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