The Complement System Concepts Complement Activation Regulation of the Complement System Biological...
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Transcript of The Complement System Concepts Complement Activation Regulation of the Complement System Biological...
The Complement SystemThe Complement System
Concepts
Complement Activation
Regulation of the Complement System
Biological Function of Complement
ConceptsConcepts
1. Simple history of complement research
1890 Behring antitoxin
1894 Pfeiffer temperature sensitive component in serum
necessary for bacteriolysis
1894 Bordet alexin (1920 Nobel prize)
1894 Ehrlich complement Ab to cause bacterolysis
1907 Ferrata C1, C2
1912 Ritz C3
1926 Gorder C4
1969 Muller-Eberhard Classical pathway
antigen (bacteria
)
antiserum to the bacterium
normal human/Guinea pig s
erum
results
fresh old fresh agglutination
lysis
Vibrio cholerae
+ + +
Vibrio cholerae
+ + -
Vibrio cholerae
+ + + +
1895 Bordet: the experiment of the lysis ofVibrio cholerae
Presumption:
1. There is a component in the fresh serum that helps the antibody to lyse the bacteria.
2. The chemical property of this component is not stable.
3. This component is not antigen specific.
• 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.
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
Complement Components involved in the classical pathway(the components were named in order of their discovery)
3. Denomination of the components of the complement system
(1) With enzymatic activity after activation: C1, C4b2b
(2) Peptide fragments formed by activation of a component: C3a, C3b (the smaller fragment is designated “a” and the larger fragment designated “b”)
(3) Inactivated components: iC2a
(4) Factors: B, P (capitalization)
4. Basic Characteristics of Complement
(1)The complement components interact in a highly regulated cascade.
(2)Complement serves by amplifying the response: C1q, C3 convertase
(3)Unstability: 56°C, 30min(4)Dualism of the functions: physiological function
s, pathological functions(5)Restriction of reaction: easy to be inactivated, a
ntibody, suppression component
Complement Activation Complement Activation
1. classical pathway
2. alternative pathway
3. lectin pathway
Complement Activation Complement Activation
1. classical pathway
a. activator
IC (immune complex)
polymerizer (heparin, polynucleotide)
dextran sulfate
protein (CRP)
liposome
mitochondria of cardiac muscle
1. classical pathway
b. activation condition The formation of an antigen-antibody complex inducesconformational changes in the Fc portion of the Ab moleculethat 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.
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 inducesconformational changes in the Fc portion of the Ab molecule.
1. classical pathway
c. activation stage
recognition stage: IC-C1
activation stage: C1s→C4, C2→C3, C5
attack stage: C5b→C5678(9)n (MAC)
Complement Activation Complement Activation
2. alternative pathway
a. activator
LPS
bacteria
zymosan
dextran
IgA
IgG4
IgE
2. alternative pathway
b. characteristics:
non-specific, rapid
distinguish self and non-self
C3b positive feedback
need a surface to stick or activate C3b
2. alternative pathway
c. activation stage
formation of C3bBb
activation stage C3→C5
attack stage: C5b→C5678(9)n (MAC)
alternative pathway
Complement Activation 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 (MA
C)
lectin pathway
Overview of the complement activation pathways.
membrane attack complex, MAC
Composition: C5b678 (9)n , 12-15 C9
Size: 10-11 nm inner diameter
Effects: This complex forms a large channelthrough the membrane of the target cell, enabling ions and small molecules to diffuse freely across the membrane.
Regulation of the Complement System 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
Regulation of the Complement SystemRegulation of the Complement System
Biological Function of ComplementBiological 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
Complement and Clinic Complement and Clinic
1. Complement deficiencies
2. Serum complement level and disease
3. Pathological damage by complement
4. Clinical application of complement
Diseases about Complement deficiencies
Proteins in defect Functions influenced Diseases
C1, C2 , C4 deficiency in cleanup of IC SLE, pyogenic infection deficiency in the activation of classical pathway C3 inability of cleanup of IC SLE, pyogenic infection
complement activation glomerular nephritisC1INH loss of control in the production hereditary angiodysplasia
of inflammatory mediators
DAF, CD59 cytotoxic function of complement paroxysmal nocturnal
to host cell hemoglobinuria
CR3 deficiency in adhesion of PBMC infection (aeruginosus Bacillus,
pseudomonad etc.)
factor H loss of control in the activation SLE, pyogenic infection
of alternative pathway glomerular nephritis
low concentration of C3 in the serum
*** 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