Transcript PowerPoint 演示文稿 - Fudan University

The Complement System
Concepts
Complement Activation
Regulation of the Complement System
Biological Function of Complement
Concepts
1. Simple history of complement research
1890
Behring
1894 Pfeiffer
antitoxin
temperature sensitive component in serum
necessary for bacteriolysis
1894
Bordet
1894 Ehrlich
alexin (1920 Nobel prize)
complement Ab to cause bacterolysis
1907
Ferrata
C1, C2
1912
Ritz
C3
1926 Gorder
C4
1969
Classical pathway
Muller-Eberhard
1895 Bordet: the experiment of the lysis of
Vibrio cholerae
antigen
(bacteria)
antiserum to the
bacterium
fresh
Vibrio
cholerae
old
normal
human/G
uinea pig
serum
fresh
+
Vibrio
cholerae
+
Vibrio
cholerae
+
+
results
agglutina
tion
lysis
+
+
+
-
+
+
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
functions, pathological functions
(5) Restriction of reaction: easy to be inactivated,
antibody, suppression component
Complement Activation
1. classical pathway
2. alternative pathway
3. lectin pathway
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 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.
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.
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
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
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)
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 channel
through the membrane of the target cell, enabling ions
and small molecules to diffuse freely across the
membrane.
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 System
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
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
C1, C2 , C4
Functions influenced
Diseases
SLE, pyogenic infection
C3
deficiency in cleanup of IC
deficiency in the activation of
classical pathway
inability of cleanup of IC
C1INH
complement activation
loss of control in the production
glomerular nephritis
hereditary angiodysplasia
factor H
of inflammatory mediators
loss of control in the activation
SLE, pyogenic infection
of alternative pathway
glomerular nephritis
SLE, pyogenic infection
low concentration of C3 in the serum
DAF, CD59
cytotoxic function of complement
to host cell
CR3
deficiency in adhesion of PBMC
paroxysmal nocturnal
hemoglobinuria
infection (aeruginosus Bacillus,
pseudomonad etc.)
*** 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