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The Complement System Concepts Complement Activation

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1 The Complement System Concepts Complement Activation
Regulation of the Complement System Biological Function of Complement

2 1. Simple history of complement research
Concepts 1. Simple history of complement research Behring antitoxin Pfeiffer temperature sensitive component in serum necessary for bacteriolysis Bordet alexin (1920 Nobel prize) Ehrlich complement Ab to cause bacterolysis Ferrata C1, C2 Ritz C3 Gorder C4 Muller-Eberhard Classical pathway

3 antiserum to the bacterium normal human/Guinea pig serum
1895 Bordet: the experiment of the lysis of Vibrio cholerae antigen (bacteria) antiserum to the bacterium normal human/Guinea pig serum results fresh old agglutination lysis Vibrio cholerae + -

4 Presumption: There is a component in the fresh serum that helps the antibody to lyse the bacteria. The chemical property of this component is not stable. This component is not antigen specific.

5 The complement is a group of temperature sensitive protein existing in the serum and tissue fluid of human and vertebrate. After activated, they have enzymatic activity. They are the major molecules of the innate immune system.

6 2. Components of the Complement System
(1) Complement Components: C1-9, MBL , SP , Bf , Df (2) Regulatory Proteins: Properdin , C1INH , C4bBp , Hf, If , CR1 , Sp (3) Complement Receptor: CR1-CR5 , C2aR , C3aR , C4aR

7 Complement Components involved in the classical pathway
(the components were named in order of their discovery)

8 3. Denomination of the components of the complement system
With enzymatic activity after activation: C1, C4b2b Peptide fragments formed by activation of a component: C3a, C3b (the smaller fragment is designated “a” and the larger fragment designated “b”) Inactivated components: iC2a Factors: B, P (capitalization)

9 4. Basic Characteristics of Complement
The complement components interact in a highly regulated cascade. Complement serves by amplifying the response: C1q, C3 convertase Unstability: 56°C, 30min Dualism of the functions: physiological functions, pathological functions Restriction of reaction: easy to be inactivated, antibody, suppression component

10 Complement Activation
1. classical pathway 2. alternative pathway 3. lectin pathway

11 Complement Activation
1. classical pathway a. activator IC (immune complex) polymerizer (heparin, polynucleotide) dextran sulfate protein (CRP) liposome mitochondria of cardiac muscle

12 b. activation condition
1. classical pathway b. activation condition The formation of an antigen-antibody complex induces conformational changes in the Fc portion of the Ab molecule that expose a binding site for the complement. C1 binds to exposed C1q-binding sites in the CH2 domain of IgG1-3 or the CH3 domain of IgM. C1 binds to at least two Fc portions of Ab.



15 C1q (1) the biggest molecular weight, composed of 18 polypeptide chains that associate to form six collagen-like triple helical arm (2) the only component of complement that circulate in the serum in functionally active forms (3) For activation, it need to bind to at least two IgG or one IgM and need the presence of Ca2+. (4) Free or soluble Ab can not bind to the complement; the formation of an antigen-antibody complex induces conformational changes in the Fc portion of the Ab molecule.


17 1. classical pathway c. activation stage recognition stage: IC-C1 activation stage: C1s→C4, C2→C3, C5 attack stage: C5b→C5678(9)n (MAC)





22 Complement Activation
2. alternative pathway a. activator LPS bacteria zymosan dextran IgA IgG4 IgE

23 2. alternative pathway b. characteristics: non-specific, rapid
distinguish self and non-self C3b positive feedback need a surface to stick or activate C3b

24 2. alternative pathway c. activation stage formation of C3bBb
activation stage C3→C5 attack stage: C5b→C5678(9)n (MAC)


26 alternative pathway

27 Complement Activation
3. lectin pathway, MBL a. activator: MASP (MBL:SP) b. activation stage formation of MASP: cleave C4, C2 activation stage: C3→C5 attack stage: C5b→C5678(9)n (MAC)

28 lectin pathway

29 Overview of the complement activation pathways.

30 membrane attack complex, MAC
Composition: C5b678 (9)n , C9 Size: nm inner diameter Effects: This complex forms a large channel through the membrane of the target cell, enabling ions and small molecules to diffuse freely across the membrane.




34 Regulation of the Complement System
1. Short half-life 2. Regulation protein up-regulation: Properdin, C3Nef down-regulation: C1INH, C4bBp, Hf, If, DAF, CR1, MCP

35 Regulation of the Complement System

36 Biological Function of Complement
1. bacteriolysis, cytosis 2. function of complement fragments a. opsonization: C3b, iC3b, C4b b. mediator of inflammation: C3a, C4a, C5a c. kinin: C2a, C5a d. chemotaxis: C3a, C5a, C567 3. C-dependent virolysis 4. clean up IC: interfere with the formation of IC, IC-C3b-CR1-RBC 5. immunological regulation: C3, CR1, CR2, C3b



39 Complement and Clinic 1. Complement deficiencies
2. Serum complement level and disease 3. Pathological damage by complement 4. Clinical application of complement

40 Diseases about Complement deficiencies
Proteins in defect Functions influenced Diseases C1, C2 , C deficiency in cleanup of IC SLE, pyogenic infection deficiency in the activation of classical pathway C inability of cleanup of IC SLE, pyogenic infection complement activation glomerular nephritis C1INH loss of control in the production hereditary angiodysplasia of inflammatory mediators factor H loss of control in the activation SLE, pyogenic infection of alternative pathway glomerular nephritis low concentration of C3 in the serum DAF, CD cytotoxic function of complement paroxysmal nocturnal to host cell hemoglobinuria CR deficiency in adhesion of PBMC infection (aeruginosus Bacillus, pseudomonad etc.)

41 *** Definition, basic characteristics and components of complement
*** Characteristics of complement activation and the sameness and differentia of three complement activation pathways ** Biological Function of Complement ** Regulation of the Complement System and its significance * Key biological significance of complement receptor and membrane-binding protein * Relation between complement system and diseases

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