医学免疫学课件：Complement system

1、Complement system Lecture 4 R.F.J.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。 霍乱弧菌霍乱弧菌+Ab 凝集凝集 接种培养接种培养 霍乱弧菌仍存活霍乱弧菌仍存活 霍乱弧菌霍乱弧菌+Ab+新鲜豚鼠血清新鲜豚鼠血清 霍乱弧菌裂解死亡霍乱弧菌裂解死亡 溶血现象：溶血现象： 绵羊红细胞绵羊红细胞+Ab+新鲜豚鼠血清新鲜豚鼠血清 溶血溶血 Jules Bodet (1870- 1961), 1899，Discoverer of Complement Ehrlich Ehrlich （ComplementComplement） 191

2、9 Nobel Prize 1. Introduction 2. Activation of the Complement System 3. Regulation of complement activation 4. Biologic functions of complement system Introduction Complement (C) - A group of serum proteins involved in the control of inflammation, the activation of phagocytes and the lytic attack on

3、 cell membranes. This activity is destroyed (inactivated) by heating serum at 56 degrees C for 30 minutes. Complement System - consists of a large number of proteins which become enzymes after being activated. Introduction Proteins of the Complement System 1. Innate proteins 2. Regulatory Proteins 3

4、. Complement receptor Introduction Proteins of the Complement System 1. innate proteins classical pathway:C1q,C1r,C1s,C4,C2 MBL pathway:MBL,MASP alternative pathway: B,D terminal pathway:C3,C5,C6,C7,C8,C9 Introduction Proteins of the Complement System 2. Regulatory proteins C1-INH, C4-BP, factor I,

5、factor H, S protein, Sp40/40, decay-accelerating factor (DAF) 3. complement receptor: CR1CR5,C3aR,C2aR,C4aR,etc. Introduction Complement produced cells Liver cells Macrophages Introduction Notation: C-complement C1,C2,C3,C4 a-small fragment C4a,C3a,C5a b-large fragment C4b,C3b,C5b,C2a -activated (en

6、zyme) C1 i-inactivated iC3b Activation of the Complement System Pathways of complement activation: 1. Classical pathway 2. MBL pathway MBL: mannan-binding lectin 3. Alternative pathway Classical pathway a suitable Ab bound to antigen (Ag), Ag-Ab complex (IC) C1,C4,C2 and C3 Ca+ and Mg+ cations 1. C1

7、 activation 2. C4 and C2 activation (generation of C3 convertase) 3. C3 activation (generation of C5 convertase) 4. Generation of C5 convertase marks the end of the classical pathway Activators: Activation of this pathway may occur via Ag-Ab complex (immune complex, IC). IgG(IgG13) and IgM are most

8、efficient in reacting with complement. ( C1-CH3 of IgM;CH2 of IgG) Only one molecule of IgM is required, whereas at least two molecules of IgG are needed. soluble antibody cant activate complement Classical pathway Three steps： 1. Recognition ( C1 activation ) The components involved：C1q, C1r, C1s A

9、g + AbICbind C1qC1rC1sC1 2. Activation The components involved：C4, C2 and C3 (1) C4 and C2 activation, generation of C3 convertase (2) generation of C5 convertase 3. Attack (terminal pathway) the components involved：C5,C6,C7,C8,C9 the membrane attack complex(MAC):C5b6789 the MAC causes lysis of cell

10、s classical pathway C1 molecule Ca+ C1r C1s C1q C4 C4a b Classical Pathway Generation of C3-convertase Classical Pathway Generation of C3-convertase C4b Mg+ C4a Ca+ C1r C1s C1q C2 C2b b C2 a C4b2a is C3 convertase Classical Pathway Generation of C5-convertase C4b Mg+ C4a Ca+ C1r C1s C1q C2b C2 a C3

11、C3a b C4b2a3b is C5 convertase; it leads into the Membrane Attack Pathway MBL 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-1 and MASP-2 cleaves C3 cleaves C4,C2

12、 to generate activate the alternative the C3 convertase (C4b2a) pathway directly MBL pathway When MBL binds to terminal mannose groups on bacterial carbohydrates, it activates MASP-1 and MASP-2, which go on to activate the classical pathway in an antibody-independent fashion. MBL pathway 1 C4b Alter

13、native pathway Activators：bacterial lipopolysaccharides (endotoxin), certain complex polysaccharides normal: Circulating plasma C3 undergoes spontaneous hydrolysis of its thioester bond to form a conformationally altered species called C3(H2O). Once the thioester group has opened, C3(H2O) acts like

14、C3b. alternative pathway 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 C3C3a

15、D Ba C3b+BC3bBC3bBb (C3 convertase) be dissociated - - I I/H abnormal: no factor I and H on the surface of bacterial C5 convertase: C3bBb3b or C3bnBb Alternative pathway characters: 1. it can recognize “self” and “non-self” 2. the amplification loop Activation of the Complement System Terminal pathw

16、ay: MAC(membrane attack complex) Activation of the Complement System Terminal pathway a a Regulation of complement activation 1.Self-regulation C4b2a, C3bBb, C4b, C3b, C5b 2.Control proteins Classical pathway:C1INH, C4bp, I, MCP, DAF Alternative pathway: H, I, CR1, DAF, P Formation of MAC: C8bp, CD5

17、9 Regulation of complement activation C1IHN缺陷引起血管神经性水肿缺陷引起血管神经性水肿 C4bp C4bp（C4 Binding Protein)C4 Binding Protein) Regulation of complement activation Regulation of complement activation Regulation of complement activation 膜结合型的补体调节蛋白膜结合型的补体调节蛋白 Regulation of complement activation Biologic function

18、of complement system plement mediates anti-infection immunity (1) Lysis of cell or microorganisms (2) opsonization (3) inflammation (1)complement mediated the lysis of cells (2) Opsonization opsonin: C3b, C4b, iC3b cell: phagocyte receptor: CR1, CR3, CR4 function: enhance phagocytosis (3) inflammatory response symptoms: redness, swelling, heat and pain inflammation mediators: C5a, C3a, C4a ( anaphylatoxins) C5a (chemotaxis) Biologic function of complement system 2. Complement ma