浙江大学医学免疫学经典05-Complement

Complement system,Weilin Chen, Ph.D Institute of immunology, ZJU,Lecture 4,IntroductionActivation of the Complement System Regulation of complement activationBiologic functions of complement system,Jules Bodet (1870-1961),1894，Discoverer of ComplementEhrlich （Complement）,Introduction,Complement (C) A group of serum proteins involved in the control of inflammation, the activation of phagocytes and the lytic attack on 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. 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, 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 (enzyme) 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 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 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 Ag + AbICbind C1qC1rC1sC1 2. Activation The components involved：C4, C2 and C3 (1) C4 and C2 activation, generation of C3 convertase (2) generation of C5 convertase3. Attack (terminal pathway) the components involved：C5,C6,C7,C8,C9 the membrane attack complex(MAC):C5b6789 the MAC causes lysis of cells,classical pathway,C1 molecule,C4,Classical Pathway Generation of C3-convertase,Classical Pathway Generation of C3-convertase,C4b,Mg+,C4a,C2,Classical Pathway Generation of C5-convertase,C4b,Mg+,C4a,C2b,C3,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 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,Alternative pathway,Activators：bacterial lipopolysaccharides (endotoxin), certain complex polysaccharidesnormal: 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 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 D Ba C3b+BC3bBC3bBb (C3 convertase) be dissociated - - I I/Habnormal: 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 pathway: MAC(membrane attack complex),Activation of the Complement System,Terminal pathway,a,a,Regulation of complement activation,1.Self-regulation C4b2a, C3bBb, C4b, C3b, C5b2.Control proteins Classical pathway:C1INH, C4bp, I, MCP, DAF Alternative pathway: H, I, CR1, DAF, P Formation of MAC: C8bp, CD59,Regulation of complement activation,C1IHN缺陷引起血管神经性水肿,C4bp（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,Regulation of complement activation,Biologic function of complement system,1.complement 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 maintains homeostasisclearance of IC: C3belimination of apoptosis cells C1q,