医学免疫学英文版课件：Chapter4 Complement systemVIP

Chapter

4

Complement

systemComplement(C):

agroup

ofglobulins

that

exist

inthe

serum

of

normal

humanor

animal

,relate

to

immune

response

andbear

of

enzyme

activity

after

beingactivated.Jules

Bodet

(1870-1961),Discoverer

of

complementPart

I

IntroductionComponent

of

Complement

and

definition1.Connatural

components

of

the

complements:components

which

take

part

in

the

activation

ofcomplementsclassical

pathway:

C1-C9,

C1----C1q,C1r,C1s-------components

.C5,C6,C7,C8,C9---------

terminal

pathwayalternative

pathway:

B,

D,

factorMBL

pathway:mannan-binding

lectin(甘露糖结合凝集素,MBL),serine

proteinase.regulatory

factors

existed

on

cells

or

in

humproperdin(备解素),C1

inhibitor

（

C1抑制物，ClINH）,I

factor,C4

binding

protein

(C4结合蛋白,C4BP),S-protein、SP40/40、membrane

cofactor

protein（膜辅助因子蛋白，MCP）、decay

accelerating

factor（衰变加速因子，DAF）、homologousrestriction

factor（同源限制因子，HRF）,membrane

inhibtor

of

reactive

lysis（膜反应性溶解抑制物，MIRL)The

complement

receptor

:

CR1,

CR2,

CR3,

CR4,CR5II.

Denomination

of

complentsclassical

pathway

components:

according

to

tfinding

time

:C1—C9Other

connatural

components

:

D

factor

,Bfactor,

etc.Regulatory

proteins:

according

to

it’s

funFragments:

“a”

small

fragments

and

“b”for

big

fragmentsactivated

components:C16.inactivated

components:

iC1III.

The

physical

and

chemical

featuresof

complementsThe

concentration

of

C

in

serum

is

stable

,

C3

highest

in

all

of

complement

components:1.20-

1.60g/LThe

liver

is

an

important

organ

producingcomplenment.Sensitive

to

heat

:

inactivated

by

heating

infor

30

minPart

II

The

activation

of

complementsystem1.Three

pathway

:classical

pathway

:from

C1

By

Ag-Abalternative

pathway:

from

C3

By

the

surfacemicrobeMBL(lectin

)pathway:

from

C4

and

C2

byMBL2.Terminal

pathway

:

same

in

the

3

pathwayI.

classical

pathwayActivator:

The

C1

molecule

binds

to

theantibody

attached

to

the

surface

of

antigen

ttrigger

the

classical

pathwayComponents:

C1---C9Process:

C1--C4,C2—C3,4,5,6,7,8,9phase

of

recognition:

recognizing

unit(C1qrs)Phase

of

activation:

activatingunit(

C4,C2,C3)Phase

of

attack:

membrane-attack

complex(MAC)1.

Phase

of

recognition:

C

1C1q

binds

to

complement-binding

site

of

AbThe

C1q

molecule

has

six

globular

heads

joineda

common

stem

by

long

filamentous

domains

.

Eachglobular

head

can

bind

to

one

Fc

domain

and

bindiof

two

or

more

globulin

heads

activates

the

C1qmoleculeFabfragmentFcfragmentExploredC1qcombingsiteConformation

of

IgC1qcombingsite

wascoveredBefore

combining

withAgAfter

combining

withAgCH1CH2Each

of

C1should

bindto

more

than

2

com-plement

binding

sitesIg

before

activationOnly

the

immuno-complex

formed

byIgG1-3

and

IgM

canactive

C1The

free

Ig

can’tactivate

C11、phase

of

activationPhase

of

recognitionFormation

of

C3

convertaseC3

convertase2.

Phase

of

activation:

generate

C3convertase

and

C5

convertaseC1

activate

C4

and

C2Phase

of

activation

-1:formation

of

C3

convertaseC3

convertase

and

C3Opsonization

of

ComplementPhase

of

activation

–2:formation

of

C5

convertaseC5

convertasePhase

of

activation

–2:formation

of

C5

convertase3.phase

of

attack(terminal

pathway)formation

of

MACmembrane-attack

complex(MAC)generate

the

MAC----C56789cytolysisClassical

pathwayIgM/IgG

–Ag

complexC4C4b

+C2C4aC2aC3C3bC3aMg++C1q

:

r

:

sCa++

Ca++C4b2b

（C3convertase）C4b2b3b（C5convertase）II.

alternative

pathway

:The

initiating

substances:some

components

of

bacteria

wallAggregated

IgA

or

IgG4-----------providing

a

surface

for

Complement

bComponents

and

process:C3,4,5,6,7,8,9Function:

spontaneous

reaction

towards

microbeThere

is

a

spontaneous

conversion

of

C3

toC3b.

Ordinarily

the

C3b

is

quicklyinactivated:

the

C3b

binds

to

inhibitoryproteins,

and

the

process

is

aborted.I(Inhibitory)factorBFactor

DSpontaneous

conversion

of

C3C3C3aC3bC3bBbP——C3转化酶（C3

convertase）C3bnBb——C5转化酶（C5

convertase）Spontaneousconversion

orfrom

classicalpathwayC3bB

factorD

factorC3bBbC3bBbC3

convertaseC3C3bC3bnBbC5

convertaseenlargeC3bC3bBC3positive

feedback

loop

of

C3DfactorC3bBbBfactorIn

alternative

pathway,

Complement

canrecognize

self

from

nonselfalternative

pathway

is

the

important

enlarmechanism

of

ComplementIII.

MBL

pathwayManose-binding

lectin(MBL)Manose-binding

protein(MBP):

acute

phase

proteinproduced

by

liverCombine

with

manose

on

thesurface

of

microbeInitiating

substances:

MBL

combine

withmanose

on

the

surface

of

microbe

,thenoperate

with

MASP(MBL-associated

serineprotease)Process:MBL-manose-MASP----C4,2-C3,5,6,7,8,9mannanMBPmannanMBPMASPC4C4a

+

C4bC2C2a

+

C2bC4b2b（C3convertase）+

MASPIV.

Terminal

pathway—generate

MACC5b+C6+C7+C8+C9

=

MACsMACMACs造成的细胞膜损伤C6

C7C8C5bC9多聚体补

体杀

伤

寄

生

虫Effect

of

MACV.

comparation

of

there

pathwaysMBL-manoseMASPPart

III. regulation

of

Complement

systemThe

explosive

potential

of

the

complementsystem

requires

that

it

be

kept

under

tightcontrol.

At

least

12

proteins

are

known

thatdo

this.Mechanism

of

C

regulationregulation

of

self-inactive

:decayactivation

of

regulatory

factorsFactor

H

removes

Bb

from

the

alternativepathway

C3

convertase

breaking

thepositive

feedback

loop.Factor

I

inactivates

C3b

and

C4b.C1

inhibitor

(C1INH)

binds

to

sites

onactivated

C1r

and

C1s

shutting

down

theirproteolytic

activity.Regulation

of

classic