introduction Activation of the Complement System Regulation of complement activation Biologic function of complement system
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Jules Bodet ( ), Discoverer of complement Nobel prize in 1919
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complement 19世纪末,继抗毒素之后,又限快发现了免疫溶菌现象。Pfeiffer(1894)用新鲜免疫血清在豚鼠体内观察到对霍乱弧菌的溶菌现象。Bordet发现如将新鲜免疫血清加热60℃30分钟可丧失溶能力。他认为在新鲜免疫血清内存在二种不同物质与溶菌作用有关。一种对热稳定的物质称为溶菌素即抗体,有特异性,另一种对热不稳定的物质,可存在于正常血清中,为非特异性成分,称之为补体
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Introduction complement Complement (C)
Complement System 补体是由30余种补体固有成分、补体受体和细胞膜补体调节蛋白的多分子系统,故称为补体系统(complement system)。
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Introduction Components of C system 1. Innate C components
complement Introduction Components of C system 1. Innate C components 2. Regulatory Proteins 3. Complement receptor
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Introduction Components of C system 1. innate components
complement Introduction Components of C system 1. innate components classical pathway:C1q,C1r,C1s,C4, C3,C2 Alternative pathway:B,D,P,C3 MBL pathway:MBL,MASP terminal pathway:C5,C6,C7,C8,C9 MASP: MBL 相关丝氨酸蛋白酶
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Introduction 2. regulatory proteins C1-INH, C4-BP, I factor, H factor
complement Introduction 2. regulatory proteins C1-INH, C4-BP, I factor, H factor S protein,Sp40/40, decay-accelerating factor (DAF) 3. complement receptor CR1—CR5,C3aR,C4aR,C5aR Inhibit help
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Introduction nomenclature : C--complement C1,C2,C3,C5 B,D,H,I,P factor
C4B,DAF a--small fragment C2a,C3a b--large fragment C2b,C3b,C5b ¯--activated(enzyme) C1 i--inactivated iC3b
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The properties of Complement glycoprotein: globulin
Labile to heat: The activity of C is destroyed (inactivated) by heating serum at 56℃ for 30 minutes . C produced cells : Hepatocytes and Macrophages Belongs acute phase protein zymogen to protease: number of complement proteins are zymogens that can be activated by proteolytic cleavage 占总蛋白的5%-6% RT 很快失活, 10度内保持3-4天
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Activation of the C System
complement Activation of the C System Pathways of complement activation: triggered-enzyme cascade 1. Classical pathway 2. Alternative pathway 3. MBL pathway MBL:mannose-binding lectin
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Classical pathway complement 1. C1 activation by Ag-Ab complex
2. C4 and C2 activation generation C3 convertase 3. C3 activation (generation of C5 convertase) 4. Generation of C5 convertase marks the end of the classical pathway
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Three steps:Classical pathway
1. Recognition ( C1 activation ) involved:C1q, C1r, C1s Ag + Ab→IC→bind C1q→C1r→C1s→C1 2. Activation involved:C4, C2 and C3 (1) C4 and C2 activation, generation of C3 convertase (2) C3 activation (generation of C5 convertase) 3. Attack (terminal pathway) involved:C5,C6,C7,C8,C9 the membrane attack complex(MAC):C5b6789 the MAC causes lysis of cells
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Recognition ( C1 activation )
complement Recognition ( C1 activation ) Activator: Ag-Ab complex /IC Combinding CH2 of IgG or CH3 of IgM One of IgM molecule or two molecules of IgG are needed. IgM>IgG3>IgG1>IgG2 Soluble antibody can’t activate complement
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complement classical pathway C1 molecule
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Activation The components involved: C4,C2 and C3 (1)C4 and C C3 convertase (2)C4,C2,C C5 convertase
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Classical Pathway Generation of C3-convertase
b Ca++ C1r C1s C1q C4
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Classical Pathway Generation of C3-convertase
C2b a C4a Ca++ C1r C1s C1q Mg++ C4b2a is C3 convertase C4b
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Classical Pathway Generation of C3-convertase
C2b C4a Ca++ C1r C1s C1q C3a b C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway Mg++ C4b C3 C2 a
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complement
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complement
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Attack (terminal pathway) involved:C5,C6,C7,C8,C9
the membrane attack complex(MAC):C5b6789 the MAC causes lysis of cells C5b67 暴露膜结合部位
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complement Terminal pathway(MAC)
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complement Terminal pathway
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Alternative pathway Activators: LPS(endotoxin),
certain complex polysaccharides, IgA and IgG4 旁路途径 ,替代激活途径, 不依赖于抗体, 而由微生物或外源异物直接激活C3。 进化过程中, 最早出现的补体活化途径。
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Alternative pathway complement factor B and factor D involved
It is rather different from the MBL and classical pathway. 1. no C1,C4 and C2 involved factor B and factor D involved 2. the presence of suitable activator surfaces,such as bacterial and fungal cell walls. 3. C3b: from the classical pathway; spontaneous produced C3b
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Characters of alternative pathway
1. it can recognize “self” and “non-self” 2. the amplification loop
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Mannan-binding lectin pathway
Activators:MBL (similar to C1q, hexamer) MBL recognizes certain carbohydrates expressed on the surface of microorganisms ↓ MBL activate two MBL-associated serine proteases --- MASP and MASP-2 ↓ ↓ cleaves C cleaves C4,C2 to generate activate the alternative the C3 convertase (C4b2a) pathway directly
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Regulation of complement activation
1.Self-regulation C4b2b C3bBb C4b C3b C5b 2.Control proteins Classical pathway: C1INH C4bp I MCP DAF (C3b和Bb) Alternative pathway:H I CR1 DAF MCP Properdin Formation of MAC: C8bp CD59(MIRL) MCP: 膜辅蛋白 MIRL: 膜反应性溶解抑制物
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Regulation of complement activation
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Regulation of complement activation
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Regulation of complement activation
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Regulation of complement activation
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Biologic function of complement system
1. mediates anti-infection immunity (1) Lysis of cell or microorganisms (2) opsonization (3) inflammation
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complement mediated the lysis of cells
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function:enhance phagocytosis
complement opsonization opsonin:C3b,C4b,iC3b cell:phagocyte receptor:CR1,CR3,CR4 function:enhance phagocytosis
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symptoms: redness, swelling,
complement (3) inflammatory response symptoms: redness, swelling, heat and pain inflammation mediators: C5a,C3a,C4a ( anaphylatoxins) C5a (chemotaxis)
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Biologic function of complement system
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2. Complement maintains homeostasis
1) clearance of IC C3b 2) elimination of apoptosis cells C1q,C3b,iC3b
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3. Complement mediates adaptive immunity
1) Induction of immune response 2) Proliferation and differentiation of immune cells c3d 3) Effective stage of immune response 4) Immune memory 4. Interaction with other enzyme system
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Summary Review the differences between the three pathways of complement in terms of how they are activated. Why the complement do not attack autologous cells?
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Thanks!
Effector mechanisms of humoral immunity The Complement System (C’) Activation pathways Effector functions Regulation of complement activation.
Chapter 6 Complement.
Complement S. Barbour Suggested Reading: Janeway, Chapter 2, pp Chapter 9, pp Office hours by arrangement: Please contact me by
AHMAD SH. SILMI Haematology and Immunology ISLAMIC UNIVERSITY GAZA.
The Complement System Concepts Complement Activation
Complement system references C was discovered several years ago as a heat labile of normal plasma that augment opsonozation of bacteria by Ab.coplement.
Elainne Kesuma ( ) Harvianto Siman Santosa ( )
Innate Defenses Complement The complement system is a biochemical cascade that helps clear pathogens from an organism It is part of the innate immune system.
Principles of Immunology Complement 2/7/06 “Nothing is to be more prized than the value of each day” Goethe.
Immunology (elective) MLIM-101 Prepared by: Dr. Mohamed S. Abdel-Latif.
第三章 体液中的免疫分子 (免疫球蛋白).
Chapter 7 The Complement System Complement-induced lesions on the membrane of a RBC Nov 7 & 9, 2006.
钠泵活动的生理意义 钠泵活动造成的细胞内高钾,是许多代谢 反应进行的必要条件 防止细胞内水肿的发生 建立一种势能贮备.
平衡态电化学 化学电池 浓差电池 电极过程动力学.
吉林大学基础医学院 生 理 学 主 讲: 葛 敬 岩. 第一章 绪 论 第一节 生理学的研究对象和任务.
分析化学与无机化学中溶液 pH 值计算的异同比较 谢永生 分析化学是大学化学系的一门基础课,课 时较少,其内容主要是无机物的化学分析。 分析化学是以无机化学作为基础的,我们 都是在已掌握一定的无机化学知识后才学 习分析化学 。所以在分析 化学的学习中会 重复许多无机化学内容,造成学习没有兴.
(Dysfunction of cellular signal transduction in disease) 细 胞 信号转导异常与疾病.
第六章 土壤酸碱性. 土壤酸碱性 是指土壤溶液的反应,它反映土壤溶液 中 H + 浓度和 OH - 浓度比例,同时也决定于 土壤胶体上致酸离子( H + 或 Al 3+ )或碱性 离子( Na + )的数量及土壤中酸性盐和碱 性盐类的存在数量。
第七章 能量代谢和体温 第一节 能量代谢 能量代谢 ( energy metabolism ) 物质代谢过程中所伴随着的能量的贮存、 释放、和利用 物质代谢过程中所伴随着的能量的贮存、 释放、和利用 一、食物的能量转化 (一)三磷酸腺苷是体内能量转化和利用的 关键物质 三磷酸腺苷磷酸肌酸.
第二节 免疫球蛋白及其遗传.
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