Complement activation and regulation Seppo Meri, Haartman Institute University of Helsinki, Finland Dubrovnik 3.10.2010 C4 C2 C3 C3b C5 C4b2a C1q C1-INH MAC (C5b-9) C5b Target cell membrane C2b C4a C1r C1s Complement activation Hadders et al, Science, 2007 Main functions of the complement system 1. Lysis of microbes (MAC) 2. Opsonization (C3b, C4b, C1q) 3. Generation of an inflammatory reaction (C5a, C3a, C5b-9) -mediator release from mast cells -contraction of smooth muscle cells -increased permeability of blood vessels 4. Chemotaxis and activation of phagocytes (C5a) 5. Processing of immune complexes (C3b, C4b, CR1) 6. Strengthening the B- and T-cell immune responses -natural (endogenous) adjuvant effects via C3d-CD21 and iC3b-CR3 Dual role of complement in the development of immunological inflammation 1. Too much: Causes inflammation and tissue damage (C5a and the membrane attack complex; MAC) 2. Too little: Failure in the clearance of damaged tissue or microbes -> debris or microbial components persist -> (auto)immune responses develop Walport, NEJM, 2001 Clearance of apoptotic or injured cells C1q, C1r, C1s, C2 or C4A-deficiencies -> problem in clearance of debris -> SLE, SLE-like sdr C4,C2 C3 C3bBb C3b,B ALTERNATIVE PATHWAY C3b C5 C6 C7 C8 lysis C4b2a Ag-Ab, CRP CR3 C9 C3bi + D, P C1q MBL C1rs microbes microbes LECTIN PATHWAY CLASSICAL PATHWAY Masp1,2,3 H CD59 I C1INH H DAF C4bp DAF,CR1 The complement system
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Complement activation - BNITM activation and regulation Seppo Meri, Haartman Institute University of Helsinki, Finland Dubrovnik 3.10.2010 C4 C2 C3 C3b C5 C4b2a C1q C1-INH
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Complement activation and regulation
Seppo Meri, Haartman Institute
University of Helsinki, FinlandDubrovnik
3.10.2010
C4
C2 C3C3b
C5
C4b2aC1q
C1-INH
MAC (C5b-9)C5b
Target cell membrane
C2b
C4a
C1r
C1s
Complement activation
Hadders et al, Science, 2007
Main functions of the complement
system
1. Lysis of microbes (MAC)
2. Opsonization (C3b, C4b, C1q)
3. Generation of an inflammatory reaction (C5a, C3a, C5b-9)
-mediator release from mast cells
-contraction of smooth muscle cells
-increased permeability of blood vessels
4. Chemotaxis and activation of phagocytes (C5a)
5. Processing of immune complexes (C3b, C4b, CR1)
6. Strengthening the B- and T-cell immune responses
-natural (endogenous) adjuvant effects via
C3d-CD21 and iC3b-CR3
Dual role of complement in the development
of immunological inflammation
1. Too much:
Causes inflammation and tissue damage
(C5a and the membrane attack complex; MAC)
2. Too little:
Failure in the clearance of damaged tissue or microbes
-> debris or microbial components persist
-> (auto)immune responses develop
Walport, NEJM, 2001Clearance of apoptotic or injured cells
C1q, C1r, C1s, C2 or C4A-deficiencies
-> problem in clearance of debris -> SLE, SLE-like sdr
C4,C2
C3
C3bBb C3b,B
ALTERNATIVE PATHWAY
C3b
C5
C6
C7
C8
lysis
C4b2a
Ag-Ab,
CRP
CR3
C9
C3bi+
D, P
C1q
MBL
C1rs microbes
microbes
LECTIN PATHWAY
CLASSICAL PATHWAY
Masp1,2,3 H
CD59
I
C1INH
H
DAF
C4bp
DAF,CR1
The complement system
Loss of self-control
-> tissue damage
-> inflammationC4,C2
C3
C3bBb C3b,B
ALTERNATIVE PATHWAY
C3b
C5
C6
C7
C8
lysis
C4b2a
Ag-Ab,
CRP
CR3
C9
C3bi+
D, P
C1q
MBL
C1rs microbes
microbes
LECTIN PATHWAY
CLASSICAL PATHWAY
Masp1,2,3 H
CD59
I
C1INH
H
DAF
C4bp
DAF,CR1
Neisseria-meningitis
MPGN
LED
bacterial infections
PNH
HAE
bacterial
infections
LAD
Neisseria-meningitis
HUS
bacterial infections
Innate Autoreactivity vs. Autoimmunity
- attack against ”self” by the innate immune system
- not caused by antibodies or autoreactive T cells
- caused by disturbances in control mechanisms - > overactivation or lack of inhibition